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The effect of allyl sulfides on the induction of phase II detoxification enzymes and liver injury by carbon tetrachloride
Abstract
Allyl sulfides, e.g., diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), are principal constituents of garlic oil. In the present study, we investigated the in vivo effect of these sulfides on the phase I and phase II drug-metabolizing enzymes, and elucidated their structure-function relationship. A highly purified form of each sulfide (more than 99% purity) was administered i.p. as a bolus to rats at a concentration of 10 or 100 micromol/kg body weight for 14 consecutive days. As to the phase I enzymes, DAS (100 micromol/kg) slightly but significantly increased cytochrome P-450 (CYP) 2E1 activity (1.6-fold vs. control), whereas DADS and DATS did not affect it or the hepatic total CYP level or CYP1A1/2 activity. With respect to the phase II enzymes, DATS (10 micromol/kg) and DADS at a 10-fold higher dose (100 micromol/kg) significantly increased the activities of glutathione S-transferase, quinone reductase, and antioxidative enzyme glutathione peroxidase; whereas DAS did not. In the carbon tetrachloride (CCl4)-induced acute liver injury model of rats, either DATS (10 micromol/kg) or DADS (100 micromol/kg) significantly reduced the injury caused by the induction of phase II enzymes with CCl4. In conclusion, the sulfides affected both phase I and phase II enzymes, the former being stimulated by the monosulfide only and the latter, strongly by the trisulfide and weakly by the disulfide. Therefore, the polysulfide DATS may be one of the important factors in garlic oil that protects our body against the injury caused by radical molecules encountered in daily life.
... On the contrary, the present finding disagree with those obtained by others who reported, that the administration of diallyl sulfide, one of greatest sulfur compound of garlic, prevented reduction of GPx activity induced by gentamycin in kidneys of rats (Jose et al., 2003). Likewise, administration of diallyl trisulfide increased the activity of GPx in the liver of rats exposed to acute liver injuries by carbon tetrachloride (Fukao et al., 2004). ...
... These results concur with those obtained previously who reported that, prophylactic treatment of animals with garlic oil before the administration of iron nitrotriacetate caused a recovery of glutathione depletion with increased activities of antioxidant enzymes (Iqbal and Athar, 1998). Garlic induces synthesis of phase II enzymes and this is dependent on the number of sulfur present as proved by diallyl trisulfide (Fukao et al., (2004). The present findings also agree with those obtained by (Sener et al., 2005). ...
... Table 4 shows that the administration of acrylamide resulted in significant decrease in glutathione levels in all tissues. This is concurs with other reports that showed significant decrease in the level of glutathione (GSH) in brain and liver of rats upon acrylamide administration (Srivastava et al., 1983;Fukao et al., 2004). Acrylamide are electrophilic compounds, which property facilitates them to react with vital cellular nucleophiles possessing SH, NH 2 and OH groups. ...
... However, treatment with DG favored an increase in the activity of this enzyme. Different compounds of garlic are linked to the increase in the activity of this enzyme including DADS and DATS which significantly increased the GST activities in liver damage [41]. Another study demonstrated that organ sulfur compounds increased the activity and mRNA of GST, and this effect was associated to DAS, DADS, and DATS [42]. ...
... − /NO 2 − Ratio, Lipoperoxidation, and Carbonylation. The endothelial dysfunction in MFS patients may inactivate eNOS and increase the iNOS expression/activity leading to an enhanced production of NO which contributes to inflammation [41]. In previous studies in MFS patients, oleic acid was increased, and it may elevate NF-KB which participates in the overproduction of iNOS [47]. ...
Marfan syndrome (MFS) is a genetic disorder of connective tissue that affects the fibrillin-1 protein (FBN-1). It is associated with the formation of aneurysms, damage to the endothelium and oxidative stress (OS). Allium sativum (garlic) has antioxidant properties; therefore, the goal of this study was to show the antioxidant effect of deodorized garlic (DG) on antioxidant enzymes and OS markers in the plasma of patients with MFS. The activity of antioxidant enzymes such as extracellular superoxide dismutase (EcSOD), peroxidases, glutathione peroxidase (GPx), gluthatione-S-tranferase (GST), and thioredoxin reductase (TrxR) was quantified, and nonenzymatic antioxidant system markers including lipid peroxidation (LPO), carbonylation, nitrates/nitrites, GSH, and vitamin C in plasma were determined in patients with MFS before and after treatment with DG. The results show that DG increased the activity of the EcSOD, peroxidases, GPx, GST, TrxR (p≤0.05) and decrease LPO, carbonylation, and nitrates/nitrites (p≤0.01). However, glutathione was increased (p=0.01) in plasma from patients with MFS. This suggests that treatment with garlic could lower the OS threshold by increasing the activity of antioxidant enzymes and could help in the prevention and mitigation of adverse OS in patients with MFS.
... Güçlü bir antioksidan kapasiteye sahiptir (10). Ürotoksisite, genotoksisite, nefrotoksisite, hepatoksisite üzerine güçlü protektif etkileri bildirilmiştir (11)(12)(13)(14). Medikal alanda yaygın kullanılmasına rağmen ağır metal toksisitesi üzerine olan etkileri ile ilgili sınırlı bilgi bulunmaktadır (15). ...
... ).Kanser önleyici bir komponent olarak düşünülen sarımsak yağı 20'den fazla organosülfür bileşiği içerir. Bu bileşikler arasında, ikincil metabolitlerin önemli bir bileşenini oluşturan dialil disülfit; kanser, genotoksisite, nefrotoksisite ve ürotoksitenin önlenmesinde güçlü bir bileşiktir(11)(12)(13)(14).Dialil disülfitin sıçanlarda siklofosfamid ile indüklenen testiküler toksisiteye karşı koruyucu etkiye sahip olduğunu bildirilmiştir(10). Bu çalışma dialil disülfitin testiküler toksisite üzerine etkisinin araştırıldığı ve literatüre geçen tek çalışmadır. ...
Bu çalışmada, önemli bir çevre kirletici ve dokular üzerine zararlı etkileri olan kadmiyumun erkek fertilitesi üzerine oluşturduğu hasara karşı resveratrolün ve dialil disülfitin koruyucu etkileri araştırıldı. Yapılan deneyde Wistar albino cinsi rat kullanıldı ve 5 grup (A: kontrol, B1: CdCl2, B2: RES + CdCl2, B3: DDS + CdCl2, B4: RES + DDS + CdCl2) oluşturuldu. Histolojik değişiklikleri değerlendirmek için testis dokuları, Hematoksilen ve Eozin ile boyandı ve Modifiye Johnsen skorlaması yapıldı. Gruplarda gözlenen apoptoz, TUNEL yöntemi ve aktif kaspaz-3 immunohistokimyası ile değerlendirildi. Elde ettiğimiz bulgulara göre, B1 grubunda, kadmiyumun seminifer tübüllerde hasara yol açtığı, spermatogenezi durdurduğu ve germ hürcelerinde apoptozu indüklediği gözlendi. Modifiye Johnsen skorlama sonuçlarında kontrole göre B1 grubunda anlamlı derecede azalma, apoptotik indeks sonuçlarında ise anlamlı derecede artış görüldü. B1 grubuyla B2, B3 ve B4 grupları karşılaştırıldığında; Modifiye Johnsen skorlama sonuçlarında B1 ile B2 grubu arasında anlamlı bir farklılık görülmezken, B3 ve B4 gruplarında anlamlı artış görüldü. Ayrıca apoptotik indeks sonuçlarında B2 grubunda anlamlı bir farklılık görülmezken, B3 ve B4 gruplarında anlamlı azalma görüldü. Sonuç olarak, sıçan testisinde kadmiyum ile oluşturulan akut hasarın baskılanmasında resveratrol ve dialil disülfitin rolüne yönelik bilgiler ortaya konuldu. Belirlediğimiz dozda resveratrol bu akut hasarın baskılanmasında etkili olmazken dialil disülfit ve resveratrol ile birlikte kullanımı hasarı önlemede etkili bulundu. Literatür analizimize göre bu çalışma kadmiyumun indüklediği testis hasarına karşı dialil disülfitin koruyucu etkilerinin gösterildiği ilk çalışmadır.
... The results showed that allyl trisulfide, 2-hydroxy-gamma-butyrolactone, 1 3dihydroxyacetone dimer, propanoic acid, and 2-propone were detected in all extracts (Table 3 and Fig. 1). These substances are produced by the degradation of alline [10,12] and have been reported to have beneficial effects, such as antioxidant and anticancer activities [19][20][21][22][23][24][25][26]. The highest content (11.56%) of allyl trisulfide was found in the water extract and the lowest content (2.73%) was found in the 100% ethanol garlic extract. ...
... Both the yield and GC-MS analysis indicated that 75% ethanol concentration was the most suitable for extraction. Table 3. Common phytocomponents identified in extracts of garlic (Allium sativum) Name of compound Activities Reference Allyl trisulfide Anti-cancer effects, platelet aggregation, blood pressure reduction, antioxidant, [19][20][21][22] cholesterol lowering, papain inactivation, detoxification, glutathione transferase activity 1,3-Dihydroxyacetone dimer ...
p align="left"> Aim of the study: The purpose of this study was to investigate the possibility of garlic extract as a feed additive to prevent and treat Salmonella infection.
Methods: Garlic extracts were prepared from fresh crushed garlic and dissolved in different concentrations of ethanol. Garlic extract ( Allium sativum ) was analyzed by using gas chromatography-mass spectrometry (GC-MS). To examine biological activity, the antimicrobial activity test was carried out by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Salmonella typhimurium. Antioxidant activity of garlic extracts was examined by ABTS radical scavenging assay
Results and discussion : In the GC-MS analysis, allyl trisulfide, 2-hydroxy-gamma-butyrolactone, 1, 3-dihydroxyacetne dimer, propanoic acid, 2-propone were confirmed as predominant components of garlic extract. the MIC was 10 mg/mL in all extracts. However, antioxidant effect was highest in 20 mg/mL of 100% ethanol garlic extract (82.1%). The amount of IC₅₀ (50% inhibitory concentration) was measured at 1.6 mg/mL.
Conclusion: 75% ethanol garlic extract was the most efficient in considering the recovery rate, antimicrobial and antioxidant activities among the various extracts. Based on the above biological results, we could confirm this possibility as a feed additive for anti-salmonella infection.</p
... Garlic oil (GO) is produced by the steam distillation of raw garlic homogenate; normally, 0.2-0.6 ml of garlic oil is obtained from 100 g of garlic homogenate. The major constituents of GO are allyl sulfides, including diallyl trisulfide (DATS), diallyl disulfide (DADS), diallyl sulfide (DAS) and methyl allyl trisulfide (MATS) (20). These sulfide compounds are considered to be responsible for the potent physiological functions of garlic. ...
... In this study, we focused on the effects of GO, which contains a variety of oil soluble organosulfur compounds. The major components of the GO used in this study were as follows (20): DATS (31.5%), DADS (21.5%), ...
Garlic (Allium sativum L.) has long been used as a medicinal food. Indeed, garlic and its constituents have been shown to possess potent regulatory activities in bodily functions, including blood coagulation, lipid metabolism, immunity and xenobiotic metabolism. In this study, we aimed to examine the anti-obesity effects of garlic oil and to elucidate the possible underlying mechanisms. For this purpose, garlic oil (GO; 80 mg/kg body weight, p.o.) or corn oil alone as a vehicle-control were administered to male Sprague-Dawley rats every other day for 10 weeks. The results revealed that GO administration significantly reduced body weight gain and white adipose tissue (WAT) mass, which had been increased by feeding on the AIN-76-based high-fat diet (60% kcal fat). Expired gas analysis was performed at 9 weeks following the GO administration to calculate fuel oxidation. GO administration enhanced O2 consumption during the dark period (at night) and increased energy expenditure through fat oxidation during the light period (daytime); however, carbohydrate oxidation remained unaltered. Western blot analysis revealed that GO administration increased UCP1 protein expression in brown adipose tissue (BAT). On the whole, the findings of this study indicated that GO suppressed body weight gain and WAT mass in the rat model of high-fat diet-induced obesity by increasing UCP1 expression and by enhancing fat oxidation and energy expenditure.
... We also examined the garlic odor components DAS, DADS, and DATS in these experiments. ACS [47,48], DADS, and DATS [49,50] have previously been reported to prevent hepatic injury when they are intraperitoneally injected, while DAS did not show such an effect. In this study, we found that oral administration of ACSO suppressed acute hepatic injury induced by CCl 4 in addition to that of DADS and DATS (Figure 3). ...
... In these experiments, DAS and DADS were detected as volatile components (Figure 8), and the amount of DADS was greater than that of DAS. These results suggest that orally administered ACSO is partially metabolized to afford DADS, a known inducer of antioxidative and detoxifying enzymes in the liver [49,50]. Taken together, the suppressive effect of oral administration of ACSO on hepatic injury induced by CCl 4 may stem from the activities of both ACSO itself and its metabolites, including DADS, that induce phase II and antioxidative enzymes in the liver by promoting Nrf2 nuclear translocation. ...
S-Allyl-l-cysteine sulfoxide (ACSO) is a precursor of garlic-odor compounds like diallyl disulfide (DADS) and diallyl trisulfide (DATS) known as bioactive components. ACSO has suitable properties as a food material because it is water-soluble, odorless, tasteless and rich in bulbs of fresh garlic. The present study was conducted to examine the preventive effect of ACSO on hepatic injury induced by CCl4 in rats. ACSO, its analogs and garlic-odor compounds were each orally administered via gavage for five consecutive days before inducing hepatic injury. Then, biomarkers for hepatic injury and antioxidative state were measured. Furthermore, we evaluated the absorption and metabolism of ACSO in the small intestine of rats and NF-E2-related factor 2 (Nrf2) nuclear translocation by ACSO using HepG2 cells. As a result, ACSO, DADS and DATS significantly suppressed the increases in biomarkers for hepatic injury such as the activities of aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH), and decreases in antioxidative potency such as glutathione (GSH) level and the activities of glutathione S-transferase (GST) and glutathione peroxidase (GPx). We also found ACSO was absorbed into the portal vein from the small intestine but partially metabolized to DADS probably in the small intestine. In in vitro study, ACSO induced Nrf2 nuclear translocation in HepG2 cells, which is recognized as an initial trigger to induce antioxidative and detoxifying enzymes. Taken together, orally administered ACSO probably reached the liver and induced antioxidative and detoxifying enzymes by Nrf2 nuclear translocation, resulting in prevention of hepatic injury. DADS produced by the metabolism of ACSO in the small intestine might also have contributed to the prevention of hepatic injury. These results suggest potential use of ACSO in functional foods that prevent hepatic injury and other diseases caused by reactive oxygen species (ROS).
... The effects noticed compared favourably with vitamin C and is consistent with the results of the biochemical assays in this study. Our report agrees with the submissions of Fukao et al. (2004) andAdeneye et al. (2015), where recovery towards normalization of serum enzymes and liver histological architecture caused by CCl 4 in rats was attributed to treatment with plant extracts. Overall, the elicited antioxidant and hepatoprotective properties of EOAE in this study could be attributed to its constituents as revealed from the GCMS data. ...
