No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Red wine alcohol promotes quercetin absorption and directs its metabolism towards isorhamnetin and tamarixetin in rat intestine in vitro
British Journal of Pharmacology
Abstract
Moderate consumption of red wine has been associated with beneficial effects on human health, and this has been attributed to the flavonoid content. Factors that influence the bioavailability of this group of polyphenolic compounds are therefore important.
Using the rat cannulated everted jejunal sac technique, we have investigated the effect of alcohol on the intestinal absorption of quercetin and its 3-O-glucoside from red wine. Tissue preparations were incubated in whole or dealcoholised red wine, diluted 1 : 1 with Krebs buffer for 20 min at 37°C, after which the mucosa was removed and processed for HPLC analysis. Tissues exposed to red wine had significantly higher amounts of both quercetin (× −3; P<0.001) and quercetin-3-O-glucoside (× −1.5; P<0.01) associated with them, compared with sacs incubated in the dealcoholised equivalent. In addition, both tamarixetin (T) and isorhamnetin (I), in the mucosal tissue from sacs exposed to the whole wine, were significantly elevated approximately two fold (P<0.05; P<0.01, respectively).
Similar results were obtained when sacs were incubated in Krebs buffer containing a mixture of pure quercetin and quercetin-3-O-glucoside with or without alcohol, and, although effects on the apparent absorption of Q and Q-3-G were not so marked, concentrations of the metabolites quercetin-3-O-glucuronide and I were significantly increased by the presence of alcohol (P<0.01 and P<0.001, respectively).
It is therefore plausible that the moderate alcohol content of red wine contributes to its beneficial health effects in humans by both increasing the absorption of quercetin and quercetin-3-O-glucoside and by channelling their metabolism towards O-methylation to yield compounds (T and I), which have potential protective effects against cancer and cardiovascular diseases.
British Journal of Pharmacology (2006) 147, 765–771. doi:10.1038/sj.bjp.0706662
... The authors suggested that resveratrol metabolite concentrations were statistically higher after the DRW compared with RW intervention (P ¼ 0.002). However, it seems clear from a great number of recent studies that the cardiovascular effects of polyphenols are dependent on their bioavailability, and alcohol in RW may improve polyphenol availability by increasing its intestinal absorption or by delaying its excretion (2,3), indicating that RW intake should produce higher concentrations of urinary resveratrol metabolites than DRW ingestion. It is, therefore, reasonable to assume that the consumption of RW and DRW also should, at least, lead to similar concentrations of urinary resveratrol metabolites, despite the fact that the resveratrol content of RW is slightly higher than that of DRW as depicted in Table 1 of their article. ...
... Epidemiologic studies have shown that moderate intake of RW protects against cardiovascular diseases, and this effect has been attributed to polyphenols (2,3,8,9). However, Chiva-Blanch et al (1) noted that there was inadequate experimental evidence to implicate specific polyphenols in RW. ...
... One of the concerns raised in the letter by Yang et al was the actual concentrations of urinary polyphenols and their metabolites. We reported 24-h urinary excretion of total resveratrol metabolites only as a measure of intervention compliance because resveratrol metabolites have been previously described as a marker of wine consumption by our research group (2). After our study was published, an error was identified in the calculation of total resveratrol metabolites in 24-h urinary excretion. ...
... Furthermore, according to Faria et al. [5], there was an invivo transcellular transport of catechin, quercetin, and cyanidin-3-glucoside in the brain of a rat model. These compounds are antioxidants with potentially protective effects against cancer and cardiovascular diseases [6]. Evidence supporting antioxidant crossing of the blood-brain barrier can also be deduced from results of carotenoids evaluation in the human brains which showed that carotenoids including lutein, zeaxanthin, cryptoxanthin and carotenes were found in the brain of babies. ...
The brain is central to human and animal well-being but it requires a high amount of oxygen for its normal functioning and this makes it an organ highly vulnerable to oxidative stress damage. Therefore, for the promotion of normal physiological and cellular functions of the brain, antioxidant intake is very critical. This study investigated the antioxidant enzymatic activities in the brain by measuring activities of superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in connection with the circulating oxidative stress biomarkers of the serum and liver of New Zealand White rabbits supplemented with microalga Chlorella vulgaris biomass in addition to regular basal diets. The study involved a random distribution of 40 rabbits of eight weeks old into five experimental group using completely randomized design. The rabbits were observed for a period of 120 when they are being supplemented after which their blood, brain, and liver were collected for analyses. The results show that the total antioxidant capacity was higher in the brain of the supplemented rabbits (P<0.05). Although, there was no significant difference in the brain malondialdehyde concentrations, there were higher activities of antioxidant enzymes in the brain of the supplemented rabbits (P< 0.05). There was a lower concentration of the circulating malondialdehyde (MDA) in the serum and liver of the supplemented rabbits. The study concluded that Chlorella vulgaris intake led to reduced circulating malondialdehyde and increased activities of the brain antioxidant enzymes in the rabbits. The study indicated that the microalga Chlorella vulgaris contains antioxidant compounds that can cross the blood-brain barrier, which could be a very important therapeutic agent against oxidative stress-induced brain complications in animals and humans.
... Since the enzymes in the brush border are more glucose-specific, the absorbability of quercetin glucosides is rapid compared to other forms of glycosides such as rutin (quercetin-3-Orutinoside) which, via the actions of enzymes from the intestinal microflora, undergoes deglycosylation to form aglycone [60][61][62][63]. Literature has outlined the significance of solubility on quercetin bioavailability in several animal models (mice, rats, humans, pigs, and chickens), stating clearly that the solubility and bioavailability of quercetin can be improved when combined with substances such as alcohol [64], nondigestible oligosaccharides [65], or with a high-fat (17%) diet [66,67]. When quercetin is absorbed into the enterocytes, it is glucuronidated, sulfated, and methylated by UDP-glucuronosyl transferases (UGTs), sulfotransferases (SULTs), and catechol-O-methyl transferase (COMT), respectively, inhabited in the gut and hepatic cells. ...
The importance of gut health in animal welfare and wellbeing is undisputable. The intestinal microbiota plays an essential role in the metabolic, nutritional, physiological, and immunological processes of animals. Therefore, the rapid development of dietary supplements to improve gut functions and homeostasis is imminent. Recent studies have uncovered the beneficial effects of dietary supplements on the immune response, microbiota, gut homeostasis, and intestinal health. The application of citrulline (a functional gut biomarker) and quercetin (a known potent flavonoid) to promote gut functions has gained considerable interest as both bioactive substances possess anti-inflammatory, anti-oxidative, and immunomodulatory properties. Research has demonstrated that both citrulline and quercetin can mediate gut activities by combating disruptions to the intestinal integrity and alterations to the gut microbiota. In addition, citrulline and quercetin play crucial roles in maintaining intestinal immune tolerance and gut health. However, the synergistic benefits which these dietary supplements (citrulline and quercetin) may afford to simultaneously promote gut functions remain to be explored. Therefore, this review summarizes the modulatory effects of citrulline and quercetin on the intestinal integrity and gut microbiota, and further expounds on their potential synergistic roles to attenuate intestinal inflammation and promote gut health.
... Several attempts have been reported to enhance the oral bioavailability of quercetin and its derivatives that includes the development of various delivery systems such as liposomes, nano-dispersion, nano-/microemulsions, polymeric micelles, and self-emulsifying systems (Dario et al., 2016;Dian et al., 2014;Karadag, Ozcelik, & Huang, 2014;Karadag, Yang, Ozcelik, & Huang, 2013;Li et al., 2013;Ting, Jiang, Ho, & Huang, 2014;Vicentini, Vaz, Fonseca, Bentley, & Fonseca, 2011;Wong & Chiu, 2010). Also, the bioavailability of quercetin derivatives in pigs and rats is reported to be enhanced when administered together with high fat (17%) diet (Lesser, Cermak, & Wolffram, 2004), alcohol (Dragoni, Gee, Bennett, Valoti, & Sgaragli, 2006), or nondigestible oligosaccharides (Matsukawa et al., 2009). The bioavailability of isoquercitrin could be further enhanced by enzymatic α-oligoglucosylation of the sugar moiety as reported for α-glycosyl isoquercitrin formulation (Makino et al., 2009;Murota et al., 2010;Nyska et al., 2016). ...
Isoquercitrin has been drawing increasing commercial concern since it has better bioavailability than quercetin and displays a wide range of in-vivo and in-vitro pharmacological effects. The main objective of the present study was to evaluate the pharmacokinetics of the IQC-γCD inclusion complex in Sprague-Dawley (SD) rats and in a controlled non-randomized, double-blind, and crossover study among the healthy volunteers. For instance, in SD rats administrated with IQC-γCD formulation by oral gavage feeding (0.05 mM/Kg body weight) showed significantly higher bioavailability (P < 0.001) of the quercetin and its metabolites compared to quercetin (control) intake. Whereas, in healthy humans (n = 8) an acute administration of IQC-γCD molecular inclusion complex (0.47 mM; the doses corresponds to 2.34 mg quercetin equivalence/Kg body weight) significantly enhanced the plasma conjugated quercetin and its metabolites concentration (P < 0.0001), and exhibited a greater pharmacokinetic profile compared to quercetin embedded in dextrin (control) supplementation. The results indicate an improved bioavailability of quercetin and its metabolites of IQC-γCD inclusion complex compared to respective controls in both animals and humans, wherein intestinal epithelial enzyme lactase-phlorizin hydrolase preferably hydrolyze the isoquercitrin of IQC-γCD inclusion complex to conjugated quercetin and its glucuronides and/or sulfates metabolites. The results also support the useful future applications of IQC-γCD inclusion complex in food additives, health supplements, and functional beverages for health benefits.
... A lesser amount of it exists in leafy green vegetables and beans [6]. Red wine is shown to promote quercetin absorption and direct its metabolism toward isorhamnetin and tamarixetin [7]. Several studies have determined luteolin and isorhamnetin in red wine. ...
Objectives
The aim of this study was to seek potential natural compounds that can resist COVID-19 using computer virtual screening technology through molecular docking of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL hydrolytic enzyme (3CLpro) and angiotensin-converting enzyme 2 (ACE2).
Methods
Molecular docking was achieved by using the Autodock Vina software. The natural phytocompounds acting on 3CLpro and ACE2 were then selected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. This was followed by speculation on the mechanism of action of phytocompounds.