... Apart from the preventive and chain-breaking antioxidant properties of these compounds, significant hepatoprotective effects of triterpenoic acid, 1,8-cineole, α-terpene and quercetin have been reported ( Santos, 2001;Jian-Guo et al., 2016;Karacaa et al., 2016;Selvaraj et al., 2016). Studies have also lent credence to the capabilities of ursolic acid, thymol, eucalyptol and procyanidins to enhance regeneration of hepatocytes following exposure to chemical hepatotoxins ( Janbaz et al., 2003;Ciftci et al., 2011;Gabriel et al., 2016;Min et al., 2016). In view of the foregoing, a tentative mechanism of antioxidative and hepatoprotective potentials of EOAE may be idealized. ...
This study investigated the protective mechanism of aqueous leaves extract of Eucalyptus obliqua (EOAE) in CCl4-mediated liver damage in Wistar rats. The animals were orally pretreated with either the extract (200 and 400 mg/kg) or vitamin C (200 mg/kg) for 10 days prior to the intraperitoneal administration of 3 mL/kg CCl4 (30% in olive oil). Subsequently, hepatic function, antioxidant and histological analyses were evaluated. The results showed that the CCl4-induced increases in the activities of ALT, ALP, AST and the concentrations of bilirubin, oxidized glutathione and malondialdehyde were significantly and dose-dependently reduced in the extract-treated rats. The extract also significantly improved the attenuated activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase as well as total protein, albumin and glutathione concentrations in the hepatotoxic animals. These improvements could be attributed to the phytoconstituents revealed by the GCMS analysis of the extract. The observed activities compared with that of vitamin C and are suggestive of hepatoprotective and antioxidant properties of EOAE and were also supported by the histological results. Overall, these data indicate that EOAE has a significant protective effect against acute CCl4-induced hepatotoxicity in rats, which may be due to its capability to fortify the antioxidant defense systems.
... Diallyl disulfide (DADS), a major component of secondary metabolites derived from garlic, has been well documented as a potent compound that can prevent cancer, genotoxicity, nephrotoxicity, urotoxicity, and hepatotoxicity (Nakagawa et al., 2001;Guyonnet et al., 2002;Pedraza-Chaverrí et al., 2003;Fukao et al., 2004;Kim et al., 2014). Previous studies have shown that DADS is effective in modulating phase I enzymes such as hepatic CYP and phase II enzymes such as NAD(P)H:quinone oxidoreductase-1 (NQO-1) and heme oxygenase-1 (HO-1) with antioxidant-activity (Guyonnet et al., 2002;Pedraza-Chaverrí et al., 2003;Fukao et al., 2004;Ehnert et al., 2012;Kim et al., 2014;Lee et al., 2015). ...
... Diallyl disulfide (DADS), a major component of secondary metabolites derived from garlic, has been well documented as a potent compound that can prevent cancer, genotoxicity, nephrotoxicity, urotoxicity, and hepatotoxicity (Nakagawa et al., 2001;Guyonnet et al., 2002;Pedraza-Chaverrí et al., 2003;Fukao et al., 2004;Kim et al., 2014). Previous studies have shown that DADS is effective in modulating phase I enzymes such as hepatic CYP and phase II enzymes such as NAD(P)H:quinone oxidoreductase-1 (NQO-1) and heme oxygenase-1 (HO-1) with antioxidant-activity (Guyonnet et al., 2002;Pedraza-Chaverrí et al., 2003;Fukao et al., 2004;Ehnert et al., 2012;Kim et al., 2014;Lee et al., 2015). Previous in vitro studies have also shown that DADS has anti-inflammatory effects by down-regulating nuclear transcription factor kappa-B (NF-kB) signaling pathway (Park et al., 2012). ...
Diallyl disulfide (DADS) is a degradation product of allicin which is contained in garlic. This study investigated the protective effects of DADS against acetaminophen (AAP)-induced nephrotoxicity and the molecular mechanisms of nephroprotective effects in rats. AAP caused severe nephrotoxicity as evidenced by significant increases in renal tubular cell apoptosis, mitochondria-mediated apoptosis, and up-regulation of nuclear transcription factor kappa-B (NF-κB), cyclooxygenase-2 (Cox-2), and tumor necrosis factor-α (TNF-α) in the kidney with histopathological alterations. After AAP administration, glutathione content and activities of catalase, superoxide dismutase, and glutathione reductase were significantly decreased whereas malondialdehyde content was significantly increased, indicating that AAP-induced kidney injury was mediated through oxidative stress. In contrast, DADS pretreatment significantly attenuated AAP-induced nephrotoxic effects, including oxidative damage, histopathological lesions, and apoptotic changes in the kidney. DADS also attenuated AAP-induced up-regulation of NF-κB, Cox-2, and TNF-α in the kidney, and microsomal CYP2E1 expression in liver and kidney. These results indicated that DADS could prevent AAP-induced nephrotoxicity. The protective effects of DADS might be due to its ability to decrease metabolic activation of AAP by inhibiting CYP2E1 and its potent antioxidant, antiapoptotic, and antiinflammatory effects via inhibition of NF-κB.
... the method of Yagi [26] TBARS were quantitated by their reactivity with thiobarbituric acid (TBA) in acidic conditions to generate a pink coloured chromophore, which was read at 530 nm. TBARS in the liver and brain were estimated by the method Fraga [27] In this method, malondialdehyde and other TBARS were measured by their reactivity with TBA in acidic conditions to generate a pink-coloured chromophore, which was read at 535 nm. Estimation of plasma, liver and brain tissues lipid hydroperoxides (HP) was done by the method of Jiang. ...
... [43] The free radical scavenging effect of DADS has been reported in previous studies. DADS could enhance the levels of SOD, CAT, GSH in hepatocarcinogenesis. [43] In fact, it has been shown that DADS have antioxidant properties both in vivo [27] and in vitro. [44] DADS changed the rat hepatic glutathione related antioxidant enzyme activities by increasing the GSH. ...
Hyperammonemia is a major contributing factor to neurological abnormalities observed in hepatic encephalopathy and in congenital defects of ammonia detoxication. Garlic (Allium sativum. L) has been used as a spice, food and folklore medicine for over 4000 years, and it is the most widely used researched medicinal plant. Our aim is to investigate the effect of diallyl disulphide on blood ammonia, plasma urea, serum liver markers, lipid peroxidation and antioxidants status in tissues (liver and brain) of ammonium chloride induced hyperammonemic rats. Male albino Wistar rats (180-200 g) were used for the study. Hyperammonemia was induced by interaperitonial injection of ammonium chloride (AC) (100 mg/kg body weight); rats were treated with diallyl disulphide (DADS) (60mg/kg body weight) via oral administration. Administration of DADS in hyperammonemic rats reduced the levels of ammonia and urea. The antioxidant property of DADS was studied by assessing the activities of thiobarbituric acid reactive substances (TBARS), hydroperoxides (HP), nitric oxide (NO) and liver markers such as alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) and the levels of superoxide dismutase (SOD), reduced glutathione (GSH), in AC treated rats. Oxidative stress was effectively modulated by DADS administration. DADS significantly improved the status of antioxidants and decreased ammonia, urea, lipid peroxidation and liver markers enzymes as compared to AC treated group, as it has improved the maintenance of cellular integrity of liver and other tissues. However, the exact underlying mechanism has still to be investigated and isolation, investigating the efficacy of active constituents on hyperammonemia is desirable.
... Previous studies have shown inhibition of chemically induced carcinogenesis in different organs by certain sulfur-containing compounds 13 . Among these compounds, diallyl disulfide (DADS), which is a major component of the sec ondary metabolites derived from garlic, has been well documented as a potent compound that prevents cancer, genotoxicity, nephrotoxicity, urotoxicity, and hepatotoxicity [15][16][17][18][19][20] . Previous studies have shown that DaDS is not only effective at modulating hepatic microsomal enzymes but also has powerful antioxidant properties 17-21 . ...
... it has been demonstrated that DaDS can protect against various pathological conditions caused by oxidative stress [16][17][18][19][20] . The results of the present study also showed that DaDS has a protective effect against the spermatotoxicity and oxidative damage induced in male rats by CP administration. ...
The present study investigated the protective effects and the mechanism of action of diallyl disulfide (DADS) against cyclophosphamide (CP)-induced spermatotoxicity and oxidative damage in rats. DADS (50 mg/kg/day) was administered orally to rats once daily for 10 days. On the first 2 days, CP (150 mg/kg/day) was injected intraperitoneally to rats 1 h after DADS treatment. CP caused decreases in body weight, food consumption, epididymal sperm motility, and the number of spermatogenic germ cells and increases in the testes and epididymides weights, spermatogenic cell apoptosis, and histopathologic alterations in the testis. The significant decreases in glutathione content and catalase, glutathione S-transferase, and glutathione reductase activities and the significant increase in malondialdehyde content indicated that CP-induced testicular toxicity was mediated through oxidative stress. In contrast, DADS administration significantly attenuated the spermatotoxicity of CP, including attenuating the decreases in sperm motility and the number of spermatogenic germ cells and the increases in reproductive organ weights, oxidative stress, apoptotic changes, and histopathologic alterations. DADS also significantly increased CYP2B1/2 and CYP3A1 expression and significantly decreased CYP2C11 expression. The results show that the protective effects of DADS against CP-induced spermatotoxicity may be mediated by its ability to decrease metabolic activation of CP by inhibiting CYP2C11 and inducing CYP3A1, and by its potent antioxidant and antiapoptotic effects.
... [12][13][14] Moreover, recent studies showed that DATS could alleviate various hepatotoxic effects caused by ethanol, naphthalene, carbon tetrachloride (Ccl 4 ), arsenic etc. through attenuating oxidative stress. [18][19][20][21] More interestingly, DATS was also reported to regulate the immune responses and enhance the function of macrophages. 20,22,23 These all imply that DATS could be a potential drug to prevent the damage caused by INH&RFP. ...
... DATS has been shown to be an effective drug against many drugs and hepatotoxins inducing liver injuries, such as ethanol, naphthalene, and carbon tetrachloride (CCl 4 ), [18][19][20][21]28 especially due to its powerful antioxidant functions. As a compound purified from garlic, DATS has less toxicity and stronger antioxidant capability than other garlic products. ...
ABSTRACT Background & Aim Diallyl trisulfide (DATS) has been verified to ameliorate hepatotoxicity induced by many drugs, but the protective actions in isoniazid (INH) and rifampicin (RFP) have not been reported. We attempted to elucidate the potential effects and mechanisms of DATS against INH/RFP-caused hepatotoxicity. Methods Male Kunming mice weighing 18-22g were divided into 6 groups. For the hepatic-protective study, co-administrations of DATS (10mg/kg, 20mg/kg, and 40mg/kg bw, respectively) were orally administered two hours before the INH/RFP (100mg/kg, 100mg/kg bw, respectively) treatments. After 11 days treatments, 10 mice in each group were performed for the carbon clearance test, while the other 10 mice were sacrificed for the collection of serum and livers for further measures, including the levels of serum alanine aminotransferase (ALT), aspartate transaminase (AST) and total bilirubin (T.Bili), the liver index, and liver histopathological examination. Malondialdehyde (MDA), glutathione (GSH), the carbon clearance test, the level of interleukin 1-β (IL-1-β) and the immunohistochemistry of F4/80 marked for activated kupffer cell (KC) were measured to investigate potential mechanisms. Results DATS co-administration significantly inhibited the increase of liver index and elevation of serum ALT, AST and T.Bili levels induced by INH/RFP, as well as improved hepatocellular structure. The further mechanistic studies demonstrated that DATS co-administration counteracted INH/RFP-induced oxidative stress in mice, which was illustrated by the restoration of GSH levels, and the reduction of MDA levels in liver. Furthermore, DATS co-administration reactivated the KCs inhibited by INH/RFP, which was illustrated by the increase of carbon phagocytosis, the restoration of the number of activated KCs and IL-1-β levels in liver. Conclusion DATS effectively protected liver against INH/RFP-induced hepatotoxicity, which might be due to its antioxidant effect and enhancement of KCs’ activities.
... After two weeks of DATS treatment (10 mmol/kg body weight/day intraperitoneally), a significant increase in quinone reductase, glutathione peroxidase, and glutathione Stransferase activity in rats was observed [36]. Similarly, DATS (89 mg/kg/day) administered orally to rats for six consecutive days significantly increased quinone reductase and glutathione S-transferase activity in a variety of tissues [37]. ...
Traditionally, garlic has a valuable role in preventing and reducing the incidence of many diseases and pathophysiological disorders. Consequently, some researchers have focused on the beneficial cardiovascular properties of diallyl trisulfide (DATS), the most potent polysulfide isolated from garlic. Therefore, in this review, we collected the available data on DATS, its biochemical synthesis, metabolism and pharmacokinetics, and gathered the current knowledge and the role of DATS in cardiovascular diseases. Overall, this review summarizes the cardioprotective effects of DATS and brings together all previous findings on its protective molecular mechanisms, which are mainly based on the potent anti-apoptotic, anti-inflammatory, and antioxidant potential of this polysulfide. Our review is an important cornerstone for further basic and clinical research on DATS as a new therapeutic agent for the treatment of numerous heart diseases.
... Chemical formula is C4H8S and has a Molecular mass of about 88.17 g.mol-1. AS is a leading compound of volatile garlic metabolites and found to exhibit antibacterial, antioxidant and anticancer properties (Fukao et al., 2004). Allicin derived products such as diallyl sulfide, diallyl disulfide, and diallyl trisulfide, constitute another source of redox modulatory molecules. ...
Cancer still continues to threaten the world as the second most prominent cause of deaths world over. Breast cancer is the common cancer diagnosed among women and its prevalence and severity is high in developing and underdeveloped countries. The present study was aimed to investigate the antioxidant, antimicrobial and anticancer activity of the natural compounds, Naringin and Allyl sulfide on breast cancer cell lines (MCF-7 cells). Naringin has showed high antioxidant activity than Allylsulfide, however, a combination of Naringin and Allyl sulfide has shown the highest antioxidant activity in terms of DPPH scavenging activity (75.15%) and NO scavenging activity (72.79 %). Antimicrobial studies revealed that, the combination of Naringin and Allyl sulfide showed considerable inhibitory activity in terms of zone of inhibition than individual compounds, when compared to standard drug (Azithromycin). In-Vitro cytotoxicity studies by MTT assay demonstrated the highest percent of cell death (55-60%) by combination of Naringin and Allyl sulfide after 24 hr than when they were treated individually. Together, our results demonstrate that Naringin and Allylsulfide (25+25µg/ml) possess potent antioxidant and anticancer activities and hence can be recommended for regular consumption as nutraceutical
... Garlic cloves are sliced and dried at a low temperature and then pulverized to make garlic powder Alliin and γ-Glutamyl-L-cysteine peptides and different percentage of allicin and its derivatives (Staba et al. 2001) Garlic juice Blending of peeled garlic cloves with distilled water Allicin, Vinyldithiins, garlicin and allitridin (Yu and Wu 1989) Garlic tincture Maceration of chopped garlic with vinegar/alcohol for 3 weeks Alliin, allicin and ajone (Santos and Carvalho 2014) In aqueous garlic extract, the tissue is protected against oxidative damage caused by nicotine (Augusti 1996). Carbontetra chloride causes liver damage, however, diallyl trisulphide helps to alleviate it (Fukao et al. 2004). Hydroxyl radicals are scavenged by allicin (Prasad et al. 1995). ...