Results
Six potential natural anti–COVID-19 phytocompounds were selected and were evaluated for absorption, distribution, metabolism and excretion (ADME) and Lipinski rules. The content of the six phytocompounds in various fruits and vegetables was determined via a literature search. Red wine, Chinese hawthorn, and blackberry were recommended as supplements because they contained antiviral phytocompounds.
Conclusion
Red wine, Chinese hawthorn, and blackberry show promise for resisting COVID-19 and are thus recommended as supplements to prevent the infection of COVID-19 during its outbreak period.
... Kern et al. suggested that polyphenolrich apple juice extract has strong EGFRinhibitory properties and an antiproliferative effect on HT-29 (22). Another study demonstrated that flavonoids of red wine have positive effects on individual human organs and methylate the biological compounds to yield products with potentially protective effects against cancer (23). Also, the anti-cancer effects of isoquercetin on colon cancer cells have been proved, whereas it has no significant influence on nontumor colon cells (24). ...
Background: Natural products derived from various sources are being used to develop chemotherapeutic drugs. Euphorbiaceae is widely used to treat different types of cancers. Colorectal cancer (CRC) is the second and third cause of cancer in women and men, respectively. CRC is strongly associated with the deregulation of the Adenomatous polyposis coli (APC) gene and Poly [ADP-ribose] polymerase (PPAR) protein. Objectives: The current study aimed to examine the effect of doxorubicin, ethanol extract, and the flavonoid-rich fraction of Euphorbia Splendida Mobayen on colon cancer HT-29 cell line death, APC gene expression, and PPAR concentration. Methods: Following treatment of cells by Euphorbia ethanol extract, Euphorbia flavonoid-rich fraction, and doxorubicin, cell viability assay was used to investigate the viability status of the HT-29 cell line. Total RNA was isolated from the cell line and converted into cDNA. The expression level of the APC gene was determined by quantitative real-time PCR. Poly (ADP-ribose) polymerase (PPAR) protein was detected by the ELIZA method. Results: We found that Euphorbia ethanol extract, Euphorbia flavonoid-rich fraction, and doxorubicin can stimulate dose-dependent cell death in the HT-29 cell line, increase ACP gene expression (P = 0.001, P = 0.041, P = 0.019), and decrease PARP level (P = 0.001, P = 0.001, P = 0.001, respectively). Conclusions: The findings indicated that doxorubicin, ethanol extract, and the flavonoid-rich fraction of Euphorbia Splendida Mobayen had cytotoxic effects on human colon cancer HT-29 cell line by possibly stimulating apoptosis.
... Other factors that may affect flavonoid absorption are food matrix (ethanol, fat, and emulsifiers) interactions [39], food processing, host age, occurrence of particular diseases, and lifestyle [40]. Quercetin bioavailability, for instance, is characterised by a substantial interindividual variation, which might turn out in different biological responses [23]. ...
Substantial experimental evidences support the hypothesis that dietary flavonoid intake has a favourable impact on cardiovascular diseases such as systemic, arterial hypertension and coronary artery diseases, which represent the leading cause of morbidity and mortality worldwide. The biological effects of flavonoids involve complex biochemical interactions with numerous, specific, cellular and molecular targets. K+ channels, fine modulators of both cardiac action potential and vascular cell membrane potential, represent one of these targets. Overexpression, downregulation or dysfunction of these channel proteins are the cause of many cardiovascular diseases. Therefore, it appears of particular interest a detailed analysis of the flavonoid potential, direct/indirect modulation of cardiovascular K+ channels as these natural compounds ingested with the diet, despite extensive gut metabolism, may accumulate at cellular level in the form of the parent aglycones. The present review will portray their effects on cardiovascular K+ channels. Molecular docking was used to strengthen experimental evidences and describe flavonoid-channel interactions at molecular level.
... 46 It reduces the prevalence of metabolic syndrome in an elderly Mediterranean population at high cardiovascular risk 47 and halves the risk of metabolic syndrome in women compared with non-drinkers. 48 The ethanol contained in wine improves the absorption of flavonoids (Fvs), 49,50 increases the degree of HDL cholesterol and reduces aggregation of blood platelets. 51 In another study, ethanol increased lipo-peroxidation and decreased antioxidants serum parameters; however, some of these changes appear to be thinner when ethanol was consumed as beer or wine. ...
... Their liquors were prepared from fresh fruit mixed with 65% ethanol at a mass ratio of 1:1 and macerated for 21 days at ambient temperature without light access [88]. According to Dragoni et al., alcohol promotes a higher absorption of quercetin in wine [89]. A similar property should be noted for Cornelian cherry liquor. ...
Cornus mas, also known as the Cornelian cherry, is a plant that grows in Eastern Europe and the Middle East. Its green leaves and reddish oval fruits are associated with many beneficial properties such as antioxidative and anti-inflammatory effects. These features are driven by the rich polyphenolic composition, with anthocyanins and iridoids in Cornelian cherry fruits as well as flavonoids and phenolic acids in leaves. The antioxidant behavior as well as the composition significantly depends on the cultivar of the plant and its genotype. The functional properties of Cornelian cherry have been recognized in many in vitro and toxicological studies. Cornus mas fruits and their extracts have been found to have significant antiatherogenic, anti-inflammatory, and neuroprotective effects. The beneficial effect of C. mas fruits as a food component has been determined in numerous papers focused on functional food. However, there is no information in existing literature about C. mas leaves in functional food applications. This paper presents the results of current studies including their synthesis to answer the question whether the Cornelian cherry exhibits positive properties due to its bioactive compound content.
... Since the brush border enzymes are specific for glucose, quercetin glucosides are absorbed more quickly than other types of glycosides, for example, rutin (quercetin-3-O-rutinoside), which can only be deglycosylated to quercetin aglycone by enzymes from the gut microbiota (Arts, Sesink, Faassen-Peters, & Hollman, 2004;Cermak, Landgraf, & Wolffram, 2003;Reinboth, Wolffram, Abraham, Ungemach, & Cermak, 2010;Russo et al., 2012). The importance of solubility is apparent from studies on the bioavailability of quercetin in pigs, rats, and humans, which can be enhanced when administered in combination with a high-fat (17%) diet Lesser, Cermak, & Wolffram, 2004), alcohol (Dragoni, Gee, Bennett, Valoti, & Sgaragli, 2006), or with nondigestible oligosaccharides (Matsukawa et al., 2009). After absorption by enterocytes, quercetin is glucuronidated by UDPglucuronosyl transferases (UGTs), sulfated by sulfotransferases (SULTs), and/or methylated by catechol-O-methyl transferase (COMT) present in intestinal and hepatic cells (Figure 1). ...
After consumption of plant‐derived foods or beverages, dietary polyphenols such as quercetin are absorbed in the small intestine and metabolized by the body, or they are subject to catabolism by the gut microbiota followed by absorption of the resulting products by the colon. The resulting compounds are bioavailable, circulate in the blood as conjugates with glucuronide, methyl, or sulfate groups attached, and they are eventually excreted in the urine. In this review, the various conjugates from different intervention studies are summarized and discussed. In addition, the substantial variation between different individuals in the measured quercetin bioavailability parameters is assessed in detail by examining published human intervention studies where sources of quercetin have been consumed in the form of food, beverages, or supplements. It is apparent that most reported studies have examined quercetin and/or metabolites in urine and plasma from a relatively small number of volunteers. Despite this limitation, it is evident that there is less interindividual variation in metabolites which are derived from absorption in the small intestine compared to catabolites derived from the action of microbiota in the colon. There is also some evidence that a high absorber of intact quercetin conjugates could be a low absorber of microbiota‐catalyzed phenolics, and vice versa. From the studies reported so far, the reasons or causes of the interindividual differences are not clear, but, based on the known metabolic pathways, it is predicted that dietary history, genetic polymorphisms, and variations in gut microbiota metabolism would play significant roles. In conclusion, quercetin bioavailability is subject to substantial variation between individuals, and further work is required to establish if this contributes to interindividual differences in biological responses.
... metabolism and ameliorate bioavailability of flavonoids. Premise of full exploitation of their health benefit in disease prevention and therapy should be: i) use of absorption enhancers (e.g., ethanol for quercetin; Dragoni et al., 2006); ii) novel delivery systems (e.g. nanodevices; Gormaz et al., 2015;Guo and Bruno, 2015;Leonarduzzi et al., 2010); iii) synthesis of flavonoid pro-drugs (Biasutto and Zoratti, 2014;Hu et al., 2016;Kim et al., 2010); iv) change the site of absorption (Grande et al., 2016;Russo et al., 2012;Thilakarathna and Rupasinghe, 2013). ...
Ion channels underlie a wide variety of physiological processes that involve rapid changes in cell dynamics, such as cardiac and vascular smooth muscle contraction. Overexpression or dysfunction of these membrane proteins are the basis of many cardiovascular diseases that represent the leading cause of morbidity and mortality for human beings. In the last few years, flavonoids, widely distributed in the plant kingdom, have attracted the interest of many laboratories as an emerging class of fine ion, in particular Cav, channels modulators. Pieces of in vitro evidence for direct as well as indirect effects exerted by various flavonoids on ion channel currents are now accumulating in the scientific literature. This activity may be responsible, at least in part, for the beneficial and protective effects of dietary flavonoids toward cardiovascular diseases highlighted in several epidemiological studies. Here we examine numerous studies aimed at analysing this feature of flavonoids, focusing on the mechanisms that promote their sometimes controversial activities at cardiovascular Cav channels. New methodological approaches, such as molecular modelling and docking to Cav1.2 channel α1c subunit, used to elucidate flavonoids intrinsic mechanism of action, are introduced. Moreover, flavonoid-membrane interaction, bioavailability, and antioxidant activity are taken into account and discussed.
... When comparing the changes in lipid profiles, grape juice consumption decreased plasma TG concentrations in only the nondiabetic participants, although insulin concentrations decreased in diabetics who consumed dealcoholized wine compared with baseline. One strength of this study is that it tested standard wine along with dealcoholized wine, which is important because alcohol can be a potential confounding factor by affecting health outcomes and/or bioavailability (30,31). Although the authors did not report the phenolic compounds in the test beverages, an analysis elsewhere suggests that 150 mL of the wine could contain ;443 mg total phenolic compounds, including 6 mg gallic acid (32). ...
Interest in the application of phenolic compounds from the diet or supplements for the prevention of chronic diseases has grown substantially, but the efficacy of such approaches in humans is largely dependent on the bioavailability and metabolism of these compounds. Although food and dietary factors have been the focus of intense investigation, the impact of disease states such as obesity or diabetes on their absorption, metabolism, and eventual efficacy is important to consider. These factors must be understood in order to develop effective strategies that leverage bioactive phenolic compounds for the prevention of chronic disease. The goal of this review is to discuss the inducible metabolic systems that may be influenced by disease states and how these effects impact the bioavailability and metabolism of dietary phenolic compounds. Because current studies generally report that obesity and/or diabetes alter the absorption and excretion of these compounds, this review includes a description of the absorption, conjugation, and excretion pathways for phenolic compounds and how they are potentially altered in disease states. A possible mechanism that will be discussed related to the modulation of phenolic bioavailability and metabolism may be linked to increased inflammatory status from increased amounts of adipose tissue or elevated plasma glucose concentrations. Although more studies are needed, the translation of benefits derived from dietary phenolic compounds to individuals with obesity or diabetes may require the consideration of dosing strategies or be accompanied by adjunct therapies to improve the bioavailability of these compounds.
... Other food components can also have effects on polyphenol uptake. Anthocyanin uptake was similar from red wine or its dealcoholised form (33) but alcohol has been suggested to increase quercetin uptake from red wine (37) . ...
Polyphenols are ubiquitous secondary products present in many plant foods. Their intake has been associated with health benefits ranging from reduced incidence of CVD, diabetes and cancers to improved neurodegenerative outcomes. Major dietary sources include beverages such as coffee, teas and foods such as chocolate. Fruits are also major sources and berries in particular are a palatable source of a diverse range of polyphenol components. There are a number of ways that polyphenol uptake could be increased and healthier polyphenol-rich foods could be produced with specific compositions to target-specific health effects. Firstly, we could exploit the genetic diversity of plants (with a focus on berries) to select varieties that have enhanced levels of specific polyphenols implicated in disease mitigation (e.g. anthocyanins, tannins or flavonols). Working with variation induced by environmental and agronomic factors, modern molecular breeding techniques could exploit natural variation and beneficially alter polyphenol content and composition, although this could be relatively long term. Alternatively, we could employ a synthetic biology approach and design new plants that overexpress certain genes or re-deploy more metabolic effort into specific polyphenols. However, such 'polyphenol-plus' fruit could prove unpalatable as polyphenols contribute to sensorial properties (e.g. astringency of tannins). However, if the aim was to produce a polyphenol as a pharmaceutical then 'lifting' biosynthetic pathways from plants and expressing them in microbial vectors may be a feasible option. Secondly, we could design processing methods to enhance the polyphenolic composition or content of foods. Fermentation of teas, cocoa beans and grapes, or roasting of cocoa and coffee beans has long been used and can massively influence polyphenol composition and potential bioactivity. Simple methods such as milling, heat treatment, pasteurisation or juicing (v. pureeing) can have notable effects on polyphenol profiles and novel extraction methods bring new opportunities. Encapsulation methods can protect specific polyphenols during digestion and increase their delivery in the gastrointestinal tract to target-specific health effects. Lastly we could examine reformulation of products to alter polyphenol content or composition. Enhancing staple apple or citrus juices with berry juices could double polyphenol levels and provide specific polyphenol components. Reformulation of foods with polyphenol-rich factions recovered from 'wastes' could increase polyphenol intake, alter product acceptability, improve shelf life and prevent food spoilage. Finally, co-formulation of foods can influence bioavailability and potential bioactivity of certain polyphenols. Within the constraints that certain polyphenols can interfere with drug effectiveness through altered metabolism, this provides another avenue to enhance polyphenol intake and potential effectiveness. In conclusion, these approaches could be developed separately or in combination to produce foods with enhanced levels of phenolic components that are effective against specific disease conditions.
... When ethanol is administered with phenolic compounds it displays a dual role. On the one hand, it has been proposed that ethanol present in red wine could promote the absorption of flavonoids (Dragoni et al., 2006). In the case of Tyr, studies with rats show that the urinary recovery of this phenolic compound is enhanced following ethanol administration, a fact that is compatible with an increase in its bioavailability. ...
Hydroxytyrosol and tyrosol are dietary phenolic compounds present in virgin olive oil and wine. Both compounds are also endogenously synthesized in our body as byproducts of dopamine and tyramine metabolisms, respectively. Over the last decades, research into hydroxytyrosol and tyrosol has experienced an increasing interest due to the role that these compounds may play in the prevention of certain pathologies (e.g. cardiovascular, metabolic, neurodegenerative diseases and cancer). The translation of promising in vitro and in vivo biological effects from preclinical studies to the context of human disease prevention initially depends on whether the dose ingested becomes available at the site of action. In this regard, information regarding the bioavailability and metabolic disposition of hydroxytyrosol and tyrosol is of most importance to evaluate the impact they may have on human health. In this review, we discuss and summarize the state of the art of the scientific evidence regarding the processes of absorption, distribution, metabolism and excretion of both hydroxytyrosol and tyrosol. We also examine the impact of these compounds and their metabolites on biological activity in terms of beneficial health effects. Finally, we evaluate the different analytical approaches that have been developed to measure the plasma and urinary levels of hydroxytyrosol, tyrosol and their metabolites.
... In 2005, Kern et al [80] reported a perspective on the antiproliferative effect and demonstrated the potent EGFRinhibitory properties of polyphenolrich apple juice extract in adenocarcinoma colon in vitro model (HT29) [80] . Another study suggested that the beneficial effects of red wine on human health were attributable to the flavonoid content, which channeled the body metabolism towards Omethylation to yield compounds with potential protective effects against cancer [81] . ...
This review was based on a literature search of PubMed and Scielo databases using the keywords "quercetin, rutin, isoquercitrin, isoquercitin (IQ), quercetin-3-glucoside, bioavailability, flavonols and favonoids, and cancer" and combinations of all the words. We collected relevant scientific publications from 1990 to 2015 about the absorption, bioavailability, chemoprevention activity, and treatment effects as well as the underlying anticancer mechanisms of isoquercitin. Flavonoids are a group of polyphenolic compounds widely distributed throughout the plant kingdom. The subclass of flavonols receives special attention owing to their health benefits. The main components of this class are quercetin, rutin, and IQ, which is a flavonoid and although mostly found as a glycoside, is an aglycone (lacks a glycoside side chain). This compound presents similar therapeutic profiles to quercetin but with superior bioavailability, resulting in increased efficacy compared to the aglycone form. IQ has therapeutic applications owing to its wide range of pharmacological effects including antioxidant, antiproliferative, anti-inflammatory, anti-hypertensive, and anti-diabetic. The protective effects of IQ in cancer may be due to actions on lipid peroxidation. In addition, the antitumor effect of IQ and its underlying mechanism are related to interactions with Wnt signaling pathway, mixed-lineage protein kinase 3, mitogen-activated protein kinase, apoptotic pathways, as well proinflammatory protein signaling. This review contributed to clarifying the mechanisms of absorption, metabolism, and actions of IQ and isoquercitrin in cancer.
... The concentration of total polyphenols in FDRW was expressed as μg of GAE/mL. As previously observed by Dragoni et al. (2006), the total polyphenol content of both red wine and FDRW samples were comparable (2.99 and 3.03 g/ L of GAE; respectively). GTN (1% in alcohol; from Polichimica s.r.l, Bologna, Italy) was diluted daily in ethanol. ...
Chronically administered organic nitrates induce nitrate tolerance and endothelial dysfunction, which limit their therapeutic use. eNOS uncoupling, ROS over-production, aldehyde dehydrogenase-2 as well as superoxide dismutase (SOD) oxidative inhibition, and cGMP desensitization are thought to play an important role. Natural polyphenols are effective antioxidants, which might counteract the mechanisms leading to nitrate tolerance. The aim of this work was to verify whether freeze-dried (dealcoholized) red wine (FDRW) was able to revert glyceryl trinitrate (GTN) tolerance and endothelial dysfunction induced in rat aorta rings with either GTN or diethyldithiocarbamate (DETCA), an irreversible inhibitor of Cu/Zn SOD. GTN induced a concentration-dependent relaxation of rings pre-contracted with phenylephrine. GTN spasmolysis was significantly reduced in rings pre-incubated with either GTN or DETCA. FDRW, at 2.8 µg of gallic acid equivalents (GAE)/mL concentration, was able to revert partially, though significantly, GTN-induced tolerance but not tolerance and endothelial dysfunction induced by DETCA. This work provides the first evidence in vitro that red wine components, at concentrations comparable to those achieved in human blood after moderate consumption of red wine, revert tolerance to nitrates with a mechanism possibly mediated by SOD. Copyright © 2015 John Wiley & Sons, Ltd.
... Because cells in the small intestine exhibit glucoside-hydrolyzing activity, the small intestine possibly acts as an absorption site for flavonoids. 58 It is of much interest for quercetin that moderate alcohol intake promotes the absorption of quercetin in rat intestines, 59 which is advantageous, as it allows red wine to display the potential health benefits of flavonoid components. ...
Background: In order to understand the antiproliferative effect of red wine in mechanistic terms, the membrane interactions of flavonoid components and their related structures were compared using liposomal biomimetic membranes prepared with different phospholipids and cholesterol. Methods and results: A series of fluorescence polarization measurements revealed that anthocyanidins, flavones, flavonols, flavanones, flavanonols, isoflavones, catechins, and chalcones interact with biomimetic membranes in a structure-dependent manner to decrease their fluidity at concentrations of 1-10 μM by preferentially acting in the deeper regions of the lipid bilayers. In the structure and membrane interactivity relationship, greater membraneinteracting potency was associated with a 3-hydroxyl group and a double bond between the 2-carbon and 3-carbon of the C ring, 3',4'-dihydroxyl groups of the B ring, and 5,7-dihydroxyl groups of the A ring. Cyanidin, quercetin, and (-)-epigallocatechin gallate meet these structural requirements, and were effective in inhibiting the proliferation of tumor cells, showing inhibition rates of 16.4% and 35.4%, 23.3% and 74.3%, and 31.3% and 75.5%, respectively, after culture for 24 and 48 hours. These antiproliferative flavonoids simultaneously decreased the membrane fluidity of tumor cells depending on culture time. The rank order of cell membrane rigidification [(-)-epigallocatechin gallate > quercetin > cyanidin] was consistent with inhibition of cell proliferation. Conclusion: Membrane interaction is very likely to underlie the antiproliferative effects of wine flavonoids. Membrane-interactive flavonoid components would contribute to the functionality of red wine.