Garlic ( Allium sativum ) is one of the oldest cultivated plants. It has been used as a spice, food, and folk medicine for many years. Garlic contains about 2000 biologically active components. For centuries, scientists have obtained a variety of compositions and physiological activities of garlic, depending on the methods of processing and extraction. Many review articles were published, where the object of the study was garlic. But there are very few broad literature reviews where garlic has been fully disclosed as a medicinal raw material. The study found that some garlic products and processing procedures were not standardized or tested for safety. A broad overview of this object can direct the attention of the scientific community in the right direction. This review contains various processing methods and yields from these extracts. In addition, most of the key physiological properties of the active substances of the raw materials are prescribed.
... Therefore, our results suggest that the DG treatment could favor the increase in the activity of this enzyme. Different compounds of garlic are linked to the increase in the activity, expression, or mRNA formation of this enzyme, including DAS, DADS, and DATS [49] ...
Deodorized garlic (DG) may favor the activity of the antioxidant enzymes and promote the synthesis of hydrogen sulfide (H2S). The objective was to test if DG favors an increase in H2S and if it decreases the oxidative stress caused by lipopolysaccharide (LPS) in rat hearts. A total of 24 rats were divided into 4 groups: Group 1 control (C), Group 2 LPS, Group 3 DG, and Group 4 LPS plus DG. The cardiac mechanical performance (CMP), coronary vascular resistance (CVR), and oxidative stress markers, such as total antioxidant capacity (TAC), glutathione (GSH), selenium (Se), lipid peroxidation (LPO), thiols, hydrogen sulfide (H2S), and the activities and expressions of thioredoxin reductase (TrxR), glutathione peroxidase (GPx), and glutathione-S-transferase (GST), cystathionine synthetase (CBS), cystathionine γ-lyase (CTH), iNOS, and eNOS-p, were analyzed in the heart. Infarct zones in the cardiac tissue were present (p = 0.01). The CMP and CVR decreased and increased (p ≤ 0.05), TAC, GSH, H2S, NO, thiols, and GST activity (p ≤ 0.01) decreased, and LPO and iNOS increased (p ≤ 0.05). The activities and expressions of TrxR, GPx, eNOS-p, CTH, and CBS (p ≤ 0.05) decreased with the LPS treatment; however, DG normalized this effect. DG treatment decreases heart damage caused by LPS through the cross-talk between the H2S and NO systems.
... The latest research has shown that numerous phytochemicals and flavonoids, such as quercetin, kaempferol, luteolin, and others, affect glutathione-related gene expression in colon tumor cells or breast cancer cells, specifically reducing GST expression. Recent research has found consistent structurefunction correlations in which the structure can alter bioavailability, antioxidant capacity, and the ability to stimulate antioxidant/detoxifying enzymes [79][80][81]. A rising number of epidemiological studies have demonstrated that polyphenol consumption slows aging and aids in the prevention and treatment of cancer, neurological, myocardial, and neurological illnesses [82]. ...
In ovo injection of nutrients can modulate the embryo’s physiological responses against aflatoxin B1 (AFB1) embryotoxicity. This hypothesis was tested using in ovo injection of Arctostaphylos uva-ursi (Ar. uu.) methanolic extract. The total polyphenols, total flavonoids, total antioxidant capacity, and GC-MS analysis were all assessed in the Ar. uu. methanolic extract. A total of 180 ten-day-old embryonated eggs were distributed into six groups of 30 replicates each. The first group was used as a control (non-injected), and the second, third, fourth, fifth, and sixth groups were injected with 10 µ double-distilled water (DDW), 500 µL methanol, 0.01 g Ar. uu./500 µL methanol, 50 ng AFB1/10 µL DDW, and 50 ng AFB1 in 10 µ DDW + 0.01 g Ar. uu./500 µL methanol, respectively. The relative embryo weight, residual yolk sac weight, tibia length and weight, and survival were recorded. Total and differential leukocytes, oxidative stress, and humoral immune responses were observed. The residual yolk sac was lower (p < 0.05) in the Ar. uu. group than other groups. The embryonic growth (tibia weight and length) was enhanced in AFB1 + Ar. uu.-injected embryos compared with those injected with AFB1 alone. In conclusion, in ovo injection of Arctostaphylos uva-ursi could modulate AFB1-induced toxicity in chicken embryos.
... For example, GO could significantly reduce the high MDA level induced by alcohol in vivo and in vitro (Zeng et al., 2012). DATS at 10 μmol/kg or DADS at 100 μmol/kg could markedly increase the GSH-Px levels in liver of acute liver injury model rats induced by carbon tetrachloride (Fukao et al., 2004). Therefore, it can be speculated that inhibition of oxidative stress may be one of the possible mechanisms by which GO acts against alcohol-induced high TG levels. ...
Garlic oil (GO) is a kind of natural extract extracted from garlic, which has strong antioxidant activity. This study elucidates the protective mechanism of GO against alcohol‐induced high triglyceride levels. Sixty male Sprague Dawley rats were assigned to five groups, including a control group (CON), a model group (MOD) treated with alcohol 56% v/v at 8 ml kg−1 day−1 for 2 weeks then 10 ml kg−1 day−1 for 8 weeks, a low‐dose GO group (GO‐L) given GO at 20 mg kg−1 day−1, a high‐dose GO group (GO‐H) given GO at 40 mg kg−1 day−1, and a positive group (POS) given diammonium glycyrrhizinate at 200 mg kg−1 day−1. The results showed that GO could significantly reduce the serum and liver triglyceride levels caused by alcohol exposure (p < .05). The GO‐H group significantly reduced MDA level, increased SOD and GSH‐Px levels in serum, liver, and colon (p < .05), significantly increased the levels of Sirt1 and PGC‐1α proteins and reduced FoxO1 protein level in liver (p < .05), and significantly increased the levels of ZO‐1 and Claudin1 proteins in the colon compared to the MOD group (p < .05). The 16S rRNA sequencing showed that the intestinal flora of the GO‐H group was significantly changed compared with the MOD group. In summary, GO has the potential to improve high triglyceride levels in serum and liver induced by alcohol exposure, which may be related to the inhibition of oxidative stress regulation of Sirt1 and its downstream proteins, and to the restoration of the intestinal barrier and intestinal flora. GO can alleviate the high triglyceride levels caused by alcohol exposure by regulating Sirt1 and its downstream proteins FoxO1 and PGC‐1α to regulate oxidative stress. GO can also repair the mechanical barrier of intestinal mucosa and regulate intestinal flora, which may be related to the reduction of high triglyceride levels in alcohol‐exposed rats.
... The aqueous extract of AS protected the tissues against the nicotine-stimulated oxidative injury and improved renal function. DATS present in the AS is an efficient antioxidant at (10 mmol/kg) and extensively increases the activities of quinone reductase and GST [76,77]. AS as an anti-oxidative and antifibrotic agent has been reported in L-arginine induced chronic pancreatitis rat model, with increased GSH activity and decreased lipid peroxidation. ...
Coronavirus disease 2019 (COVID-19) is one of the worst pandemics to have hit humanity. The manifestations are quite varied, ranging from severe lung infections to being asymptomatic. Hence, there is an urgent need to champion new tools to accelerate the end of this pandemic. Compromised immunity is a primary feature of COVID-19. Allium sativum (AS) is an effective dietary supplement known for its immune-modulatory, antibacterial, anti-inflammatory, anticancer, antifungal, and anti-viral properties. In this paper, it is hypothesized that carbon dots derived from AS (AS-CDs) may possess the potential to downgrade the expression of pro-inflammatory cytokines and revert the immunological aberrations to normal in the case of COVID-19. Carbon dots (CDs) have already been explored in the world of nanobiomedicine as promising theranostic candidates for bioimaging and drug/gene delivery. The antifibrotic and antioxidant effects of AS are elaborated, as demonstrated in several studies. It is found that the most active constituent of AS, allicin has a highly potent antioxidant and reactive oxygen species (ROS) scavenging effect. The antibacterial, antifungal, and anti-viral effects along with their capability of negating inflammatory effects and cytokine storm, are discussed. The synthesis of theranostic CDs from AS may provide a novel weapon in the therapeutic armamentarium for the management of COVID-19 infection and, at the same time, could act as a diagnostic agent for COVID-19.
... Considering the possible relationship between natural antioxidants and enzyme activities highlighted from above studies, it is likely that the presence of polyphenols in the diet administered to goats could have affected the activities of endogenous enzymes. From in vitro tests, it emerged that this wide class of plant secondary compounds seems to act differently on different enzymatic activities and that even limited differences in the structure of polyphenols can influence not only the antioxidant capacity of the single compounds but also their ability to modulate the expression of antioxidant/detoxifying enzymes [65,66]. In a recent study, a slight increase of GPX activity was observed in goats, in mid-lactation, fed with fresh legume fodder, containing polyphenol and barley meal compared to a dry diet [53]. ...
Forty late-lactation Girgentana goats were used to study the effect of diets fed ad libitum and αS1-casein (CSN1S1) genotype on redox balance. The goats genotyped at CSN1S1 locus (A/A, A/F) were subjected to four feeding treatments different for percentage inclusion of dry and fresh forage: DAF100 (98% of Dry Alfalfa Forage), DAF65 (65% of Dry Alfalfa Forage), FSF100 (100% of Fresh Sulla Forage) and FSF65 (65% of Fresh Sulla Forage). Blood samples were analyzed for superoxide dismutase (SOD) and glutathione peroxidase (GPX) activity, reactive oxygen metabolites (ROMs), biological antioxidant potential (BAP) and non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), albumin, glucose and cholesterol contents. The oxidative stress index (OSI) was calculated as percentage ratio of ROMs to BAP. Redox balance was improved by Sulla inclusion, as reflected in the lower OSI values found in FSF100 and FSF65 groups. DAF100 group displayed the highest GPX activity, while other groups exhibited the highest SOD activity. Fresh forage diets increased albumin concentration while no effect of tested factors was noted on glucose, NEFA, BHBA and cholesterol contents. The interaction diet × genotype was significant only for GPX activity. GPX and albumin were negatively correlated and were correlated positively and negatively with ROMs, respectively. Diet rather than genotype affects redox balance in dairy goats and a possible role of forage polyphenol compounds on oxidative status needs to be tested in future studies.
... (4): Composition of some new compounds such as 2-Aminoethanethiol hydrogen sulfate (Ester) in Sids 40 cultivar, 2-Trimethylsilyl-1,3-dithiane and Trisulfide, methyl 2-propenyl in Balady cultivar and Methanone,[4-][4-mthyl-5-(phenylmethyl)-4H-1,2,4-tria zol-3-yl]thio]-3-nitrophenyl]2-pyridinyl-, Benzylsulfanyla cetic acid, (benzothiazol-2-yl) methyl ester and 2- 4,6,furan-3-carbonitrile. The degradation of alline produces these compounds, which have proved their importance and effective impact such as antioxidant and anticancer activities (Enders & Balensiefer, 2004;Fukao, Hosono, Misawa, Seki, & Ariga, 2004;Lawson & Wang, 2003;Mochizuki, Yamamoto, Suzuki, & Nakazawa, 1995;Park, Ko, & Kim, 2015;Rattanachaikunsopon & Phumkhachorn, 2008;Son & Lee, 2010;Sparnins, Mott, Barany, & Wattenberg, 1986;Stoll & Seebeck, 2006;Wu et al., 2001). ...
Egyptian garlic (Allium sativum) cultivars Balady and Sids 40 were exposed to different gamma radiation doses 10, 20, 30 and 40 Gy. Gamma radiation sensitivity of the two varieties was varied whereas cv. Sids 40 tolerated up to 30 Gy, whilst cv. Balady tolerated up to 10 Gy. Genomic DNA was isolated from irradiated and un-irradiated garlic leaves from both cultivars for SCoT markers. Organosulfur compound analysis by GC-MS was from irradiated and un-irradiated garlic cloves from M 1 V 1 in both cultivars. Plant height and garlic bulbs size produced were reduced by increasing gamma radiation dose in M 1 V 1. One clove bulbs mutations in cv. Sids 40 were reversed in the M 2 V 2. Fifteen SCoT primers were used to evaluate the genetic diversity between garlic cultivars and among their treatments. These primers produced total amplified band 104 which polymorphic 43 (41.35%) with an average 6.93 band per primer, and 99 which polymorphic 31 (31.31%) with an average 6.6 band per primer in cvs. Balady and Sids 40, respectively. Polymorphic information content (PIC) values were varied from 0.12 (SCoT-36) to 0.46 (SCoT-28) with an average 0.29 (PIC < 0.5), and from zero (SCoT-16 and SCoT-22) to 0.46 (SCoT-12) with an average 3.63 (PIC < 0.5) in cvs. Balady and Sids 40, respectively. The effect of gamma radiation on organosulfur compounds as analyzed by GC-MS was limited to increased production as Diallyl disulfide; reduced production as 1,8-Dioxaspiro[4.5]decan-2-one4-(2-ami-nothiazol-4-yl)-7,7-dimethyl-; disappearance of some compounds as 2-Amino-4,4,6,6-tetra-methyl-4,6-dihydro-thieno[2,3-c]furan-3-carbonitrile, or formation of some new compounds as Methanone,[4-][4-mthyl-5-(phenylmethyl)-4H-1,2,4-triazol-3-yl]thio]-3-nitrophenyl]2-pyridi-nyl-, Benzylsulfanylacetic acid, (benzothiazol-2-yl)methyl ester, and 2-Amino-4,4,6,6-tetra-methyl-4,6-dihydro-thieno[2,3-c]furan-3-carbonitrile. ARTICLE HISTORY
... The oxidative stress plays an important role in the damage induced by IR [5][6][7] and since we observed that DATS treatment protected against brain damage and motor behavioral impairment induced by the IR insult and there is evidence indicating the antioxidant role of DATS [19,[22][23][24], we hypothesized that DATS could decrease the oxidative stress induced by the IR insult. ...