... Methylation is extensive in rats [130], but likely of less importance in humans [121]. The methylation rate is affected by other components of the diet [49]. ...
... A good proportion of flavonols is absorbed in the intestinal tract. Quercetin is predominantly present in wine as quercetin-βglycoside; it is absorbed in larger quantities in the rat intestine when ethanol is present [40]. In addition, low levels of quercetin-3-O-rhamnoglucoside (rutin) and quercetin-3-O-rhamnoside (quercitrin) are also found in wine [41], and can be hydrolyzed to quercetin only by α-rhamnosidases from colonic microflora in the large intestine [42]. ...
Influence of wine phenolic components on intestinal cell function. The scheme summarized the main activities of phenolics, which are the predominant non-alcoholic components of wine. They can interfere with the development of inflammatory intestinal diseases and colorectal cancer. Phenolics multiple properties are due to both direct antioxidant effects and indirect activation of redox-sensitive cell pathways involved in negative regulation of inflammation and immune modulation.
Furthermore, microbiota plays a role in phenolics activity: it is essential for their metabolism, enabling them to reach highest concentrations in the gut. Diversity of phenolic composition is a reflection of interindividual variation in colonic microflora; on the other hand, phenolics act as prebiotics, increasing microflora growth.
Ethanol matrix has an undoubted role in the impact of wine on intestinal functions. Despite the well-known deleterious consequences of high ethanol consumption, it has been proved that small concentrations of ethanol are able to act as cell signals, and influence microbiota growth together with phenolics.
Figure optionsDownload full-size imageDownload as PowerPoint slide
... However, later studies demonstrated that quercetin glycosides exhibit higher bioavailability than the aglycone (Hollman et al., 1995(Hollman et al., , 1997(Hollman et al., , 1996 while quercetin glucosides are absorbed more rapidly than other types of glycosides such as rutin (Arts et al., 2004;Cermak et al., 2003;Reinboth et al., 2010;Russo et al., 2012). The bioavailability of isoquercitrin (and quercetin) in pigs and rats can be increased when administred together with a high fat (17%) diet (Lesser et al., 2004), alcohol (Dragoni et al., 2006) or nondigestible oligosaccharides (Matsukawa et al., 2009). ...
The flavonoid isoquercitrin (quercetin-3-O-β-d-glucopyranoside) is commonly found in medicinal herbs, fruits, vegetables and plant-derived foods and beverages. This article reviews the occurrence, preparation, bioavailability, pharmacokinetics, toxicology and biological activity of isoquercitrin and "enzymatically modified (α-glucosylated) isoquercitrin" (EMIQ). Pure isoquercitrin can now be obtained on a large scale by enzymatic rutin hydrolysis with α-L-rhamnosidase. Isoquercitrin has higher bioavailability than quercetin and displays a number of chemoprotective effects both in vitro and in vivo, against oxidative stress, cancer, cardiovascular disorders, diabetes and allergic reactions. Although small amounts of intact isoquercitrin can be found in plasma and tissues after oral application, it is extensively metabolized in the intestine and the liver. Biotransformation of isoquercitrin includes deglycosylation, followed by formation of conjugated and methylated derivatives of quercetin or degradation to phenolic acids and carbon dioxide. The acceptable daily intake of (95%) isoquercitrin and of EMIQ was estimated to be 5.4 and 4.9mg/kg/day, respectively. Adverse effects of higher doses in rats included mostly (benign) chromaturia; nevertheless some drug interactions may occur due to the modulation of the activity and/or expression of drug metabolizing/transporting systems. With respect to the safety, affordability and beneficial pharmacological activities, highly pure isoquercitrin is a prospective substance for food supplementation.
... For example, quercetin and baicalein are two typical flavonoids that utilize the passive diffusion mechanism (Nait Chabane et al., 2009;Zhang et al., 2007); some transporters, including organic anion transporting peptide (OATP), P-glycoproteins (P-gp) and multidrug resistance proteins (MRPs), have been proven to participate in the absorption of these two flavonoids (Akao et al., 2007;Li et al., 2012a;Walgren et al., 2000 et al., 2012). Meanwhile, quercetin could be transformed into isorhamnetin in vitro (Dragoni et al., 2006) through a process possibly involving catechin-O-transferase (Cornish et al., 2002). Therefore, isorhamnetin's absorption mechanism most likely differs from that of quercetin, similar to baicalein and its displayed metabolite (Zhang et al., 2007). ...
Flavonoid isorhamnetin occurs in various plants and herbs, and demonstrates various biological effects in humans. This work will clarify the isorhamnetin absorption mechanism using the Caco-2 monolayer cell model. The isorhamnetin transport characteristics at different concentrations, pHs, temperatures, tight junctions and potential transporters were systemically investigated. Isorhamnetin was poorly absorbed by both passive diffusion and active transport mechanisms. Both trans- and paracellular pathways were involved during isorhamnetin transport. Active transport under an ATP-dependent transport mechanism was mediated by the organic anion transporting peptide (OATP); isorhamnetin's permeability from the apical to the basolateral side significantly decreased after estrone-3-sulfate was added (p < 0.01). Efflux transporters, P-glycoproteins (P-gp), breast cancer resistance proteins (BCRP) and multidrug resistance proteins (MRPs) participated in the isorhamnetin transport process. Among them, the MRPs (especially MRP2) were the main efflux transporters for isorhamnetin; transport from the apical to the basolateral side increased 10.8-fold after adding an MRP inhibitor (MK571). This study details isorhamnetin's cellular transport and elaborates isorhamnetin's absorption mechanisms to provide a foundation for further studies.
... As previously observed by Dragoni et al. (2006), the total polyphenol content of the red wine and the FDRW samples were comparable (2.99 and 3.03 g/L of GAE; respectively). ...
The effect of freeze-dried red wine (FDRW) on cardiac function and electrocardiogram (ECG) in Langendorff-isolated rat hearts was investigated. FDRW significantly decreased left ventricular pressure and coronary perfusion pressure, the latter being dependent on the activation of both phosphatidylinositol 3-kinase and eNOS. FDRW did not affect the QRS and QT interval in the ECG, although at 56 μg of gallic acid equivalents/mL, it prolonged PQ interval and induced a second-degree atrioventricular block in 3 out of 6 hearts. This is the first study demonstrating that at concentrations resembling a moderate consumption of red wine, FDRW exhibited negative inotropic and coronary vasodilating activity leaving unaltered ECG, whereas at very high concentrations, it induced arrhythmogenic effects.
... The everted gut sac system was first reported for the study of the transport of glucose and amino acids across rat and hamster intestine [26]. With the everted sac technique, the intestine is everted and either closed on both sides actually creating a closed sac [27] or canulated on both sides and perfused [28]. Under optimal conditions the tissue is viable for up to two hours, and the system is predominantly used for studying drug absorption mechanisms, intestinal metabolism of drugs, roles of transporter in drug absorption, and for investigating the role of intestinal enzymes during drug transport through the intestine [29]. ...
... Similarly, Pace-Asciak et al. [35] found that platelet aggregation was strongly inhibited by RW and moderately inhibited by GJ. Thus, the most pronounced effects observed in rats that received RW may be associated with the presence of ethanol [60]. It is important to point out, that in contrast with some studies, when the ethanol was tested alone no alteration in the ectonucleotidases activities and platelet aggregation was observed in our study [56,61]. ...
This study investigated the ex vivo effects of the moderate red wine (RW) and grape juice (GJ) consumption, and the in vitro effects of the resveratrol, caffeic acid, gallic acid, quercetin, and rutin on NTPDase (nucleoside triphosphate diphosphohydrolase), ecto-nucleotide pyrophosphatase/phosphodiesterase (E-NPP), 5'-nucleotidase, and adenosine deaminase (ADA) activities in platelets and platelet aggregation from streptozotocin-induced diabetic rats. The animals were divided into six groups (n = 10): control/saline, control/GJ, control/RW, diabetic/saline, diabetic/GJ, and diabetic/RW. RW and GJ were administered for 45 days; after this period, the blood was collected for experimental determinations. Results showed that NTPDase, E-NPP, 5'-nucleotidase, and ADA activities as well as platelet aggregation were increased in the diabetic/saline group compared to the control/saline group. Treatment with RW and GJ increased ectonucleotidases activities and prevented the increase in the ADA activity in the diabetic/GJ and diabetic/RW groups. Platelet aggregation was also decreased by the treatment with RW and GJ in the diabetic/GJ and diabetic/RW groups. In the in vitro tests, resveratrol, caffeic acid, and gallic acid increased ATP, ADP, and AMP hydrolysis, while quercetin and rutin decreased the hydrolysis of these nucleotides in platelets of diabetic rats. The ADA activity and platelet aggregation were reduced in platelets of diabetic rats in the presence of all polyphenols tested in vitro. These findings suggest that RW, GJ, and all polyphenols tested were able to modulate the ectoenzymes activities. Moreover, a decrease in the platelet aggregation was observed and it could contribute to the prevention of platelet abnormality, and consequently vascular complications in diabetic state.
... Quercetin is thus more bioavailable than resveratrol. In terms of wine consumption, de Vries and others (2001) questioned whether wine is a significant source of quercetin, although alcohol has been shown to increase quercetin absorption in a rate model (Dragoni and others 2006). The minor contribution of quercetin from wine or grape products is supported by Davalos and others (2006), who reported that quercetin from a glass of grape juice is bioavailable, but only leads to a small increase in plasma quercetin compared to ingestion of onions. ...
Functional foods may be regarded as foods that have nutritional value, but in particular, they also have beneficial effects on one or more body functions. Thus, functional foods may improve health and/or reduce the risk of developing certain diseases when taken in amounts that can be consumed in a normal diet. Based on nearly 2 decades of research since the term “French paradox” was first coined in 1992, wine would appear to fit this definition. Yet there seems to be reluctance to consider wine as a functional food. In this review, we present an overview of the accumulated evidence for the health benefits of wine—and its key phenolic components such as resveratrol, quercetin, catechin—and show that these alone are not enough to firmly establish wine as a functional food. What is required is to create clearly defined products based on wine that are targeted to consumers’ needs and expectations when it comes to purchasing functional foods. Moreover, the crucial question of alcohol and health also needs to be addressed by the functional food industry. Suggestions are presented for working through this issue, but in many regards, wine is like any other food—it should be consumed sensibly and in amounts that are beneficial to health. Overindulgence of any kind does not promote good health.
... It is well known that moderate consumption of wine may prevent some types of cancers [28][29][30]. These studies concerning wine consumption suggested that anti-oxidant agents, such as polyphenols, including catekin, quercetin and resveratrol, contributed to the cancer-preventive effect of wine [31]. Thus, anti-oxidant agents seem to play a key role in the beneficial effects of wine. ...
... Although numerous animal studies have shown that dopamine does not play a critical role in maintaining alcohol consumption (Dragoni et al., 2006;Fumagalli et al., 2006;Oniciu et al., 2006), 0376-8716/$ -see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. ...
Alcohol cues can precipitate the desire to drink and cause relapse in recovering alcohol-dependent patients. Serotonin and dopamine may play a role in alcohol cue-induced craving. Acute combined tryptophan (Trp), tyrosine (Tyr), and phenylalanine (Phe) depletion (CMD) in the diet attenuates the synthesis of serotonin and dopamine in the human brain. However, no study of the effects of acute CMD has been previously conducted. Therefore, we investigated whether the attenuation of serotonin and dopamine synthesis changes cue-induced alcohol craving in recently abstinent alcoholics.
In this double-blind, randomized, placebo-controlled, crossover design, 12 male patients who met the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for alcohol dependence were divided into two conditions: (1) monoamine depletion (i.e., consumption of a concentrated amino acid beverage that resulted in a rapid and significant decrease in plasma-free Tyr/Phe/Trp) and (2) balanced condition (i.e., consumption of a similar beverage that contained Tyr/Phe/Trp). The participants were scheduled for two experimental sessions, with an interval of ≥7 days. The cue-induced craving test session was conducted 6h after each amino acid beverage administration. Drinking urge, blood pressure, heart rate, working memory, and attention/psychomotor performance were assessed before and after administration.
Compared with the balanced condition, the monoamine depletion condition significantly increased drinking intention/desire and diastolic blood pressure. Cognitive performance was not different between the two conditions.
Acute combined serotonin and dopamine depletion may increase drinking intention/desire and diastolic blood pressure without influencing cognitive function.
Tamarixetin and its glycosides are widely distributed in natural plants, and they are also natural flavonoid derivatives of quercetin. Its main pharmacological effects include antioxidant, anti-inflammatory, antiviral, anticancer, cardiovascular effects, etc. The pharmacokinetics showed that the distribution of direct absorption differed from that of biosynthesis. At the same time, research shows that tamarixetin is safe to use because it has little self-toxicity. In this paper, 181 articles on tamarixetin published from 1976 to 2023 are obtained from PubMed, China Knowledge Base Database, Wanfang Data, and other electronic databases. Tamarixetin is searched based on keywords, and 121 articles remain. Transformation synthesis, pharmacokinetics, pharmacological action, and structure-activity relationship of tamarixetin were reviewed.
O livro enfatiza fatores que regem a vida humana do início ao fim e que podem ser muito diferentes entre indivíduos e populações: 1) caracteres genéticos herdados diretamente de nossos pais e indiretamente de nossos ancestrais, os quais permanecem relativamente estáveis ao longo da vida; 2) fatores ambientais (alimentação, condição e estilo de vida) até certo ponto controláveis, sendo a alimentação o mais importante. A primeira parte do livro trata da definição e da conceituação do processo de envelhecimento e seus efeitos na saúde. Seguem-se a apresentação e a discussão de mecanismos que promovem degradação molecular e celular responsáveis por distúrbios metabólicos que podem resultar em doenças crônico-degenerativas. A maior parte do texto é dedicada à apresentação de alimentos e compostos bioativos que agem combatendo o envelhecimento precoce e retardando doenças da idade. Por fim, faz-se uma discussão sobre conceitos de dietas saudáveis com sugestões para pesquisas, visando melhorar o perfil alimentar do brasileiro.
It is well known, that grapevine seeds are rich in significant antioxidants. However, the issue of dealing with the analysis and comparison of antioxidant components in the seeds of Vitis vinifera L. in individual cultivars has not yet been sufficiently studied. The experiment was performed with extracts of three varieties (Blaufränkish, Italian Riesling and Cabernet Moravia) and three interspecific cultivars (Nativa, Marlen and Kofranka). Contents of nine major flavonoids (apigenin, astragalin, hyperoside, isorhamnetin, kaempferol, myricetin, quercetin, quercitrin and rutin) and two procyanidins (procyanidin A2 and procyanidin B1) were assessed by the HPLC/MS method. The highest contents of antioxidants were found out in interspecific cultivars Marlen and Nativa while the lowest one was assessed in the cultivar Cabernet Moravia. The most represented flavonoid was hyperoside (cultivar Marlen – 15.66 mg∙l–1), least represented was kaempferol (cultivar Cabernet Moravia – 1.81 μg∙l–1).
Fruit and vegetable intake has been associated with a reduced risk of cardiovascular disease. Quercetin and kaempferol are among the most ubiquitous polyphenols in fruit and vegetables. Most of the quercetin and kaempferol in plants is attached to sugar moieties rather than in the free form. The types and attachments of sugars impact bioavailability, and thus bioactivity. This article aims to review the current literature on the bioavailability of quercetin and kaempferol from food sources and evaluate the potential cardiovascular effects in humans. Foods with the highest concentrations of quercetin and kaempferol in plants are not necessarily the most bioavailable sources. Glucoside conjugates which are found in onions appear to have the highest bioavailability in humans. The absorbed quercetin and kaempferol are rapidly metabolized in the liver and circulate as methyl, glucuronide, and sulfate metabolites. These metabolites can be measured in the blood and urine to assess bioactivity in human trials. The optimal effective dose of quercetin reported to have beneficial effect of lowering blood pressure and inflammation is 500 mg of the aglycone form. Few clinical studies have examined the potential cardiovascular effects of high intakes of quercetin- and kaempferol-rich plants. However, it is possible that a lower dosage from plant sources could be effective due to of its higher bioavailability compared to the aglycone form. Studies are needed to evaluate the potential cardiovascular benefits of plants rich in quercetin and kaempferol glycoside conjugates.
To explore whether alcohol has an effect on the pharmacokinetic behavior of phenolic acids, the main bioactive constituents in red wine, a highly sensitive and simple ultra‐fast liquid chromatography coupled with triple quadrupole mass spectrometry (UFLC‐MS/MS) method was developed for simultaneous quantitation of eight phenolic acids in plasma samples. Plasma samples were extracted by liquid–liquid extraction and the chromatographic separation was achieved on a ZORBAX SB‐C18 column within 7.0 min. Results of the validated method revealed that all the calibration curves displayed good linear regression (r > 0.99). The intra‐ and inter‐day precisions of the analytes were less than 14.0% and accuracies ranged from −8.5% to 7.3%. The extraction recoveries of the analytes were from 71.2% to 110.2% and the matrix effects ranged from 86.2% to 105.5%. The stability of these compounds under various conditions satisfied the requirements of biological sample measurement. The method was successfully applied to a comparative pharmacokinetic study of phenolic acids in rat plasma. For gallic acid and gentisic acid, the parameters of AUC0‐t and AUC0‐∞ increased remarkably (p < 0.05) after oral administration of red wine, which suggested that alcohol might enhance their absorption. This is the first report to compare the pharmacokinetic behavior of phenolic acids in red wine and dealcoholized red wine.
Background
Isorhamnetin (IS) is a flavonoid component with many biological activities such as antioxidant, anti-inflammatory, and anticancer, which is also the main active component in total flavones of Elaeagnus rhamnoides (L.) A. Nelson (Elaeagnaceae) (TFH); however, the interaction between IS and other components in TFH is unclear.
Purpose
The aim of the present study was to investigate the enhancement of quercetin (QU) or kaempferol (KA) on the intestinal absorption of IS coexisting in TFH, and then preliminarily illuminate the related mechanisms.
Methods
Firstly, the intestinal absorption of IS in the presence or absence of QU or KA was conducted by in vivo pharmacokinetics model, in situ single-pass intestinal perfusion model (SPIP), and MDCK II-MRP2 monolayer cell model to confirm the enhancement of QU or KA on IS absorption. Secondly, the effects of multidrug resistance-associated protein 2 (MRP2) inhibitors on the IS intestinal absorption were investigated to ascertain the mediation of MRP2 on IS absorption. Finally, the effects of QU or KA on MRP2 activity, protein expression, and mRNA level were performed by SPIP, everted-gut sacs, western blotting, and real-time polymerase chain reaction experiments to elucidate the related mechanisms.
Results
QU or KA increased IS intestinal absorption according to the increased AUC0–96h, Cmax, and Peff of IS after co-administrated with QU or KA to rats; the oral absorption of IS was mediated by MRP2 based on the facts that the average plasma concentration, AUC0–96h, and Peff of IS were increased when co-administrated with PR or MK571 (MRP2 inhibitors) as well as the Pratio(BL/AP) of IS was decreased by MK571 in MDCK II-MRP2 cell monolayer; the activity, protein expression, and mRNA level of MRP2 were inhibited or down-regulated by QU or KA because of the increased Peff of MRP2 substrate calcein (CA) and the down-regulated relative protein and mRNA intensity after co-treated with QU or KA.
Conclusion
QU and KA increased the intestinal absorption of IS in TFH by regulating the activity and expression of MRP2, which provides useful information for the investigation of the transporter-mediated interaction of flavonoid components in herbal extracts.