Stroke is a public health problem due to its high mortality and disability rates; despite these, the pharmacological treatments are limited. Oxidative stress plays an important role in cerebral damage in stroke and the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) confers protection against oxidative stress. Different compounds, such as diallyl trisulfide (DATS), have the ability to activate Nrf2. DATS protects against the damage induced in oxygen-glucose deprivation in neuronal cells; however, in in vivo models of cerebral ischemia, DATS has not been evaluated. Male Wistar rats were subjected to 1 h of ischemia and seven days of reperfusion and the protective effect of DATS was evaluated. DATS administration (IR + DATS) decreased the infarct area and brain damage in the striatum and cortex; improved neurological function; decreased malondialdehyde and metalloproteinase-9 levels; increased Nrf2 activation in the cortex and the expression of superoxide dismutase 1 (SOD1) in the nucleus, SOD2 and glutathione S-transferase (GST) in the striatum and cortex; and increased the activity of catalase (CAT) in the striatum and glutathione peroxidase (GPx) in the cortex. Our results demonstrate the protective effect of DATS in an in vivo model of cerebral ischemia that involves Nrf2 activation.
... Whether DAS can play a role in estradiol synthesis pathways, estradiol turnover, or expression/activity of SULT1E1 in other tissues/organs needs to be clarified [74]. Another study indicates that administration of DADS or DATS increases the activities of the phase II enzymes, quinone reductase and glutathione S-transferase, and antioxidative enzyme glutathione peroxidase in rat liver cytosol, suggesting that DADS/DATS could increase the detoxification and antioxidant effects of the liver [77]. Similarly, DADS and DATS have been shown to increase the activities of both GSH reductase and GSH S-transferase in rat livers [78]. ...
Hydrogen sulfide (H 2 S), a colorless gas smelling of rotten egg, has long been recognized as a toxic gas and environment pollutant. However, increasing evidence suggests that H 2 S acts as a novel gasotransmitter and plays important roles in a variety of physiological and pathological processes in mammals. H 2 S is involved in many hepatic functions, including the regulation of oxidative stress, glucose and lipid metabolism, vasculature, mitochondrial function, differentiation, and circadian rhythm. In addition, H 2 S contributes to the pathogenesis and treatment of a number of liver diseases, such as hepatic fibrosis, liver cirrhosis, liver cancer, hepatic ischemia/reperfusion injury, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, hepatotoxicity, and acute liver failure. In this review, the biosynthesis and metabolism of H 2 S in the liver are summarized and the role and mechanism of H 2 S in liver health and disease are further discussed.
... Experimental studies have shown preventive effects of garlic, as well as its isolated constituents on cancer development through different molecular mechanisms [38][39][40][41][42][43][44][45]. These mechanisms may include modulation of metabolizing enzymes, such as cytochrome P450s and glutathione S-transferases, which may have implications for the deactivation or detoxification of carcinogens, suppression of the formation of DNA adducts, induction of cell-cycle arrest, apoptosis, cell differentiation and cell invasion [5,6]. ...
Although the major risk factors for liver cancer have been established, preventive factors for liver cancer have not been fully explored. We evaluated the association between raw garlic consumption and liver cancer in a large population-based case-control study in Eastern China. The study was conducted in Jiangsu, China, from 2003 to 2010. A total of 2011 incident liver cancer cases and 7933 randomly selected population-controls were interviewed. Epidemiological data including raw garlic intake and other exposures were collected, and serum markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection were assayed. Overall, eating raw garlic twice or more per week was inversely associated with liver cancer, with an adjusted odds ratio (aOR) of 0.77 (95% confidence interval (CI): 0.62–0.96) compared to those ingesting no raw garlic or less than twice per week. In stratified analyses, high intake of raw garlic was inversely associated with liver cancer among Hepatitis B surface antigen (HBsAg) negative individuals, frequent alcohol drinkers, those having history of eating mold-contaminated food or drinking raw water, and those without family history of liver cancer. Marginal interactions on an additive scale were observed between low raw garlic intake and HBsAg positivity (attributable proportion due to interaction (AP) = 0.31, 95% CI: -0.01–0.62) and heavy alcohol drinking (AP = 0.28, 95% CI: 0.00–0.57). Raw garlic consumption is inversely associated with liver cancer. Such an association shed some light on the potential etiologic role of garlic intake on liver cancer, which in turn might provide a possible dietary intervention to reduce liver cancer in Chinese population.
... Garlic oil is a rich source of sulfhydryl derivative that protects against tissue damage from radiation (Jaiswal & Bordia, 1996). The protective mechanism is dependent on clearing oxygen free radicals (Fukao, Hosono, Misawa, Seki, & Ariga, 2004 ...
Natural resources such as plants are an upright curing option in treating cancers and reducing the side effects of current therapeutic modalities. Allium genus vegetables are of the most interesting herbs in restricting cancers that includes garlic, onions, leeks, chives, and shallots. These plants have been exploited in folk medicine because of their beneficial health effects in improving numerous diseases. The phytochemical analysis of various Allium genus members showed that, to date, 16 species have proved potential anticancer properties due to the accumulation of various sulfur and organic compounds like S‐allyl mercaptocysteine, quercetin, flavonoids, and ajoene. These compounds with various mechanisms such as hindering cell cycle, inhibiting signaling pathways, inducing apoptosis, and antioxidant activity interfere with diverse stages of formation, growth, differentiation, and metastasis of cancer cells. Similar to garlic and onion, other species have exhibited anticancer activities, so that active natural molecules extracted from them might serve as possible anticancer agents. Therefore, evaluating the main ingredients and studying their anticancer mechanisms are of great importance. In this review, we aim to summarize the available data on anticancer mechanisms of 16 species of Allium genus and their major compounds to assist further researches on the treatment and prevention of cancers.
... Maintenance of health of heart, immune system and digestive system [20,92,113,208] Dithiolthiones ...
... The detoxification effect may prevent symptoms of inflammation. This was confirmed by a study on rats where prolonged administration of diallyl disulfide protected poisoning of their intestinal cells (Fukao et al., 2004). Oser, (1978) reported that 6-(Methylthio) hexa-1,5dien-3-ol has an antimicrobial properties and can be used as an additive in meat while Campaigne et al., (1996) reported 5-cyano-7-methyl-6(methylthio) benzo[c] carbazole as colorless crystals with a melting point of 173-174ºC. ...
This study was undertaken to identify antimicrobial compounds in garlic grown in Laikipia County. Bioactive compounds and their structures were identified in garlic extract using GC-MS, (30 m × 0.25 mm × 0.2 μm film thicknesses) cm. The compounds identified were these compounds, with sulfur group, have previously been shown to have antimicrobial activity against pathogens. It was concluded that variety of garlic grown in Laikipia County, Kenya, has potential for use as a meat decontaminant and preservative after slaughter. Diallyl-disulphide (2.89%), 6-(Methylthio) hexa-1,5-dien-3-ol (2.79%), Trisulfide di-2-propenyl (5.11%), 2-Vinyl-[4H]-1,3-dithiane(23.43%), Tetrasulfide, Hexadecanoic acid,2,3-dihydroxy propyl ester (2.58%), Oleic acid (1.34%), 5-cyano-7-methyl-6(methylthio)benzo[c] carbazole (5.83%), 5-cyano-7-methyl-6(methylthio)benzo[c] carbazole (5.44%), Tetrasulfide, di-2-propenyl (10.17 %) and Abietic acid (5.75%). Eight of the 10 compounds identified contain a sulfur group, while three (3); Hexadecanoic acid, Oleic acid and Abietic acid did not. Concentration of vinyl-dithiane(23.43%) and tetrasulfide, (10.17 %) compounds from garlic extract were higher compared to others. Garlic from Laikipia County has organosulfur and non organosulfur compounds that are effective in control of meat pathogens.
... Diallyl disulfide increases the production of the enzyme glutathione S-transferase which acts as a detoxicator of the cells. Garlic protects nerve cells from oxidative stress in vitro [57][58][59][60][61][62][63][64]. ...
The thermodynamic parameters Eact, ΔH≠, ΔS≠, and ΔG≠for various processes involving antioxidants were calculated using literature kinetic data (k, T). The ΔG≠values of the antioxidants' processes vary in the range 91.27-116.46 kJmol-1at 310 K. The similarity of the ΔG≠values (for all of the antioxidants studied) is supported to be an indication that a common mechanism in the above antioxidant processes may be taking place. A value of about 10-30 kJmol-1is the activation energy for the diffusion of reactants depending on the reaction and the medium. The energy 92 kJmol-1is needed for the excitation of O₂ from the ground to the first excited state (¹Δg, singlet oxygen). We suggest the same role of the oxidative stress and specifically of singlet oxygen to the processes of antioxidants as in the processes of proteinaceous diseases. We therefore suggest a competition between the various antioxidants and the proteins of proteinaceous diseases in capturing singlet oxygen's empty π* orbital. The concentration of the antioxidants could be a crucial factor for the competition. Also, the structures of the antioxidant molecules play a significant role since the various structures have a different number of regions of high electron density.
... These products were found to have a higher antioxidant activity [19]. Intraperitoneal administration of DAS and DADS significantly decreased the cytochrome P-450, CYP2E1 activity [20] and increase the phase II detoxifying enzymes such as glutathione S-transferase, quinone reductase and glutathione peroxidase enzyme [21], respectively. Raw garlic homogenate significantly decreased serum glycated hemoglobin and improved insulin sensitivity in fructose fed rats [22]. ...
... The antioxidant properties of Allium sp. could be related to increased activities of the catalase (antioxidative enzymes), superoxide dismutase and glutathione peroxidase (Rose et al., 2005). In a study by Imai et al. (1994) they observed that S-allyl cysteine (SAC) and S-allyl mercaptocysteine (SAMC) reduced lipid peroxidation (Imai et al., 1994) while diallyl-tri-sulphide was shown to reduce liver injury caused by carbon tetrachloride (Fukao et al., 2004). ...
From ancient times, species from Allium genus were used for both culinary and medicinal applications. Most of the beneficial health promoting properties of these species were attributed to their high content of bioactive organosulfur compounds (OSCs). The OSC, consequently attracted interest from food and pharmaceutical industries to be used as additives or supplements. Therefore, a growing awareness for extraction of these molecules from natural resources has been shown. However, content and concentrations of OSC may be affected during processing and storage. Considering these premises, several studies evaluated traditional and innovative processing techniques, particularly pressure and electric based processes, for processing Allium based products. At this stage of development, there is a growing need to understand how processing affects the extractability and stability of the OSC in Allium sp. In the current review, we summarize and report the main findings regarding the stability and extractability of OSC from Allium sp. treated by traditional and innovative processing techniques and suggest possible prospective for further research.
... Histopathological analysis also showed that cyclophosphamide-treated group showed severe necrosis in tissues, but sulfur compounds showed normal bladder pathology [6]. Allyl sulfides, including diallyl sulfide, showed an effective action on the phase I and phase II drug-metabolizing enzymes with structure-function relationship [81]. ...
Diallyl sulfide (C6H10S, DAS) is one of the novel natural organosulfur compounds, which is mostly obtained from the genus Allium plants. Numerous studies have revealed several unique properties of DAS in terms of its health-promoting effects. DAS has proved to be anticancer, antimicrobial, anti-angiogenic, and immunomodulatory like unique functions as demonstrated by the multiple investigations. Diallyl sulfide can also impede oxidative stress and chronic inflammation as suggested by the literature. Studies also explored that DAS could thwart the development of chronic diseases like cancer, neuronal, cardiovascular disease through modulating mechanistic pathways involved in pathogenesis. In this book chapter, we have attempted to give the comprehensive view on DAS about the physiochemical and biological properties, and its preventive role in chronic diseases with a mechanistic overview.
... The effect of allylsulfides on modifying Cyp P450s appears to be specific rather than general and is supported by the observation that the activities of several Cyp P450s (e.g., Cyp 1A1, 1A2, 3A4, 2B1, 2B4) are increased by various allyl organosulfur components, and others are downregulated (9)(10)(11). Concurrent with selective modification of phase I P450 enzymes, organosulfides facilitate detoxification of carcinogens through upregulation of phase II-conjugating enzymes such as glutathione S-transferases, epoxide hydrolase, quinone reductase, and UDP-glucuronosyltransferase (12)(13)(14)(15). In addition, induction of glutathione peroxidase and an increase in the ratio of glutathione (GSH) to glutathione disulfide (GSSG) may contribute to the protective effects of organosulfur compounds in diminishing oxidative stress within cells (16,17). ...
Molecular investigations support existing clinical and epidemiological data that garlic-derived allylsulfides reduce cancer risk. Various allylsulfides can diminish progression of cancer cells at either the G(1)/S or G(2)/M phase. Allylsulfide derivatives modify redox-sensitive signal pathways and cause growth inhibition, mitotic arrest, and apoptosis induction. Whether allylsulfides modify intracellular redox potentials by affecting the ratio of glutathione:glutathione disulfide and/or by interacting directly with sulfhydryl domains on regulatory or catalytic-signal proteins requires further investigation. To understand the possible biochemical mechanisms contributing to the protective effects of allylsulfides, we investigated the ability of these compounds to undergo enzyme-catalyzed transformations. In addition to catalyzing gamma-elimination reactions, gamma-cystathionase can perform beta-elimination reactions with cysteinyl S-conjugates derived from garlic extracts when the S-alkyl group (R) is larger than ethyl. The reaction products are pyruvate, ammonium, and a sulfur-containing fragment (RSH). beta-Lyase substrates of gamma-cystathionase thus far identified from garlic include: S-allyl-L-cysteine (R = CH2 = CHCH2-), S-allylmercapto-L-cysteine (R = CH2 = CHCH2S-), and S-propylmercapto-L-cysteine (R = CH3CH2CH2S-). Mercapto derivatives yield persulfide products (RSSH) that are potential sources of sulfane sulfur, which may modify protein function by reacting at important cysteinyl domains. Thus, p-elimination reactions with cysteine S-conjugates in garlic may modify cancer-cell growth by targeting redox-sensitive signal proteins at sulfhydryl sites, thereby regulating cell proliferation and/or apoptotic responses. These interactions may be useful in identifying efficacy of garlic-derived compounds and/or developing other novel organosulfur compounds that may modify intracellular redox potentials or interact with thiols associated within cysteine domains in regulatory, catalytic, signal, or structural proteins.
Antimicrobial resistance poses a huge challenge to the healthcare system, prompting the need to develop new remedies to fight bacterial infection. Natural products derived from herbs and spices are gaining interest as potential antibacterial agents as they are generally regarded as safe for consumption. This study investigates the correlation between antibacterial efficacy and host response of six phytochemicals: berberine, curcumin, capsaicin, 6-gingerol, piperine, and allicin. The inhibitory and sensitization effects of the tested phytochemicals against Bacillus subtilis, methicillin-resistant Staphylococcus aureus, Escherichia coli, Salmonella Typhimurium, and Pseudomonas aeruginosa were evaluated. Curcumin and berberine exhibited potent inhibitory activity against Gram-positive bacteria. They enhanced the susceptibility of MRSA to ampicillin and tetracycline by 4-fold. Curcumin and berberine also increased the susceptibility of B. subtilis to tetracycline by 4-fold and 2-fold, respectively. Despite weaker bacterial inhibition, capsaicin treatment reduced the MIC for tetracycline by 4-fold in B. subtilis. Allicin, piperine, and 6-gingerol showed weak antibacterial and no sensitization effect. Analysis of the in vivo xenobiotic responses in Caenorhabditis elegans revealed that berberine and piperine strongly induced the detoxification mechanism genes (cyp-35C1, gst-5, ugt-21, ugt-25, irg-4), indicating elevated stress in the host. Curcumin and capsaicin moderately upregulated detoxification enzyme genes and repressed the stress response genes (irg-4, hsp-16.2), indicating a lower adverse host response. Allicin and 6-gingerol exhibited mild xenobiotic response. The bacterial sensitization effects of curcumin and capsaicin, coupled with their mild xenobiotic response, suggest their potential application as antibacterial agents.