Polyphenols are a large family of phytochemicals with great chemical diversity, known to be bioactive compounds of foods, species, medicinal plants and nutraceuticals. These compounds are ingested through the diet in significant amounts, around 1 g per day, an amount that be may be increased through supplements. The in vitro action of many representative polyphenols has been reported. However, their beneficial effects and their role in modulating the risk of high-prevalence diseases are difficult to demonstrate due to the wide variability of polyphenol structures and bioactive actions; the complexity of estimating the polyphenol content of food as a result of their variability in foods and cooked dishes; the potential modulation of the effects of polyphenols by food matrices; the addition of polyphenols and their synergistic interactions with each other and with other dietary bioactive components; the modulation of polyphenol bioavailability as a consequence of food composition and culinary techniques; their metabolism by the human body and the polyphenol gut microbiota metabolism in each metabotypes. Computational strategies, including virtual screening, shape-similarity-screening and molecular docking, were recently used to identify potential targets of polyphenols and thus gain a better understanding of the therapeutic effects exerted of polyphenols and modify natural polyphenol structures to potentiate specific activities. Here, we present the most relevant current knowledge and propose directions for future research in these fields, from the culinary world to the clinical setting. We hope this commentary will prompt scientists and clinicians to consider the therapeutic value of bioactive polyphenols and help shed some light on how much scientific truth lies in Hippocrates' famous quote: "Let your food be your medicine".
The possible adverse effect of excessive alcohol consumption on the pancreas has been known since many years. Alcohol (ethanol) is generally consumed in the form of alcoholic beverages which contain numerous non-alcoholic compounds. On gastric acid secretion it has been convincingly demonstrated that alcohol and alcoholic beverages have markedly different effects. In this chapter we provide an overview about the effect of beer and different non-alcoholic constituents of beer on the pancreas and their possible interaction with molecular mechanisms leading to " alcoholic " pancreatitis, diabetes and pancreatic carcinoma. The present data indicate that pancreatic enzyme secretion in humans is stimulated by non-alcoholic constituents of beer which are generated by alcoholic fermentation of glucose. Natural phenolic compounds (e.g. quercetin, resveratrol) of beer have been shown to exert different effects on the pancreas in in vitro experiments, such as inhibition of pancreatic enzyme output, of pancreatic stellate cell activation and of pancreatic cancer growth. However, some compounds, for example resveratrol and catechins, showed also protective effects against oxidative stress and on experimentally induced acute pancreatitis or experimentally induced diabetes in rats. Bioavailability and effi cacy of these compounds are summarized at the end of this chapter.
In this review an original and unique approach was undertaken to unite the notions "heterocycles" and "wine principles." Indeed, it is astonishing that natural wines contain numerous heterocyclic principles in varying quantities (as low as nanograms!) that contribute to flavor, smell, taste, and aftertaste (" finish" ) sensations, all of which are characteristic of the different grape types. During aging and maturation of the wines in barrels and bottles, manifold additional heterocycles are formed or extracted. The odor threshold plays an important role in all cases, which is ultimately dependent on the chirality centers of the isomers involved in aroma. These heterocyclic classes are manifold: O-heterocycles (lactones, furans, flavones, carbohydrates), O-glucosides of terpenes, tannins, flavones, procyanidins, heterocyclic polyphenols with significant benefits to human health, S-heterocycles stemming from yeast metabolism and possessing strong organoleptic properties, N-heterocycles (pyrroles, pyrimidines, pyrazines, the latter constituents having a typical green pepper flavor and aroma). Finally, the role of fungicides and pesticides in wine is discussed.
It is known that moderate consumption of red wine may protect against many diseases, in particular because of its polyphenols. We studied in particular the effect of these polyphenols on colorectal cancer, one of the most common cancers in industrialized countries. Some purified polyphenols from red wine, like resveratrol and quercetin, showed antiproliferative effects against colorectal cancer cells.Our first approach was to use polyphenolic extracts from Burgundy red wine. We then studied their in vitro effects on human colorectal tumor cell lines SW480's proliferation and the interactions between the polyphenols and the transport and metabolism of resveratrol; and secondly, the effects on CF-1 mice of regular consumption of these polyphenols in the diet on the occurrence of chemically induced pre-neoplastic lesions by azoxymethane in the colon.Our second approach was directed towards changes in the chemical structure of resveratrol. By the addition of hydroxyl and methoxyl groups, and the isomerization of its structure (cis or trans), we wanted to identify structure-function relationships of resveratrol and create more bioactive derivatives.We show that the red wine polyphenols inhibit proliferation of colon cancer cells by blocking the cell cycle. Some wine polyphenols such as quercetin are able to increase the ability of SW480 cells to accumulate resveratrol. [We show that] in mice, the regular intake of red wine polyphenols in the diet reduces the overall number of pre-neoplastic lesions, especially large lesions which may become intestinal polyps. The chemical changes in the structure of resveratrol show that the methoxylated analogues of cis-resveratrol are potent antiproliferatives by blocking mitosis, while the mechanism of action of derivatives of trans-resveratrol blocks the cell cycle at the S phase.This work supports the idea that the use of wine polyphenols in the prevention of colon adenocarcinomas is possible and that this field of research is a promising way. Concerning therapeutic purposes, the search for analogues of resveratrol with improved bioavailability is a way to pursue
The light to moderate consumption of alcoholic beverages has been observed to reduce the risk of, and death from, cardiovascular disease (CVD) by potentially 20-50% compared to abstention and excessive consumption. The main component considered responsible for the reduced risk is ethanol. One of the alcoholic beverages, wine, additionally contains phenolic compounds, that are also observed in fruits and vegetables, the consumption of which is associated with a similar reduced risk of CVD. It has thus been proposed that consumers of wine have a greater reduction in the risk of CVD than do consumers of beer and spirits, but potential confounders include the drinking pattern and associated diet and lifestyle of consumers. What is perplexing scientists, however, is the amount of phenolic compound that is necessary to elicit a cardioprotective effect e.g. on platelet aggregation or coagulation. In in vitro studies effects are generally elicited with a 10- or 100-fold greater concentration of phenolic compounds than is present in blood and at cellular sites of action following moderate consumption. This suggests that the metabolites of phenolic compounds may also be bioactive. This paper reviews the data generated to date on the amount of phenolic compounds necessary to elicit certain cardioprotective effects, and whether isolated individual phenolic compounds are as effective as those administered in a wine medium. The data suggests that although the phenolic compounds are absorbed into the blood stream in measurable amounts, the metabolite is more likely to be the biologically active compound in vitro. Furthermore, when seed-derived phenolic compounds are together with the skin and flesh-derived phenolic compounds in wine, they exhibit greater cardioprotective effects than when present individually in a non-wine medium and are potentially equipotent to certain conventional pharmaceutical products at reducing the risk of CVD.
Resveratrol exerts a variety of biological and pharmacological activities, which are observed despite its extremely low bioavailability and rapid clearance from the circulation due to extensive sulfation and glucuronidation in the intestine and liver. In order to more accurately quantify all known resveratrol metabolites, a sensitive and optimized analytical assay was developed and validated by pure standards. Methodology improvements aimed to the chromatographic detection of disulfates and sulfoglucuronides, improving resolution of sulfates, by using a buffered solution, with recovery values of resveratrol and its metabolites, even of sulfates, of 99%. The adapted methodology was then applied to a clinical study with high cardiovascular risk subjects, after the moderate consumption of red wine (RW) or dealcoholized red wine (DRW) for 28 days. Up to 21 resveratrol metabolites, including those formed by gut and microbial metabolism, were identified in 24-h urine samples. Interestingly, after long-term consumption of RW and DRW, resveratrol metabolite concentration significantly increased in urine with no differences between the two interventions, indicating that bioavailability and biotransformation of resveratrol is not affected by the alcoholic matrix of wine. In summary, we established a sensitive analytical assay for the quantification of a wide resveratrol metabolic profile in human urine, also regarding gut microbial-derived metabolites, which may also be applied to blood and tissue samples. The resveratrol metabolic pattern might therefore act as an excellent marker for the efficacy of resveratrol in clinical and epidemiological studies for the study of the beneficial effects of grape product consumption. In this sense, having a more precise concentration value of all the resveratrol metabolites in target tissues would finally lead to a better interpretation of the obtained results.
Phenolic compounds are produced in the seeds and skins of grapes, and are transferred into wine during the fermentation process. Phenolic compounds can also be imparted into wine from maturation and storage in oak wood barrels after fermentation. The consumption of wine, an alcoholic beverage, has been observed in epidemiological studies to reduce the risk of cardiovascular disease and certain cancers, as well as diabetes and dementia, in a J-shaped relationship between amount consumed and level of risk. The bioactivity of wine primarily observed in vitro and ex vivo, may result from wine's relatively high content of phenolic compounds, which is similar to that observed in fruits and vegetables; a Mediterranean fruit and vegetable rich-diet is also associated with a reduced risk of cardiovascular disease and cancers. If the wine-derived phenolic compounds or their active metabolites are not absorbed in sufficient amounts and in a readily available form for cells, however, then they are less likely to have any significant in vivo activity. This review considers and discusses the available data to date on the bioavailability of the different wine-derived phenolic compounds in humans.
The world is increasingly threatened by chronic diseases, related to lifestyle, stress, lack of physical exercise and excessive
intake of high caloric diets. Almost all chronic diseases have in common an increased level of oxidative stress and inflammatory
state.
A wide variety of dietary plants including vegetables, fruits and beverages, like tea and wine, are rich in polyphenols. These
compounds have attracted much attention with regard to human health as they seem to protect the establishment of several diseases
with high prevalence in western countries, like cancer, cardiovascular disorders and diabetes. Here we will discuss general
aspects of polyphenols classification, metabolism and bioavailability, their role as anti-oxidants and modulators of cell
signalling, focusing especially in inflammation and angiogenic pathways. Recent reports suggesting beneficial effects of these
compounds on metabolic syndrome will also be referred.
As an important edible and medicinal material, tartary buckwheat ( Fagopyrum tataricum Gaertn.) is commonly used as a kind of food or drug in eastern Asian countries. To investigate the pharmacokinetic profile of total quercetin after a single oral dose of tartary buckwheat extract in rats, a sensitive, simple, and accurate HPLC-UV method was developed to determine total quercertin following plasma enzyme hydrolysis with glucuronidase/sulfatase. Eighteen male Wistar rats were randomly assigned into three groups, which were given three different doses of tartary buckwheat extract. The pharmacokinetic results showed that the area under the plasma concentration-time curve (AUC) of total quercetin after single oral doses of tartary buckwheat extract presented a linear relationship. The peak plasma concentrations (C(max)) of total quercetin afte plasma enzyme hydrolysis with glucuronidase/sulfatase were 0.55 ± 0.26, 1.10 ± 0.53, and 2.05 ± 0.26 μg/mL; the peak times (T(max)) were 2.33 ± 1.94, 2.75 ± 3.67, and 2.50 ± 1.82 h; the areas under the curves (AUC(0-36h)) were 5.29 ± 1.35, 10.02 ± 4.43, and 22.51 ± 3.05 μg·mL(-1)·h(-1) for three doses of tartary buckwheat extract (60, 120, and 240 mg/kg). The present study has provided a basic pharmacokinetic profile of total quercetin after a single oral dose of tartary buckwheat extract in rats.