Metabolic enzyme inducibility is of major significance, because it plays an important role in the susceptibility of individuals to foreign compound–mediated toxicities. Although some xenobiotics exhibit intrinsic toxicity, while some others are metabolically activated to potential toxicants by activation enzymes. The generated metabolites undergo detoxification enzyme–catalyzed reactions for detoxification, before foreign compounds are ready for excretion.
Onion or Allium cepa (A. cepa) is one of the most important condiment plants grown and consumed all over the world. This plant has various therapeutic effects attributed to its constituents, such as quercetin, thiosulphinates and phenolic acids. In the present article, various pharmacological and therapeutic effects of A. cepa were reviewed. Different online databases using keywords such as onion, A. cepa, therapeutic effects, and pharmacological effects until the end of December 2019 were searched for this purpose. Onion has been suggested to be effective in treating a broad range of disorders, including asthma, inflammatory disorders, dysentery, wounds, scars, keloids and pain. In addition, different studies have demonstrated that onion possesses numerous pharmacological properties, including anti-cancer, anti-diabetic and anti-platelet properties as well as the effect on bone, cardiovascular, gastrointestinal, nervous, respiratory, and urogenital systems effects such as anti-osteoporosis, anti-hypertensive, antispasmodic, anti-diarrheal, neuro-protective, anti-asthmatic and diuretic effects. The present review provides detailed the various pharmacological properties of onion and its constituents and possible underlying mechanisms. The results of multiple studies suggested the therapeutic effect of onion on a wide range of disorders.
Wounds can occur due to any injury, disease state or insect bite or abrasions. Wound healing is a complex process that includes many phases and involves a number of inflammatory mediators wound can be classified as acute and chronic. Other than this wound can also be classified on the basis of layer of skin that gets damaged: Superficial wound, Partial thickness wound and Full thickness wound. Garlic (Allium sativum) has been used as food and also used for the treatment of many diseases, for healing of wounds etc. Garlic is perennial liliaceous herb with a bulb having organosulphur compounds like Diallyl disulphide, diallyl sulphide, diallyl trisulphide and sulphur dioxide others are allin, allicin, etc. Garlic having major properties includes anti-cancer, against cardiovascular disease, antioxidant,anti-microbial, in wound healing etc
Scope
Diallyl trisulfide (DATS), an organosulfur compound generated in crushed garlic, has various beneficial health effects. A growing body of evidence indicates that miRNAs are involved in the pathology of lifestyle diseases including obesity. We have previously reported the anti-obesogenic effect of garlic; however, the effects of DATS on obesity, and the relationship between garlic compounds and the involvement of miRNA remains unclear. Here, we investigated the anti-obesogenic activity of DATS and the potential role of miRNA in a diet-induced obesity rat model.
Methods and results
Oral administration of DATS suppressed body and white adipose tissue (WAT) weight gain in rats fed a high-fat diet compared with vehicle-administered rats. DATS lowered the plasma and liver triglyceride levels in obese rats, and decreased lipogenic mRNA levels including those of Srebp1c, Fasn, and Scd1 in the liver. DATS also suppressed de novo lipogenesis in the liver. Transcriptomic analyses of miRNA and mRNA in the epididymal WAT of obese rats using microarrays revealed that DATS decreased miRNA-335 expression and normalized the obesity-related mRNA transcriptomic signatures in epididymal WAT.
Conclusion
We clearly demonstrate the potent anti-obesogenic effects of DATS and its possible mechanism of action.
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Aims
To investigate the protective effects and underlying mechanisms of diallyl trisulfide (DATS) against acute liver injury induced by concanavalin A (Con A).
Materials and methods
DATS (20, 40, 80 mg/kg) were gavaged to ICR mice 1 h before Con A (20 mg/kg) tail vein injection. The survival rate of mice, alterations of serum biochemical markers and liver histopathology were measured to evaluate the protective effects of DATS at 24 h after Con A exposure. The indexes of inflammation, oxidative stress and apoptosis were determined to explore the possible mechanisms.
Key findings
DATS pretreatment increased survival rate of mice in a dose-dependent manner, inhibited the increase of liver-to-spleen ratio and serum liver injury markers, and attenuated liver pathological damage induced by Con A. Further study showed that DATS pretreatment inhibited the activation of Kupffer cells/macrophages, release of tumor necrosis factor-α (TNF-α) and caspase-1-dependent inflammation induced by Con A. Moreover, DATS pretreatment alleviated the oxidative stress induced by Con A, which was evidenced by increased superoxide dismutase (SOD) and catalase (CAT) activities and decreased malondialdehyde (MDA) content in DATS and Con A co-treated mice compared with Con A alone group. Finally, DATS pretreatment reduced eosinophilic body formation, TUNEL positive staining and increased Bcl-2/Bax ratio in liver of Con A-injected mice, indicating attenuated apoptosis.
Significance
Collectively, the results suggest that DATS displays potent protective effects against Con A-induced acute liver injury in mice possibly through inhibition of inflammation, oxidative stress and apoptosis.
Ethnopharmacological relevance
Allium hooshidaryae Mashayekhi, Zarre & R.M. Fritsch sp. nova (sect. Compactoprason) is a wild plant in northwestern Iran. The plant is traditionally used, besides as spice, also for its medicinal properties.
Aim of the study
Due to the shortcoming evidence in scientific research and the importance of this plant in folk medicine, this study aims to assess the chemical compositions and biological activities, which have no longer reported to date.
Materials and Methods
The bulbs of A. hooshidaryae were collected from West Azerbaijan, Iran. The plant essential oil was obtained by hydrodistillation using Clevenger-type apparatus according to the European pharmacopeia. The plant hydromethanolic extract was obtained using maceration method. The volatile oil compositions of A. hooshidaryae bulbs were evaluated by use of combined gas chromatography/flame ionization detector (GC/FID) and gas chromatography/mass spectrometry (GC/MS) techniques. Furthermore, different biological activities of the yielded essential oil and hydromethanolic extract were in vitro evaluated. The antibacterial and antifungal activities were assessed using disc diffusion assay, tube dilution assay, minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), and minimal fungicidal concentration (MFC). The cytotoxic activities were assayed by reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) toward two human cancerous cell lines (MOLT-4 and MCF-7). Antioxidant activity was investigated using 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging assay.
Results
GC/FID and GC/MS analyses allowed detecting 62 components in the A. hooshidaryae essential oil representing the 91.87% of the total oil. The volatile compounds were identified by comparison of the relative retention indices (RRI), mass spectra with those in NIST08/NIH and Wiley (257 and 7L) libraries and co-elution with authentic samples where available. Surprisingly, the most abundant compound was obtained as menthol (19.0%) followed by carvacrol (10.1%), menthone (6.4%), methyl (methylthiomethyl) disulfide (4.2%), dimethyl disulfide (3.8%), and thymol (3.8%). Contrary to the other Allium species enriched by sulfur compounds, just three compounds accounting for 10.7% of the total oil were obtained as the sulfur-sulfur bond containing components (Dimethyl disulfide, Methyl (methylthio) methyl disulfide, Bis-methylthiomethyl disulfide). The hydromethanolic extract of A. hooshidaryae showed higher anti-radical (IC50 DPPH of 9.81 μg/mL) and cytotoxic (for MOLT-4 and MCF-7, IC50s were 76.3 and 128.6 μg/mL, respectively) activities rather than that of the obtained essential oil (IC50 DPPH of 39.9 μg/mL; IC50 MOLT-4 of 109.2 μg/mL, and IC50 MCF-7 of 297.5 μg/mL). While, the essential oil exhibited the anti-Staphylococcus aurous and anti-Escherichia coli activities approximately the same as Chloramphenicol (positive control). The MIC values were 31.25 and 62.5 μg/mL and the disk inhibition zone values were 23 and 21 mm, respectively. In addition, Candida albicans had moderate sensitivity (MFC of 62.5 μg/mL) for the essential oil.
Conclusions
The hydromethanolic extract of A. hooshidaryae shows the potency to be used for food protection in addition to further cytotoxic investigations. Associated with antimicrobial abilities of both A. hooshidaryae products, the compatible results was observed with the traditional claim having being not investigated to date. These findings will facilitate the development of A. hooshidaryae for further deep investigations.
This study involved testing the effect of four subinhibitory concentrations of garlic extracts (aqueous and alcoholic) on the mutagenicity of short wave ultraviolet (UVC 253.7 nm) in conidia of the fungus Aspergillus amstelodami. The concentrations of the aqueous extract tested were 2.5 , 5 , 7.5 and 10 mg / ml conidial suspension, The concentrations of alcoholic extract were 0.5 , 1 , 1.5 and 2 mg / ml conidial suspension. Tests were done using the pre-treatment method. Both the aqueous and alcoholic extracts caused inhibition in the mutagenicity of UVC in conidia of the fungus A. amstelodami.
The redox reactions of organic trisulfides containing various hydrocarbon groups with alkenes in aprotic solvents were studied. The electrooxidation of trisulfides proceeds irreversibly by the ECE mechanism, with formation of sulfur-centered RS+ and RSS+ intermediates. The generated cations enter into electrophilic addition reactions with alkenes, forming asymmetric di- and monosulfides. The electrochemical reduction of trisulfides leads to the formation of a radical anion, which is fragmented into the RSS anion and RS radical. In the presence of acetic acid, the cathodic activation of trisulfides is accompanied by the formation of alkyl and phenyl hydrodisulfides (RSSH).
Both activation and detoxification enzymes are involved in toxicity and carcinogenesis mediated by xenobiotic metabolism. The modulation of cytochrome P450s as a defense against xenobiotic-mediated toxic effects is a complex subject. Considerable evidence has supported the prospect of modulating the activity of detoxification enzymes as a major strategy to manipulate the risk of xenobiotic-mediated toxicity and carcinogenesis. Detoxification enzyme inducers are diverse, including isothiocyanates; 1,2-dithiole-3-thione and its derivatives; indole-3-carbinol; polyphenols, flavonoids, and isoflavones; diallyl sulfides; terpenes, terpenoids, and carotenoids; and other compounds. Characteristics of metabolic enzyme modulators generally consist of functional groups with unsaturated carbon-carbon bonds and hydroxy groups on aromatic rings.
Diallyl trisulfide (DATS) is a secondary metabolite of allicin, a volatile organosulfur flavoring compound generated by the crushing of garlic. These compounds have various medicinal effects such as antiplatelet activity. In this study, we demonstrated for the first time the cellular mechanism involved in the inhibition of platelet aggregation by DATS and dipropyl trisulfide (DPTS), which is a saturated analogue of DATS. Washed murine platelets were incubated with these sulfides, and platelet aggregation was evaluated by light transmission aggregometry. The amount of reaction products produced by DATS, DPTS, and glutathione (GSH) were measured using liquid chromatography-mass spectrometry. Compared with DPTS, DATS potently inhibited platelet aggregation induced by thrombin, U46619, and collagen. N-Ethylmaleimide, which is commonly used to modify sulfhydryl groups, also suppressed platelet aggregation. The reactivity of DATS with GSH was higher than DPTS. These data suggested that DATS inhibited platelet aggregation through the reaction of sulfhydryl groups.
The renal-protective effect of diallyl disulfide (DADS) on tricholoromethane (CHCl3)-induced renal toxicity was investigated. Twenty five rats, divided into five groups of five animals each were used. CHCl3 at the dose of 200 mg/kg was orally administered, and concomitantly treated with DADS (50 mg/kg), 5 days/week for a period of 3 weeks. Compared with control, there was no significant increase in kidney malondialdehyde (MDA), but a significant increase in levels of nuclear factor kappa B (NFkB) expressions, TUNEL positive cells (apoptosis), as well as hydrogen peroxide (H2O2), nitric oxide (NO) and reduced glutathione (GSH) concentrations. In addition, a significant decrease in expressions of kidney p53 and catalase (CAT) activity, and a non-significant decrease in glutathione peroxidase (GPx) activity were recorded following CHCl3 administration. Conversely, following DADS treatment, there was a significant increase in the expressions of p53, and a significant and non-significant decrease in apoptotic positive cells and NFkB expressions respectively. Administration of DADS significantly reduced the levels of H2O2 and NO, but did not have effect on the level of GSH, while CAT and GPx activities were significant improved. Protection by DADS against TCM-induced renal-toxicity may therefore be via suppressions of NFkB activation, oxidative stress and apoptosis in rats.
Trichloromethane (TCM) serves as an ingredient in pesticide formulations and fire extinguishers.
It is a reported hepato- and renal-toxin. We therefore investigated the chemo-preventive effect of diallyl disulfide (DADS) on TCM-induced hepatotoxicity. Twenty five rats, divided into five groups of five animals each were used. TCM at the dose of 200 mg/kg was orally administered, and concomitantly treated with DADS (50 mg/kg), 5 days per week for 3 weeks. Compared with control, there was a significant increase in hepatic expressions of nuclear factor kappa B (NFkB), TUNEL positive cells (apoptosis), and concentrations of malondialdehyde (MDA), hydrogen peroxide (H2O2), and nitric oxide (NO). Also, a significant decrease in expressions of p53, and activities of catalase (CAT) and glutathione peroxidase (GPx), as well as level of reduced glutathione (GSH) was recorded following TCM administration. Following treatment, DADS intervention significantly reduced the hepatic NFkB expressions, apoptotic positive cells as well
as levels of MDA, H2O2, and NO, and also significantly increased the level of GSH, activities of CAT and GPx compared with TCM group, while its effect on expressions of p53 was insignificant. Hepato-protection by DADS against TCM-induced hepatotoxicity may therefore be via suppressions of NFkB activation, apoptosis, and oxidative stress in rats.
Experimental and epidemiological studies over the past few decades have provided ample evidences with regard to the association amid plant food consumption and decreased cancer risk. Many phytochemicals have proved their anticancer potential to be used as therapeutics against cancer. Among them garlic (Allium sativum) has been of much interest, mostly due to the epidemiological reports, which linked the increased garlic consumption with reduced prevalence of many human diseases. Garlic and their constituent organosulfur compounds (OSCs) have been attributed to several medicinal properties like hypocholesterolemic, fibrinolytic, immunostimulatory, antimicrobial, antiviral, antifungal, and anticancer effects. The OSCs have been shown to have strong anticarcinogenic property against a variety of chemical carcinogens in different preclinical animal model studies. Extensive researches are still being carried out to elucidate the molecular mechanism of action of OSCs. The main focus of the present chapter is to give an overview of the past and present studies undergoing on organosulfur compounds for exploring their potential as an adjunct in cancer chemotherapeutics and research.
A convenient method for the preparation of unsymmetrical trisulfides using 9-fluorenylmethyl (Fm) disulfide as the precursors is reported. This method gives the desired trisulfides in good yields under mild conditions.
Enzyme systems in detoxification processes including phase I and phase II enzymes protect the cells from toxic effects mediated by a variety of foreign compounds. The hypotheses underlying the defense against xenobiotics-mediated toxicity include (a) the reduction of activation by inhibiting phase I activation enzymes, (b) the enhancement of detoxification by inducing phase II detoxification enzymes, and (c) the glutathione antioxidant protection against reactive oxygen species. Phase I enzyme inhibition is mainly concentrated on CYP450. Phase II enzyme induction is largely focused on UDP-glucuronosyl transferases, glutathione S-transferases, and quinone reductases. Glutathione is considered as not only a nucleophilic scavenger of reactive oxygen species, but also a conjugation cofactor in glutathione S-transferase catalyzed reactions.
The study of health promoting and disease preventing compounds in food or by themselves, so called nutraceuticals or functional foods, has become a major field of research in food science. Natural flavor compounds are usually present in food, essential oils, spices, and herbs. These compounds can produce aroma, not only by themselves, but also in combination with other compounds. Today, however, greater interest is being paid to the health promoting properties of natural flavor substances rather than their flavoring properties. In fact, a number of naturally occurring flavor compounds that possess health promoting and disease preventing properties have been extensively studied and identified. The beneficial properties of natural volatile flavor compounds as well as non-volatile substances in spices and herbs discussed in this review include antioxidant, anticarcinogenic, anti-inflammatory, and immune enhancing activities.
It has been reported that several naturally occurring and related synthetic organosulfur compounds exert chemopreventive effects in several target organs in rodent models. The chemopreventive actions of 40 and 80% maximum tolerated doses (MTD) of organosulfur compounds, namely anethole trithione, diallyl disulfide, N-acetylcysteine, and taurine, administered in AIN-76A diet, on azoxymethane (AOM)-induced neoplasia were investigated in male F344 rats. Also, the effects of these agents on the activities of phase II enzymes, namely glutathione S-transferase (GST), NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase, in the liver and colonic mucosa and tumors were assessed. The MTD levels of anethole trithione, diallyl disulfide, N-acetylcysteine, and taurine were determined in male F344 rats and found to be 250, 250, 1500, and 1500 ppm, respectively. At 5 weeks of age, animals were fed the control diet (AIN-76A) or experimental diets containing 40 or 80% MTD levels of each test agent. All animals in each group, except those allotted for vehicle (saline) treatment, were administered AOM s.c. at a dose rate of 15 mg/kg body weight once weekly for 2 weeks. All animals were necropsied during week 52 after the second AOM injection. Colonic mucosal and tumor and liver enzyme activities were measured in animals fed 80% MTD levels of each test agent. Colon tumors were subjected to histopathological evaluation and classified as invasive or noninvasive adenocarcinomas. Colon tumor incidence (percentage of animals with tumors) and tumor multiplicity (tumors/animal) were compared among various dietary groups. The results indicated that administration of 200 ppm (80% MTD) anethole trithione significantly inhibited the incidence and multiplicity of both invasive and noninvasive adenocarcinomas, whereas feeding of 100 ppm (40% MTD) anethole trithione or 100 (40% MTD) or 200 ppm (80% MTD) diallyl disulfide suppressed only invasive adenocarcinomas of the colon. Although diets containing N-acetylcysteine and taurine inhibited colon tumor multiplicity, the effect was somewhat marginal. GST, NAD-(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase activities in colonic mucosa and tumor and liver were significantly elevated in animals fed anethole trithione or diallyl disulfide, compared to those fed the control diet. N-Acetylcysteine and taurine slightly but significantly increased only the GST activity in the liver. Although other mechanisms are not excluded, inhibition of AOM-induced colon carcinogenesis by anethole trithione and diallyl disulfide may be associated, in part, with increased activities of phase II enzymes such as GST, NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase in the liver and colon.
Allium vegetables and their associated organosulfur constituents are extensively studied for their chemopreventive potential against cancer. This article overviews their anticarcinogenic and antigenotoxic properties. Epidemiological studies (mostly case-control studies) provide strong evidence that Allium vegetable consumption reduces the incidence of gastric and colon cancer while the association between Allium vegetable consumption and other cancers is less convincing. Furthermore, many experimental studies have demonstrated that organosulfur compounds and Allium extracts have inhibitory effects on carcinogenesis in animals. These inhibitory effects are supported by many diverse mechanisms, including inhibition of carcinogen formation, modulation of carcinogen metabolism, inhibition of mutagenesis and genotoxicity, inhibition of cell proliferation and increase of apoptosis, inhibition of angiogenesis, and immune system enhancement. Before such constituents or extracts can be used in chemopreventive trials, it is important to verify their lack of toxicity and to investigate further their precise mechanisms of action throughout the whole process of carcinogenesis.
Glutathione S-transferases and glutathione play an important role in the detoxification of most toxic agents. In the present study, the protective effects of some antioxidants (L-ascorbic acid (AA), vitamin E (VE) or garlic) on carbon tetrachloride-induced changes in the activity of alanine amino transferase (ALT), aspartate amino transferase (AST), glutathione S-transferase (GST), and the level of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) were studied. The activities of ALT, and AST were assayed in plasma, whereas the activity of GST and the levels of GSH and TBARS were determined in the livers of rats. The current study included two experiments. In the first experiment, animals received single oral dose of CCl4 (400 mg/kg body weight) after administration of AA (100 mg/kg b.w.), VE (100 mg/kg b.w.) or garlic (800 mg/kg b.w.) as single oral doses. In the second experiment, rats received repeated oral doses of antioxidants for 12 consecutive days followed by a single oral dose of CCl4 on the 13th day and killed after that by 24 h. Treatment of male rats with CCl4 significantly increased the activity of ALT and AST in plasma, and the levels of both GSH and TBARS in the liver. On the other hand, CCl4 inhibited the activity of GST after single dose treatment. Single-dose treatments of rats with AA, VE or garlic prior to the administration of CCl4 could not restore the alterations in the activity of ALT and AST caused by CCl4 to the normal control level. However, repeated dose treatments with these agents restored such alterations to the normal level. We observed that VE is more effective than AA and garlic in restoring the inhibition of GST activity caused by CCl4 to the normal level after single dose treatments. On the other hand, AA and VE are more effective than garlic in restoring the induced TBARS level caused by CCl4 to the normal control level after repeated dose treatments. It has been observed that the tested antioxidants were able to antagonize the toxic effects of CCl4, and such counteracting effects were more pronounced when they were administered as repeated doses prior to administration of CCl4.
Epidemiological and laboratory studies provide insight into the anticarcinogenic potential of garlic and its constituent compounds. Both water- and lipid-soluble allyl sulfur compounds are effective in blocking a myriad of chemically induced tumors. Part of the protection from these compounds probably relates to a block in nitrosamine formation and metabolism. However, blockage in the initiation and promotion phases of the carcinogenicity of various compounds, including polycyclic hydrocarbons, provide evidence that garlic and its constituents can alter several phase I and II enzymes. Their ability to block experimentally induced tumors in a variety of sites including skin, mammary and colon, suggests a general mechanism of action. Changes in DNA repair and in immunocompetence may also account for some of this protection. Some, but not all, allyl sulfur compounds can also effectively retard tumor proliferation and induce apoptosis. Changes in cellular thiol and phosphorylation stains may account for some of these antitumorigenic properties. The anticarcinogenic potential of garlic can be influenced by several dietary components including specific fatty acids, selenium, and vitamin A. Since garlic and its constituents can suppress carcinogen formation, carcinogen bioactivation, and tumor proliferation it is imperative that biomarkers be established to identify which individuals might benefit most and what intakes can occur with ill consequences..
We investigated the allosteric and kinetic properties of the heat-stable L-lactate dehydrogenase (EC 1.1.1.27) from Thermus caldophilus GK24. In the absence of an effector, the pyruvate and l-lactate saturation curves for the enzyme were sigmoid. In the presence of 0.2 mM fructose 1,6-bisphosphate, the most potent effector, the substrate saturation curves ceased to show the positive cooperativities. The maximum velocity of pyruvate reduction increased 7-fold on the addition of fructose 1,6-bisphosphate. This fructose 1,6-bisphosphate-dependent enzyme activity was strongly inhibited by high concentrations of the substrate (pyruvate). In contrast, the NADH and NAD + saturation curves for the enzyme were hyperbolic independent of fructose 1,6-bisphosphate. Glucose 1,6-bisphosphate, fructose 2,6-bisphosphate and 5-phosphoribosyl 1-pyrophosphate also activated the enzyme to some extent. Inorganic phosphate slightly activated the enzyme, while it was rather inhibitory for the fructose 1,6-bisphosphate-dependent enzyme reaction. Oxamate, an analogue of pyruvate, activated the enzyme and caused the positive cooperativity for pyruvate to disappear. The intracellular concentrations of fructose 1,6-bisphosphate and pyruvate and the kinetic properties of L-lactate dehydrogenase of T. caldophilus Gk24 indicate that the enzyme exhibits the pyruvate reduction activity in concert with glycolysis under allosteric regulation by fructose 1,6-bisphosphate.
A potent platelet aggregation inhibitor, methylallyl trisulfide (MATS), found in the steam-distilled oil components from garlic (Allium sativum L.), was studied to reveal its inhibition mechanism. MATS suppressed the synthesis of thromboxane A2 (TXA2) in platelets, and showed quite a different mode of inhibition from any of the known specific inhibitors, e.g., aspirin in inhibiting cyclooxygenase (COX); esculetin, lipoxygenase (LPX); and OKY-046, thromboxane synthase (TXS). MATS inhibited both COX and LPX, but had little effect on TXS, even at 10-4 M. MATS was judged to inactivate prostaglandin endoperoxide synthase (PGH synthase); however, the inhibition was confined to the second catalytic phase of enzymatic activity, peroxidase activity. COX activity, the other activity at the first catalytic phase of this bifunctional enzyme, which has been found to be inhibited specifically by aspirin, seemed to be unaffected by MATS, since arachidonic acid was metabolized at a rate similar to the control. Although a detailed interaction between MATS and PGH synthase has not yet been demonstrated, MATS would be expected to prevent the reduction of a substrate, prostaglandin G2 (PGG2), through its alkyl trisulfide structure.
We investigated the allosteric and kinetic properties of the heat-stable L-lactate dehydrogenase (EC 1.1.1.27) from Thermus caldophilus GK24. In the absence of an effector, the pyruvate and L-lactate saturation curves for the enzyme were sigmoid. In the presence of 0.2 mM fructose 1, 6-bisphosphate, the most potent effector, the substrate saturation curves ceased to show the positive cooperativities. The maximum velocity of pyruvate reduction increased 7-fold on the addition of fructose 1, 6-bisphosphate. This fructose 1, 6-bisphosphate-dependent enzyme activity was strongly inhibited by high concentrations of the substrate (pyruvate). In contrast, the NADH and NAD+ saturation curves for the enzyme were hyperbolic independent of fructose 1, 6-bisphosphate. Glucose 1, 6-bisphosphate, fructose 2, 6-bisphosphate and 5-phosphoribosyl 1-pyrophosphate also activated the enzyme to some extent. Inorganic phosphate slightly activated the enzyme, while it was rather inhibitory for the fructose 1, 6-bisphosphate-dependent enzyme reaction. Oxamate, an analogue of pyruvate, activated the enzyme and caused the positive cooperativity for pyruvate to disappear. The intracellular concentrations of fructose 1, 6-bisphosphate and pyruvate and the kinetic properties of L-lactate dehydrogenase of T. caldophilus Gk24 indicate that the enzyme exhibits the pyruvate reduction activity in concert with glycolysis under allosteric regulation by fructose 1, 6-bisphosphate.
The inorganic sulfane tetrathionate (−O3SSSSO3−) resembles glutathione trisulfide (GSSSG) in that it remarkably activates the reduction of cytochrome c by GSH, both under aerobic and anaerobic conditions. These observations can be explained by the formation of the persulfide GSS−, due to nucleophilic displacements of sulfane sulfur. The GSS− species has previously been proposed to act as a chain carrier in the catalytic reduction of cytochrome c, and perthiyl radicals GSS·, formed in the reduction step, were thought to recycle to sulfane via dimerization to GSSSSG.2 The present study provides some arguments in favour of a chain mechanism involving the GSS· + GS− (GSSSG)− equilibrium and sulfane regeneration by a second electron transfer from (GSSSG)· − to cytochrome c.
Thiosulfate sulfurtransferase (rhodanese) is shown to act as a cytochrome c reductase in the presence of thiosulfate and GSH, and again the generation of GSS− can be envisaged to explain this result.
Cellular responses to xenobiotic-induced stress can signal proliferation, differentiation, homeostasis, apoptosis, or necrosis. To better understand the underlying molecular mechanisms after exposure to xenobiotics or drugs, we studied the signal transduction pathways, the mitogen-activated protein kinase (MAPK), and the basic leucine zipper transcription factor Nrf2, activated by different agents in the induction of Phase II drug metabolizing enzymes (DMEs). The MAPKs, characterized as proline-directed serine/threonine kinases, are essential components of signaling pathways that convert various extracellular signals into intracellular responses through serial phosphorylation cascades. Once activated, MAPKs can phosphorylate many transcription factors, such as c-Jun, ATF-2, and ultimately lead to changes in gene expression. Two classes of Phase II gene inducers, which are also cancer chemopreventive agents, were studied: (1) the phenolic antioxidants, namely butylated hydroxyanisole (BHA) and its active de-methylated metabolite t-butylhydroquinone (tBHQ), and phenolic flavonoids such as green tea polyphenols (GTP) and (-)-epigallocatechin-3-gallate (EGCG); and (2) the naturally occurring isothiocyanates, namely phenethyl isothiocyanate (PEITC), and sulforaphane. BHA and tBHQ are both well-known phenolic antioxidants used as food preservatives, and strongly activate c-Jun N-terminal kinase 1 (JNK1), extracellular signal-regulated protein kinase 2 (ERK2), or p38, in a time- and dose-dependent fashion. Free radical scavengers N-acetyl-L-cysteine (NAC), or glutathione (GSH), inhibited ERK2 activation and, to a much lesser extent, JNK1 activation by BHA/tBHQ, implicating the role of oxidative stress. Under conditions where MAPKs were activated, BHA or GTP also activated ARE/EpRE (antioxidant/electrophile response element), with the induction of Phase II genes such as NQO. Transfection studies with various cDNAs encoding wild-type or dominant-negative mutants of MAPKs and/or transcription factor Nrf2, substantially modulated ARE-mediated luciferase reporter activity in the presence or absence of phenolic compounds. Other phytochemicals including PEITC, and sulforaphane, also differentially regulated the activities of MAPKs, Nrf2, and ARE-mediated luciferase reporter gene activity and Phase II enzyme induction. A model is proposed where these xenobiotics (BHA, tBHQ, GTP, EGCG, PEITC, sulforaphane) activate the MAPK pathway via an electrophilic-mediated stress response, leading to the transcription activation of Nrf2/Maf heterodimers on ARE/EpRE enhancers, with the subsequent induction of cellular defense/detoxifying genes including Phase II DMEs, which may protect the cells against toxic environmental insults and thereby enhance cell survival. The studies of these signaling pathways may yield insights into the fate of cells upon exposure to xenobiotics.