Red wine consumption may decrease the risk of coronary heart disease through the actions of its constituent flavonoids. (+)-Catechin is an abundant flavonoid in red wine.
The objective was to determine changes in plasma (+)-catechin concentrations after ingestion of a single, moderate serving of dealcoholized red wine reconstituted with either water (DRW) or water and alcohol (ARW).
Nine subjects (5 men, 4 women) ingested, in random order, 120 mL DRW on one day and 120 mL ARW on another day. Both the DRW and ARW contained 35 mg (121 micromol) free (+)-catechin. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, and 8 h. Plasma was analyzed by gas chromatography-mass spectrometry for (+)-catechin after enzymatic release of sulfate and glucuronide conjugates.
Calcium ions were needed to effectively hydrolyze (+)-catechin conjugates in plasma containing EDTA. Neither the ARW or DRW nor sex affected the area under the curve at 8 h, the maximum concentration (c(max)), or the time it took for plasma total (+)-catechin to reach maximum concentration (t(max)). Pooled mean (+/-SEM) values for the ARW and DRW were as follows: area under the curve, 306.1 +/- 29.5 nmol*h/L; c(max), 76.7 +/- 7.5 nmol/L; and t(max), 1.44 +/- 0.13 h. The half-life of (+)-catechin in plasma was significantly less (P = 0.038) after ingestion of the ARW (3.17 h) than after ingestion of the DRW (4.08 h).
Increases in plasma total (+)-catechin concentrations were not significantly different after single moderate servings of either the ARW or DRW. Alcohol in the ARW hastened the elimination of (+)-catechin from the plasma compartment. (+)-Catechin elimination may represent excretion or conversion to methylated derivatives.
Flavonoids are polyphenolic plant secondary metabolites with antioxidant and other biological activities potentially beneficial to health. Food-borne flavonoids occur mainly as glycosides, some of which can be absorbed in the human small intestine; however, the mechanism of uptake is uncertain. We used isolated preparations of rat small intestine to compare the uptake of the quercetin aglycone with that of some quercetin glucosides commonly found in foods, and investigated interactions between quercetin-3-glucoside and the intestinal hexose transport pathway. The nature of any metabolism of quercetin and its glucosides during small intestinal transport in vitro was determined by HPLC. The presence of quercetin-3-glucoside in the mucosal medium suppressed the uptake of labeled galactose by competitive inhibition and stimulated the efflux of preloaded galactose. Quercetin-3-glucoside and quercetin-4'-glucoside, but not quercetin-3,4'-diglucoside, were transported into everted sacs significantly more quickly than quercetin aglycone. Intact quercetin glucosides were not detected in mucosal tissue or within the serosal compartment, but both free quercetin and its metabolites were present, mainly as quercetin-3-glucuronide and quercetin-7-glucuronide. Evidently, quercetin derived from quercetin-3-glucoside passes across the small intestinal epithelium more rapidly than free quercetin aglycone. Monoglucosides of quercetin interact with the sodium-dependent glucose transporter. During passage across the epithelium, quercetin-3-glucoside is rapidly deglycosylated and then glucuronidated.
Several studies have indicated that quercetin promotes relaxation of vascular smooth muscle both in vivo and in vitro. However, Saponara et al. [(2002) Br J Pharmacol 135: 1819-1827] have demonstrated that quercetin is an activator of vascular L-type Ca(2+) channels.
We investigated the mechanical and electrophysiological properties of quercetin and its rutoside, rutin, in an attempt to clarify how Ca(2+) channel activation might be related to the myorelaxing activity.
Aorta ring preparations and single tail artery myocytes were employed for functional and patch-clamp experiments, respectively.
Rutin was found to relax intact rat aorta rings, which had been precontracted with phenylephrine (pIC(50) = 5.65 +/- 0.31) but in contrast had no effect on depolarised (60 mM K(+)) preparations or on those from which the endothelium had been removed. Furthermore, rutin did not affect L-type Ca(2+) current recorded in rat tail artery myocytes. The quercetin-induced relaxation of intact rings precontracted with phenylephrine exhibited two components characterised by 6.23 +/- 0.38 and 4.66 +/- 0.09 pIC(50), respectively. Removal of the endothelium abolished the first component, leaving the second unaltered. Moreover, quercetin was found to relax 60 mM K(+) depolarised rings with a pIC(50) of 4.59 +/- 0.03. The application of quercetin in isolated smooth muscle cells brought about a marked increase of L-type Ca(2+) current (pEC(50) = 5.09 +/- 0.05). Unlike quercetin, Bay K 8644 contracted aorta rings preincubated with 10, 20 or 30 mM K(+). The myotonic effect of Bay K 8644 was observed both in the absence or presence of 30 microM quercetin. The application of Bay K 8644 (10-100 nM) caused a further significant increase in L-type Ca(2+) current in rat tail artery myocytes stimulated with 30 microM quercetin.
Quercetin is a naturally occurring L-type Ca(2+) channel agonist. This effect, however, is overwhelmed by quercetin-induced vasorelaxation taking place via pathways which are more relevant than L-type Ca(2+) influx in the hierarchy of functional competencies.
Marimastat, low molecular weight heparins and captopril have antiangiogenic activity in vitro and in animal models. We studied the safety and efficacy of the combination of these drugs in patients with advanced cancer. In all, 50 patients were enrolled. Captopril was given orally at a dose of 50 mg bd daily. Fragmin was administered as a daily subcutaneous injection of 200 units kg(-1) for the first 28 days and 5000 units thereafter. Marimastat was given at 10 mg bd orally. Serum, plasma and urinary angiogenic factors were measured at baseline and after 1 month of treatment. Inhibition of release of tumour necrosis factor alpha (TNF-alpha) from peripheral lymphocytes was used as a surrogate pharmacodynamic end point. There was one case of haemorrhagic stroke and one upper gastrointestinal haemorrhage. The commonest toxicity was myalgia. One of 10 patients with renal cancer had a partial response, and three patients had a prolonged period of stable disease. The treatment significantly inhibited phytohaemagglutinin (PHA)-stimulated TNF-alpha release from patient's lymphocytes. The combination of marimastat, fragmin and captopril is well tolerated and has in vivo activity. Inhibition of PHA-stimulated TNF-alpha release from lymphocytes is a surrogate pharmacodynamic marker of metalloprotease inhibition.
Quercetin (3,5,7,3',4'-pentahydroxyflavone) is a flavone with putative ability to prevent cancer and cardiovascular diseases. Its metabolism was evaluated in rats and human. Rats received quercetin via the intravenous (i.v.) route and metabolites were isolated from the plasma, urine and bile. Analysis was by high-performance liquid chromatography and confirmation of species identity was achieved by mass spectrometry. Quercetin and isorhamnetin, the 3'-O-methyl analogue, were found in both the plasma and urine. In addition, several polar peaks were characterised as sulphated and glucuronidated conjugates of quercetin and isorhamnetin. Extension of the metabolism studies to a cancer patient who had received quercetin as an i.v. bolus showed that (Quercetin removed) isorhamnetin and quercetin 3'-O-sulphate were major plasma metabolites. As a catechol, quercetin can potentially be converted to a quinone and subsequently conjugated with glutathione (GSH). Oxidation of quercetin with mushroom tyrosinase in the presence of GSH furnished GSH conjugates of quercetin, two mono- and one bis-substituted conjugates. However, these species were not found in biomatrices in rats treated with quercetin. As cyclo-oxygenase-2 (COX-2) expression is mechanistically linked to carcinogenesis, we examined whether quercetin and its metabolites can inhibit COX-2 in a human colorectal cancer cell line (HCA-7). Isorhamnetin and its 4'-isomer tamarixetin were potent inhibitors, reflected in a 90% decrease in prostaglandin E-2 (PGE-2) levels, a marker of COX-2 activity. Quercetin was less effective, with a 50% decline. Quercetin 3- and 7-O-sulphate had no effect on PGE-2. The results indicate that quercetin may exert its pharmacological effects, at least in part, via its metabolites.
The association of light to moderate alcohol consumption with risk for ischemic stroke remains controversial, as do the roles of beverage type and drinking pattern.
To assess the association of drinking patterns and beverage type with risk for ischemic stroke among men.
Prospective cohort study.
United States.
38 156 male health professionals who were free of known cardiovascular disease or cancer at baseline in 1986.
With a semi-quantitative food-frequency questionnaire, the authors individually ascertained consumption of regular and light beer, red and white wine, and liquor every 4 years. Alcohol consumption was categorized as light (0.1 to 9.9 g/d, or <1 drink daily), moderate (10.0 to 29.9 g/d, or 1 to 2 drinks daily), and heavier (> or =30.0 g/d, or > or =3 drinks daily).
During a follow-up period of 14 years, 412 cases of incident ischemic stroke were documented. Compared with abstainers, light drinkers had a multivariate-adjusted relative risk of 0.99 (95% CI, 0.72 to 1.37), moderate drinkers had a multivariate-adjusted relative risk of 1.26 (CI, 0.90 to 1.76), and heavier drinkers had a multivariate-adjusted relative risk of 1.42 (CI, 0.97 to 2.09; P = 0.01 for trend). Consumption of 10.0 to 29.9 g of alcohol per day on 3 to 4 days per week appeared to be associated with the lowest risk (relative risk, 0.68 [CI, 0.44 to 1.05]). Red wine consumption was inversely associated with risk in a graded manner (P = 0.02 for trend), but other beverages were not. The apparently higher risk for ischemic stroke with heavier alcohol use appeared to be most pronounced for the embolic subtype.
This study had limited power to examine specific drinking patterns and heavy drinking and could not assess risk for hemorrhagic stroke.
In this sample of male health professionals, light and moderate average alcohol use was generally not associated with an increased risk for ischemic stroke, although drinking pattern and beverage type modified this relation. Intake of more than 2 drinks per day may be associated with a higher risk for ischemic stroke.