DT diaphorase is widely distributed in the animal kingdom, and is a flavin adenine dinucleotide (FAD)-eontaining flavoprotein, which catalyzes the oxidation of NADH and NADPH by various dyes and quinones with a maximal velocity of the order of 107 moles per mole of flavin per minute. Bovine serum albumin (0.07%), polyvinylpyrrolidone (5%), and certain nonionic detergents such as Tween-20 or -60 (0.2%) are activators of DT diaphorase; the concentrations in parentheses are those required for maximal activation. The activation is reversible and implies both an elevation of the Vmax of the enzyme and an increase of its affinity for NADH and NADPH. The need for an activator increases during the purification and storage of the enzyme, probably because of the removal or destruction of a naturally occurring activator. Various electron acceptors for DT diaphorase are listed. 2, 6-Diehlorophenolindophenol (DCPIP) and certain benzo- and naphthoquinones are the best electron acceptors, whereas methylene blue and ferricyanide are relatively inefficient, and cytochromes c and b5 are practically inactive as electron acceptors. The chapter also describes the assay and purification procedure of DT diaphorase, and discusses the DT diaphorase relation to other diaphorases and related enzymes.
Diallyl sulfide, a major flavor ingredient from garlic, was previously shown to inhibit chemically induced carcinogenesis and cytotoxicity in animal model systems. It modulated cytochrome P-450 compositions by inactivating P-450 2E1 and inducing P-450 2B1. The present studies examined the inhibition of P-450 2E1 mediated p-nitrophenol hydroxylase activity by diallyl sulfide and its putative metabolites diallyl sulfoxide and diallyl sulfone (DASO2). Each compound displayed competitive inhibition of p-nitrophenol hydroxylase activity in incubations using liver microsomes from acetone-pretreated male Sprague-Dawley rats. Preincubation of the microsomes with DASO2 inactivated p-nitrophenol hydroxylase activity in a process that was time- and NADPH-dependent and saturable, exhibited pseudo-first-order kinetics, was protected by alternate substrate, was accompanied by a loss of microsomal P-450-CO binding spectrum, and was unaffected by exogenous nucleophile. The Ki value for DASO2 was 188 microM and the maximal rate of inactivation was 0.32 min-1. DASO2 was ineffective in the inactivation of ethoxyresorufin dealkylase, pentoxyresorufin dealkylase, or benzphetamine demethylase activity. Purified P-450 2E1 in a reconstituted system was inactivated in a time- and NADPH-dependent manner by DASO2. The metabolic conversion of diallyl sulfide to the sulfoxide and sulfone was observed in vivo and in vitro. The results suggest that diallyl sulfide inhibits the metabolism of P-450 2E1 substrates by competitive inhibition mechanisms and by inactivating P-450 2E1 via a suicide-inhibitory action of DASO2.
The antiplatelet activity of methyl allyltrisulfide (MATS), a component commonly present in steam-distilled garlic oil, has been demonstrated by the authors. MATS inhibits arachidonic acid cascade at the reaction site with PGH synthase. However, this enzyme catalyzes two successive reactions, from arachidonic acid to PGG2, and from PGG2 to PGH2. The present study revealed that MATS inhibited the latter reaction. In addition, our recent findings that to a promyelocytic leukemia cell HL60, Allium oils shows marked anti-neoplastic effects representing both growth suppression and differentiation activities are described. The garlic oil and onion oil showed almost equal ability in inducing the proliferation, which measured either by nitroblue-tetrazolium reducing activity assay or by flow cytometry for detecting CD11b expression. The combination use of one of these oils with all-trans retinoic acid or with dimethyl sulfoxide lead to the marked differentiation of the cells, and their effects were estimated to be synergistic.
A major foundation of the field of cancer chemoprevention has resided in an impressive number of animal studies showing that cancer can be prevented by a variety of chemical compounds. In the search for increasingly effective inhibitors, both synthetic and naturally occurring compounds are being investigated. One group of naturally occurring compounds of particular interest consists of minor dietary nonnutrients. Foods of plant origin frequently contain as much as several per cent of these compounds. In recent years there has been a growing awareness that they may have important effects on the consequences of exposure to carcinogenic agents. This information comes from studies of whole diets; individual dietary constituents, particularly those from plants; and finally from investigations of pure compounds. The nonnutrient inhibitors of carcinogenesis have several different mechanisms of action. Some are blocking agents; i.e., they prevent carcinogens from reaching or reacting with critical target sites. Others are suppressing agents; i.e., they prevent evolution of the neoplastic process in cells that otherwise would become malignant. Occasionally, one compound will show both mechanisms. The nonnutrient compounds have the important attribute of there being data on their consumption by humans. Thus, it may be possible to evaluate their impact on cancer risk. Ultimately, information pertaining to these compounds may be useful in terms of diet selection or their use as dietary supplements.
The content of dialk(en)yl thiosulfinates, including allicin, and their degradation products has been determined by high performance liquid chromatography (HPLC), using the respective determined extinction coefficients, for a number of commercially available garlic products. Quantitation has been achieved for the thiosulfinates; diallyl, methyl allyl, and diethyl mono-, di-, tri-, tetra-, penta-, and hexasulfides; the vinyldithiins; and (E)- and (Z)-ajoene. The thiosulfinates were found to be released only from garlic cloves and garlic powder products. The vinyldithiins and ajoenes were found only in products containing garlic macerated in vegetable oil. The diallyl, methyl allyl, and dimethyl sulfide series were the exclusive constituents found in products containing the oil of steam-distilled garlic. Typical steam-distilled garlic oil products contained about the same amount of total sulfur compounds as total thiosulfinates released from freshly homogenized garlic cloves; however, oil-macerated products contained only 20% of that amount, while garlic powder products varied from 0 to 100%. Products containing garlic powder suspended in a a gel or garlic aged in aqueous alcohol did not contain detectable amounts of these non-ionic sulfur compounds. A comparison of several brands of each type of garlic product revealed a large range in content (4-fold for oil-macerates and 33-fold for steam-distilled garlic oils), indicating the importance of analysis before garlic products are used for clinical investigations or commercial distribution.
A persuasive body of evidence indicates that substantial protection against chemical carcinogenesis can be achieved by induction of enzymes concerned with the metabolism of carcinogens. There are two classes of anticarcinogenic enzyme inducers: (a) monofunctional inducers (e.g., phenolic antioxidants, isothiocyanates, coumarins, thiocarbamates, cinnamates, 1,2-dithiol-3-thiones) that elevate Phase II enzymes (such as glutathione S-transferases, NAD(P)H:quinone reductase, UDP-glucuronosyl-transferases) in various tissues without significantly raising the Phase I enzyme, aryl hydrocarbon hydroxylase (cytochrome P1-450); and (b) bifunctional inducers (e.g., polycyclic aromatic hydrocarbons, flavonoids, and azo dyes) that induce both Phase I and Phase II enzymes of xenobiotic metabolism. Induction of Phase II enzymes appears to be a sufficient condition for achieving chemoprotection, and since certain Phase I enzymes are responsible for activating carcinogens to their ultimate reactive forms, selective Phase II enzyme inducers offer intrinsically safer prospects for achieving chemoprotection. Whereas induction of both Phase I and II enzymes by bifunctional inducers depends on the Ah receptor, induction of Phase II enzymes by monofunctional inducers is independent of a functional Ah receptor. Studies on the structural requirements for induction of quinone reductase [NAD(P)H:(quinone acceptor) oxidoreductase; EC 1.6.99.2] by monofunctional inducers in Hepa 1c1c7 murine hepatoma cells have revealed that such inducers contain a distinctive chemical feature (or acquire this feature by metabolism) that regulates the synthesis of this protective enzyme. The inducers are all Michael reaction acceptors characterized by olefinic (or acetylenic) linkages that are rendered electrophilic by conjugation with electron-withdrawing groups. Typical examples are alpha, beta-unsaturated aldehydes, ketones (including quinones), thioketones, sulfones, esters, nitriles and nitro groups. The potency of these inducers parallels their reactivity as Michael acceptors. These generalizations have provided mechanistic insight into the vexing question of how so many seemingly unrelated anticarcinogens induce chemoprotective enzymes. They have also led to the prediction of entirely new and unsuspected structures of inducers, with potential for chemoprotective activity.
p-Nitrophenol is widely employed as a substrate for the study of the glucuronide and sulfate conjugation pathways. However, in perfused livers from ethanol-treated rats, p-nitrophenol was rapidly metabolized to 4-nitrocatechol. The 4-nitrocatechol formed competed with p-nitrophenol for conjugation with glucuronic acid and sulfate, and interfered with the direct spectral measurement of p-nitrophenol. In isolated microsomes, rates of p-nitrophenol hydroxylation were increased 6-fold after chronic ethanol treatment. Much smaller induction was observed after pretreatment of rats with phenobarbital (70% increase) or beta-naphthoflavone (30% increase). In addition, the 6-fold increase in rates of p-nitrophenol hydroxylation after chronic ethanol treatment was greater than increases in activity observed for the microsomal metabolism of aniline, 7-ethoxycoumarin, benzo(a)pyrene, ethanol, or aminopyrine. These data demonstrate that p-nitrophenol may be an extremely useful substrate for the study of changes in drug-metabolizing activity induced by ethanol treatment.
The purification of homogeneous glutathione S transferases B and C from rat liver is described. Kinetic and physical properties of these enzymes are compared with those of homogeneous transferases A and E. The letter designations for the transferases are based on the reverse order of elution from carboxymethylcellulose, the purification step in which the transferases are separated from each other. Transferase B was purified on the basis of its ability to conjugate iodomethane with glutathione, whereas transferase C was purified on the basis of conjugation with 1,2 dichloro 4 nitrobenzene. Although each of the 4 enzymes can be identified by its reactivity with specific substrates, all of the enzymes are active to differing degrees in the conjugation of glutathione with p nitrobenzyl chloride. Assay conditions for a variety of substrates are included. All four glutathione transferases have a molecular weight of 45,000 and are dissociable into subunits of approximately 25,000 daltons. Despite similar physical properties and overlapping substrate specificities of these enzymes, only transferases A and C are immunologically related.
The amino-acid sequence of the seleno-enzyme glutathione peroxidase from bovine erythrocytes was completely determined. Fragmentation of the carboxymethylated protein comprised cleavages with trypsin, with endoproteinase Lys-C, and with cyanogen bromide in 70% formic acid. The resulting peptides were separated by reversed-phase high-performance chromatography or by gel filtration. For sequence determination automated solid or liquid phase techniques of Edman degradation were used. The proper alignment of fragments was experimentally proven in all but one instance. In this case, consistent indirect evidence was provided. The monomer of glutathione peroxidase was shown to consist of 198 amino acids representing a molecular mass ob about 21 900 Da. The active site selenocysteine was localized at position 45. In addition, four cysteine residues were found at positions 74, 91, 111, and 152. The N-terminal part of the sequence obtained revealed a pronounced homology with a partial sequence of the rat liver enzyme. Moreover, tentative sequence data predicted from X-ray crystallographic analysis of bovine glutathione peroxidase were found to agree in about 80% of the residues with the sequence presented. Differences between the predicted and the experimentally determined sequence are discussed.
1. The effects of feeding allyl sulphides to rat (2000 ppm of the diet for 15 days) were investigated on various microsomal hepatic drug-metabolizing enzymes by their immunochemical detection and catalytic activity. 2. Allyl sulphides provoked a temporary dietary restriction, which enhanced the microsomal level of P450 and the activities of NADH-cytochrome c reductase and p-hydroxybiphenyl UDP-glucuronyltransferase (UDPGT 2), and lowered the activities of p-nitrophenol hydroxylase (PNPH), N-nitrosodimethylamine demethylase (NDMAD), laurate omega-hydroxylase (LAH) and glutathione S-transferase (GST). Therefore, pair-fed animals were used as a more relevant control for the dietary effects of allyl sulphides. 3. Diallyl sulphide (DAS) as well as diallyl disulphide (DADS) produced an enhancement of the microsomal level of P4501A2, 2B1/2 and 3A1/2, and epoxide hydrolase (EH) proteins, with an increase in the enzymatic activities they catalyse: ethoxyresorufin O-deethylase (EROD), aryl hydrocarbon hydroxylase (AHH), methoxyresorufin O-demethylase (MROD), ethoxycoumarin O-deethylase (ECOD), pentoxyresorufin O-depentylase (PROD), benzoxyresorufin O-debenzylase (BROD) and EH. Although P4502E1 proteins were lowered on treatment, NDMAD activity was not modified, and PNPH activity was even enhanced by allyl sulphides. Only DAS treatment raised erythromycin N-demethylase (ERDM) activity. 4. Both DAS and DADS increased the activity of GST and p-nitrophenol UDP-glucuronyltransferase (UDPGT 1), whereas UDPGT 2 activity was enhanced only by DAS.
Six organosulfur compounds found in garlic were examined for their ability to alter the growth of canine mammary tumor cells (CMT-13) in culture. Water-soluble organosulfur compounds (S-allyl-cysteine, S-ethyl-cysteine and S-propyl-cysteine) did not significantly alter the growth of CMT-13 cells when added to cultures at 1.0 mM or less. However, oil-soluble organosulfur compounds (diallyl sulfide, diallyl disulfide and diallyl trisulfide) markedly inhibited growth. Increasing addition of diallyl disulfide (DADS) resulted in a progressive decrease in CMT-13 cell growth. Addition of glutathione before DADS markedly decreased the severity of the growth inhibition. Treatment with DL-buthionine-SR-sulfoxamine, a specific inhibitor of glutathione synthesis, accentuated the growth inhibition caused by DADS. These studies show that some organosulfur compounds found in garlic are effective inhibitors of the growth of the neoplastic CMT-13 cell. The inhibitory effects of these compounds are modified by intracellular glutathione.
The present studies examined the impact of a processed garlic powder on the in vivo occurrence of DNA adducts caused by N-nitroso compounds (NOC) in rats. Addition of 2% garlic powder to diets containing aminopyrine and sodium nitrite (each at 600 mg/kg) reduced the occurrence of both 7-N-methyldeoxyguanosine (7-N-mG) and 6-O-methyldeoxyguanosine (6-O-mG) adducts to rat liver DNA by approximately 55%; and over 80% when 4% garlic was provided. Dietary supplementation with garlic powder (2 and 4%) also reduced the occurrence of 7-N-mG and 6-O-mG adducts by approximately 40 and 60% respectively, in rats intubated with N-nitrosodimethylamine (150 mg/kg body wt). The quantity of 7-N-mG and 6-O-mG adducts in mammary tissue of rats given intravenous N-methyl-N-nitrosourea (50 mg/kg body wt) was reduced over 50% in rats fed 2% garlic compared to controls. The depression in the occurrence of these adducts was approximately 70% when dietary garlic was increased to 4%. These experiments suggest the reduction in DNA adducts caused by processed garlic powder likely reflects a depression in the formation of NOC from precursors and changes in the bioactivation and/or denitrosation of NOC.
The present studies examined the anti-proliferative effects of diallyl disulfide (DADS) on the growth of human colon tumor cell line, HCT-15, xenografts in 6-wk-old female NCr nu/nu mice with an initial body weight of 20-22 g. Intraperitoneal injection of 1 mg DADS thrice weekly reduced tumor volume by 69% (P < 0.05) without apparent ill consequences such as altered growth of the host. Providing this quantity of DADS intragastrically also inhibited growth of the HCT-15 tumor. At equivalent DADS dosages, intraperitoneal treatment was proportionately more effective (P < 0.05) in reducing tumor growth than gastric intubation. Tumor inhibition caused by DADS (0.5 mg thrice weekly) was similar to that occurring with 5-fluorouracil (5-FU) treatment (0.5 mg thrice weekly). Combining DADS and 5-FU was no more effective in inhibiting tumor growth than using either compound alone. However, concurrent DADS treatment significantly (P < 0.05) inhibited the depression in leukocyte counts and spleen weight and prevented the elevated plasma urea caused by 5-FU treatment. These data suggest that DADS, a constituent of garlic oil, reduces the toxicity of 5-FU and is an effective antitumorigenic agent against xenografts resulting from an established human colon tumor cell line.
The present studies compared the effects of various oil-soluble compounds containing allyl and disulfide groups on the proliferation of cultured human colon tumor cells (HCT-15). Diallyl disulfide (DADS) was more effective in inhibiting the growth of HCT-15 cells than isomolar concentrations of S-allyl cysteine, dipropyl disulfide (DPDS), allyl chloride, allyl glycidyl ether and allyl alcohol. These studies clearly demonstrate the importance of both the diallyl and the disulfide groups in DADS. Treatment of HCT-15 cells with 100 microM DADS increased the intracellular calcium levels by 40%, while DPDS caused only a 12% increase in intracellular calcium. Exposure to 100 microM DADS or more, but not DPDS, caused the cells to undergo apoptosis as determined by morphological changes and DNA fragmentation. A positive correlation (r=0.944) was found between DADS-induced DNA fragmentation and its ability to increase intracellular free calcium levels. The widespread effectiveness of DADS was evident by its ability to inhibit the growth of human colon (HCT-15), skin (SK MEL-2) and lung (A549) tumor cell lines.
The modulation of CCl4-induced hepatotoxicity in response to alkyl sulfides and alkyl ethers including allyl disulfide (ADS), allyl sulfide (AS), allyl ether (AE), propyl disulfide (PDS), propyl sulfide (PS), propyl ether (PE) and butyl sulfide (BS) was studied. Whereas pretreatment of rats with either ADS or AS (50 mg/kg, 7 days) blocked a CCl4-induced increase in plasma alanine aminotransferase (ALT) activity by 91 and 56%, respectively, AE, PDS, PS, PE or BS treatment enhanced CCl4-induced ALT activity by 52, 55, 238, 25 or 86%, respectively. Histochemical examinations supported the results of plasma ALT activity. Injection of GdCl3 to PS-pretreated rats failed to block the potentiated ALT increase, whereas GdCl3 completely prevented vitamin A-enhanced elevation of ALT activity. AS treatment completely blocked PS-potentiated CCl4 intoxication. Concomitant treatment of animals with both PS and vitamin A followed by a CCl4 insult resulted in super-potentiation of CCl4-induced hepatotoxicity, suggesting that the mechanism of PS-enhanced hepatotoxicity differs from that caused by vitamin A. Pyridine or phenobarbital potentiation of CCl4-induced increases in ALT activity implys that cytochrome P450 2E1 (P450 2E1) and P450 2B expression may be associated with the increased toxicity. P450 2E1 expression appeared to be associated with the alkyl sulfide-modulated hepatotoxicity, as evidenced by both immunoblot analyses and metabolic activity. P450 2B immunoblot analysis revealed that either AS or PS substantially induced hepatic P450 2B1/2 levels. Thus, PS-enhanced CCL4 hepatotoxicity may be related in part with P450 2B induction. ADS, AS or PS treatment caused increases in the glutathione S-transferase (GST) conjugating activity toward 1-chloro-2,4-dinitro-benzene. ADS, AS or PS induced Ya and Yb1 subunits by 2- to 3-fold. ADS or AS treatment also significantly elevated the levels of Yc subunits. PS failed to induce Yc expression, although this agent effectively increased Yb2 expression. Northern blot analyses revealed that ADS and AS concomitantly stimulated GST Ya, Yb1 and Yc2 gene expression, whereas PS increased the levels of Ya, Yb1, and Yb2 mRNA, but not Yc2 mRNA levels. The expression of GST subunit Yc2 in response to these compounds might be associated with hepatoprotective effects. These results demonstrate that ADS and AS have distinct capability of blocking CCl4-induced hepatotoxicity, whereas certain saturated alkyl sulfides rather potentiate CCl4-induced hepatotoxicity and that the underlying mechanism is associated with P450 2E1 and P450 2B expression, and possibly with certain GST expression.
Most studies on garlic during the past 15 years have been primarily in the fields of cardiovascular and cancer research. Cardiovascular studies have been mainly related to atherosclerosis, where effects were examined on serum cholesterol, LDL, HDL, and triglycerides. Although the studies were not consistent in relation to the dosage, standardization of garlic preparations, and period of treatment, most findings suggest that garlic decreases cholesterol and triglycerides levels in patients with increased levels of these lipids. Lowering of serum lipids by garlic ingestion may decrease the atherosclerosis process. The other major beneficial effect of garlic is due to its antithrombotic actions. This field of garlic research has been extensively studied. Garlic extracts and several garlic constituents demonstrate significant antithrombotic actions both in vitro and in vivo systems. Allicin and adenosine are the most potent antiplatelet constituents of garlic because of their in vitro effects. Since both allicin and adenosine are rapidly metabolized in human blood and other tissues, it is doubtful that these compounds contribute to any antithrombotic actions in the body. In addition, ajoene also seems not to be an active antiplatelet principle, because it is not naturally present in garlic, garlic powders, or other commercial garlic preparations. Only a small amount of ajoene can be found in garlic oil-macerates; however, ajoene is being developed as a drug for treatment of thromboembolic disorders. Recent findings on the identification of potent enzyme inhibiting activities of adenosine deaminase and cyclic AMP phosphodiesterase in garlic extracts are interesting, and may have a significant role in the pharmacological actions in the body. Presence of such enzyme inhibitors in garlic may perhaps explain several clinical effects in the body, including the antithrombotic, vasodilatory, and anticancer actions. Epidemiological studies have suggested that garlic plays a significant role in the reduction of deaths caused by malignant diseases. This had led many investigators to examine garlic and garlic constituents for their antitumor and cytotoxic actions both in vitro and in laboratory animals. The data from these investigations suggest that garlic contains several potentially important agents that possess antitumor and anticarcinogenic properties. In summary, the epidemiological, clinical, and laboratory data have proved that garlic contains many biologically and pharmacologically important compounds, which are beneficial to human health from cardiovascular, neoplastic, and several other diseases. Numerous studies are in progress all over the world to develop effective and odorless garlic preparations, as well as to isolate the active principles that may be therapeutically useful.
The present studies compared the antiproliferative effects of diallyl trisulfide (DATS) and diallyl disulfide (DADS) on cultured human neoplastic (A549) and nonneoplastic (MRC-5) lung cells. Addition of 10 microM DATS reduced A549 growth by 47%, whereas 10 microM DADS decreased growth by only 20%. DATS treatment (10 microM) did not alter MRC-5 cell growth. DATS (10 microM) caused a marked and progressive increase in intracellular Ca2+ in A549 cells during the first four hours after treatment. Intracellular Ca2+ in A549 cells exposed to DATS returned to near control levels within one hour after refeeding complete medium without DATS. Exposure to 1 microM DATS for 24 hours significantly induced apoptosis, as indicated by increased DNA fragmentation. The ability of DATS and DADS to suppress neoplastic growth is consistent with increasing evidence that several garlic components have anticarcinogenic and antitumorigenic properties.
Most carcinogens require activation to electrophilic metabolites or species that generate reactive oxygen in order to initiate the tumorigenic process. These reactive intermediates can, in turn, be detoxified by endogenous enzyme systems that and in the protection of cells from either toxic or mutagenic product formation. The levels of many of these enzymes are elevated by numerous compounds found in the diet, or by antioxidants. Recent evidence describes the mechanism for this induction of carcinogen detoxication enzymes to be regulated at the transcriptional level. Nuclear transcription factors bound to sites common among these carcinogen detoxication genes are activated by as yet unknown signal transduction pathways. The activity of these nuclear transcription factors are modulated by pro- and antioxidant reagents, suggesting that a redox-sensitive component governs the induction of enzymes involved in carcinogen metabolism. In this review, evidence for the redox regulation of the genes encoding carcinogen detoxication enzymes is presented. Evidence is also presented suggesting the participation of nuclear factor kappa B (NF-kappa B), mitogen-activated protein (MAP) kinase, and basic leucine zipper (bZIP) proteins and their activation pathways in this induction.
The naturally occurring organosulfur compounds (OSCs) diallyl sulfide (DAS), diallyl disulfide (DADS), dipropyl sulfide (DPS), and dipropyl disulfide (DPDS) were studied with respect to their effects on hepatic, intestinal, renal, and pulmonary phase II drug metabolizing enzymes, i.e., glutathione S-transferase (GST), microsomal epoxide hydrolase (mEH), quinone reductase (QR), and UDP-glucuronosyltransferase (UGT). OSCs were administered po to male SPF Wistar rats. In addition to assays of total enzyme activity, the ability of OSCs to modify the levels of mEH and rGSTA1/A2, A3/A5, M1, M2, and P1 was assessed by Western blotting. Remarkably, DADS significantly increased all Phase II enzyme activities, except the pulmonary mEH. It was noteworthy that only DADS induced QR activity. DAS, DPS, and DPDS induced mEH, GST, and UGT activities in the liver. Interestingly, DAS, DPS, and DPDS significantly decreased renal GST activity. In the same manner, DAS, DPS, and DPDS decreased rGSTA1/A2 and A3/A5 levels in the kidney. Conversely, all OSCs were able to induce GST of alpha and mu classes in the liver. In the intestine, DADS and DAS increased rGSTA1/A2, M2, and P1, while rGSTA3/A5 and M2 were only increased by DADS. In addition, DADS induced rGSTP1 dramatically in the four tissues analyzed. DADS also increased the mEH levels in the liver, intestine, and kidney, while DAS and DPS moderately induced mEH level in the liver. This study brings additional insights into the effects of OSCs on Phase II enzymes and suggests that DADS could be a promising chemopreventive agent considering its pleiotropic capacity of induction.
Diallyl disulfide (DADS), a substance that is formed from the organosulfur compounds present in garlic, is known to increase tissue activities of the phase II detoxification enzymes quinone reductase (QR) and glutathione transferase (GT) in animals. In previous experiments, however, high doses of DADS were employed and only a limited range of tissues were examined. In the present studies, increased activities of QR and GT were recorded in the forestomach, glandular stomach, duodenum, jejunum, ileum, cecum, colon, liver, kidneys, spleen, heart, lungs, and urinary bladder of rats given DADS over a wide range of dose levels. Large variations in response were recorded among the different organs, with forestomach, duodenum, and jejunum being the most sensitive to enzyme induction by DADS. In these organs, significant increases in QR activity were observed at a dose of only 0.3 mg/kg/day. Such a dose level is close to that which may be achieved through human consumption of garlic, suggesting that induction of phase II enzymes may contribute to the protection that is afforded by this vegetable against cancer of the gastrointestinal tract in humans.
Garlic (Allium sativum) and onion (Allium cepa) are among the oldest of all cultivated plants. Additionally, both plants have been used as medicinal agents for thousands of years. Both garlic and onion have been shown to have applications as antimicrobial, antithrombotic, antitumor, hypolipidaemic, antiarthritic and hypoglycemic agents. In recent years, extensive research has focussed on the beneficial and medicinal properties of garlic and onions. In particular, the use of these agents in the treatment and prevention of cardiovascular disease and cancer is an area of considerable investigation and interest.
Phytochemicals present in the genus Allium have potential pharmacological effects, such as antimicrobial, antithrombotic, antitumor, hypolipidaemic and hypoglycemic activities. In this present study, we examined the effects of garlic and onion oils on human promyelocytic leukemia cells, HL-60. Incubation of HL-60 with garlic or onion oil (20 microg/ml) caused a marked suppression of HL-60 proliferation; the suppression was almost identical with those obtained by all-trans-retinoic acid (ATRA) or dimethyl sulfoxide (DMSO) used as positive controls. These oils induced the generation of nitroblue tetrazolium (NBT)-reducing activity, and about 20% of the HL-60 cells became NBT positive. CD11b, another marker of the differentiation of these cells, was also significantly induced by garlic oil or onion oil. The combination of garlic or onion oil with ATRA was more effective than either alone. These data suggest that garlic and onion oils have the ability to induce differentiation of HL-60 cells into those of the granulocytic lineage.
Induction of Phase 2 enzymes is an effective and sufficient strategy for achieving protection against the toxic and neoplastic effects of many carcinogens. It is proposed that the concept of Phase 2 enzymes as being responsible only for the conjugation of functionalized xenobiotics with endogenous cellular ligands such as glutathione (glutathione S-transferases) and glucuronic acid (UDP-glucuronosyltransferases) be expanded to include proteins with the following common characteristics: (a) coordinate induction by a broad range of chemical agents that all have the capacity to react with sulfhydryl groups; (b) possible regulation by common promoter elements; and (c) catalysis of reactions that lead to comprehensive protection against electrophile and reactive oxygen toxicities, by a wide variety of mechanisms. These mechanisms include: conjugation with endogenous ligands, chemical modification of reactive features of molecules that can damage DNA and other macromolecules, and generation or augementation of cellular antioxidants. In addition to the above conjugating enzymes, a provisional and partial list of Phase 2 proteins might include: NAD(P)H:quinone reductase, epoxide hydrolase, dihydrodiol dehydrogenase, gamma-glutamylcysteine synthetase, heme oxygenase-1, leukotriene B4 dehydrogenase, aflatoxin B1 dehydrogenase, and ferritin.