An in-depth analysis of the mechanism of the L-type Ca(2+) current [I(Ca(L))] stimulation induced by myricetin was performed in rat tail artery myocytes using the whole-cell patch-clamp method. Myricetin increased I(Ca(L)) in a frequency-, concentration-, and voltage-dependent manner. At holding potentials (V(h)) of -50 and -90 mV, the pEC(50) values were 4.9 +/- 0.1 and 4.2 +/- 0.1, respectively; the latter corresponded to the drug-apparent dissociation constant for resting channels, K(R), of 67.6 microM. Myricetin shifted the maximum of the current-voltage relationship by 10 mV in the hyperpolarizing direction but did not modify the threshold for I(Ca(L)) or the T-type Ca(2+) current. The Ca(2+) channel blockers nifedipine, verapamil, and diltiazem antagonized I(Ca(L)) in the presence of myricetin. Myricetin increased the time to peak of I(Ca(L)) in a voltage- and concentration-dependent manner. Washout reverted myricetin effect on both current kinetics and amplitude at V(h) of -90 mV while reverting only current kinetics at V(h) of -50 mV. At the latter V(h), myricetin shifted the voltage dependence of inactivation and activation curves to more negative potentials by 6.4 and 13.0 mV, respectively, in the mid-potential of the curves. At V(h) of -90 mV, myricetin shifted, in a concentration-dependent manner, the voltage dependence of the inactivation curve to more negative potentials with an apparent dissociation constant for inactivated channels (K(I)) of 13.8 muM. Myricetin induced a frequency- and V(h)-dependent block of I(Ca(L)). In conclusion, myricetin behaves as an L-type Ca(2+) channel agonist that stabilizes the channel in its inactivated state.
Flavonols are efficient antioxidants with the potential to protect biological macromolecules from oxidative damage in vivo, and if absorbed into the circulation they may protect against cardiovascular disease. Although flavonol aglycones are present in foods at low concentrations, their glycosides are abundant in onions, apples, beans and tea, and are thought to be stable under the conditions of the human stomach and small bowel. There is, however, recent evidence to suggest that intact glycosides of quercetin may be absorbed from the small intestine by a mechanism involving the glucose transport pathway. In the present study we tested this hypothesis by measuring the effect of quercetin glycosides on the rate of efflux of galactose from the jejunal mucosa. Everted sacs of rat jejunum preloaded with 14C-galactose were exposed to quercetin glycosides isolated from onions. Quercetin mono- and diglucosides were shown to accelerate the carrier-mediated efflux of galactose via a sodium-dependent pathway. HPLC analysis confirmed the stability of the glycosides under conditions simulating those in the upper alimentary tract. These studies suggest that purified quercetin glucosides are capable of interacting with the sodium dependent glucose transport receptors in the mucosal epithelium and may therefore be absorbed by the small intestine in vivo.
Flavonols are efficient antioxidants with the potential to protect biological macromolecules from oxidative damage in vivo, and if absorbed into the circulation they may protect against cardiovascular disease. Although flavonol aglycones are present in foods at low concentrations, their glycosides are abundant in onions, apples, beans and tea, and are thought to be stable under the conditions of the human stomach and small bowel. There is, however, recent evidence to suggest that intact glycosides of quercetin may be absorbed from the small intestine by a mechanism involving the glucose transport pathway. In the present study we tested this hypothesis by measuring the effect of quercetin glycosides on the rate of efflux of galactose from the jejunal mucosa. Everted sacs of rat jejunum preloaded with 14C-galactose were exposed to quercetin glycosides isolated from onions. Quercetin mono- and diglucosides were shown to accelerate the carrier-mediated efflux of galactose via a sodium-dependent pathway. HPLC analysis confirmed the stability of the glycosides under conditions simulating those in the upper alimentary tract. These studies suggest that purified quercetin glucosides are capable of interacting with the sodium dependent glucose transport receptors in the mucosal epithelium and may therefore be absorbed by the small intestine in vivo.
The effects of quercetin were studied on contractile responses induced by noradrenaline, high KCl, Ca2+ and phorbol 12-myristate, 13-acetate in rat aortic strips and on spontaneous mechanical activity in rat portal vein segments. Quercetin, 10−6−10−4 M, inhibited in a concentration-dependent manner the contractions induced by noradrenaline, high KCl and Ca2+, this effect being observed when the drug was added before or after the induced contractions. The spontaneous myogenic portal activity was also inhibited. Mechanical removal of endothelium did not affect the relaxant effects of quercetin on noradrenaline-induced contractions. In addition, at the same range of concentrations, quercetin also relaxed the contractions induced by phorbol 12-myristate, 13-acetate. Quercetin, 10−5 and 5 × 10−5 M, increased the aortic cyclic AMP content. However, pretreatment with 10−7 M isoprenaline did not modify the relaxant effects of quercetin on noradrenaline-induced contractions and quercetin did not modify the relaxant effects of forskolin, which suggested that the vasodilator effects of quercetin were not mediated by inhibition of cyclic AMP phosphodiesterases. In conclusion, in isolated rat aorta quercetin produced a vasodilator effect that seems to be mainly related to the inhibition of protein kinase C. However, and since this drug exerts multiple biochemical effects, inhibition of other transduction pathways may be involved in this effect.
1.1. Flavonoidsproducedaconcentration-dependentrelaxationofthecontractileresponses induced by noradrenaline, KCI, or phorbol 12-myristate-13-acetate in rat aortic rings. Only the flavonoid with three contiguous hydroxyls in B rings (myricetin), at low concentrations, potentiates the contractions evoked by these agonists.2.2. The relaxant effects of flavanone on the noradrenaline-induced contractions were potentiated by isoprenaline and those of morin, chrysin, flavanone, and naringenin by sodium nitroprusside.3.3. Several mechanisms are implicated in the vasodilatory effects of flavonoids: inhibition of protein kinase C; inhibition of cyclic nucleotide phosphodiesterases; and/or decreased Ca2+ uptake.
To examine the acute effect of red wine and de-alcoholized red wine on endothelial function.
High frequency ultrasound was used to measure blood flow and percentage brachial artery dilatation after reactive hyperaemia induced by forearm cuff occlusion in 12 healthy subjects, less than 40 years of age, without known cardiovascular risk factors. The subjects drank 250 ml of red wine with or without alcohol over 10 min according to a randomized procedure. Brachial artery dilatation was measured again 30 and 60 min after the subjects had finished drinking. The subjects were studied a second time within a week of the first study in a cross-over design. After the red wine with alcohol the resting brachial artery diameter, resting blood flow, heart rate and plasma-ethanol increased significantly. After the de-alcoholized red wine these parameters were unchanged. Flow-mediated dilatation of the brachial artery was significantly higher (P<0.05) after drinking de-alcoholized red wine (5.6+/-3.2%) than after drinking red wine with alcohol (3.6+/-2.2%) and before drinking (3.9+/-2.5%).
After ingestion of red wine with alcohol the brachial artery dilated and the blood flow increased. These changes were not observed following the de-alcoholized red wine and were thus attributable to ethanol. These haemodynamic changes may have concealed an effect on flow-mediated brachial artery dilatation which did not increase after drinking red wine with alcohol. Flow-mediated dilatation of the brachial artery increased significantly after de-alcoholized red wine and this finding may support the hypothesis that antioxidant qualities of red wine, rather than ethanol in itself, may protect against cardiovascular disease.
We investigated in rats fed a purified diet for 2 and 4 months whether wine drinking was associated with the rebound effect on thrombin-induced platelet aggregation observed after alcohol withdrawal. With 6% ethanol drinking or its equivalent in red or white wine, platelet aggregation was reduced similarly by 70% when the animals drank the alcoholic beverages up to the venipuncture. Depriving the rats of alcoholic beverages for 18 hours was associated with an increase in the platelet response of 124% in those receiving 6% ethanol, of 46% with white wine but a decrease of 59% in those with red wine. The protective effect of red wine on platelets could be reproduced by tannins (procyanidins) extracted from grape seeds or red wine and added to 6% ethanol, but not by glycerol or wine without alcohol. That was related to inhibition of the alcohol-induced lipid peroxidation as shown by the lowering of conjugated dienes, lipid peroxides, and the increase in vitamin E in plasma. Owing to tannins, the platelets of rats drinking red wine did not exhibit the rebound effect observed hours after alcohol drinking, eventually associated with sudden death and stroke in humans.
The effects of quercetin were studied on contractile responses induced by noradrenaline, high KCl, Ca2+ and phorbol 12-myristate,13-acetate in rat aortic strips and on spontaneous mechanical activity in rat portal vein segments. Quercetin, 10(-6)-10(-4) M, inhibited in a concentration-dependent manner the contractions induced by noradrenaline, high KCl and Ca2+, this effect being observed when the drug was added before or after the induced contractions. The spontaneous myogenic portal activity was also inhibited. Mechanical removal of endothelium did not affect the relaxant effects of quercetin on noradrenaline-induced contractions. In addition, at the same range of concentrations, quercetin also relaxed the contractions induced by phorbol 12-myristate,13-acetate. Quercetin1 10(-5) and 5 x 10(-5) M, increased the aortic cyclic AMP content. However, pretreatment with 10(-7) M isoprenaline did not modify the relaxant effects of quercetin on noradrenaline-induced contractions and quercetin did not modify the relaxant effects of forskolin, which suggested that the vasodilator effects of quercetin were not mediated by inhibition of cyclic AMP phosphodiesterases. In conclusion, in isolated rat aorta quercetin produced a vasodilator effect that seems to be mainly related to the inhibition of protein kinase C. However, and since this drug exerts multiple biochemical effects, inhibition of other transduction pathways may be involved in this effect.
1. Flavonoids produced a concentration-dependent relaxation of the contractile responses induced by noradrenaline, KCl, or phorbol 12-myristate-13-acetate in rat aortic rings. Only the flavonoid with three contiguous hydroxyls in B rings (myricetin), at low concentrations, potentiates the contractions evoked by these agonists. 2. The relaxant effects of flavanone on the noradrenaline-induced contractions were potentiated by isoprenaline and those of morin, chrysin, flavanone, and naringenin by sodium nitroprusside. 3. Several mechanisms are implicated in the vasodilatory effects of flavonoids: inhibition of protein kinase C; inhibition of cyclic nucleotide phosphodiesterases; and/or decreased Ca2+ uptake.
Controversy exists concerning the site (stomach vs. liver) and magnitude of first-pass metabolism of ethanol. We quantitated gastric and total ethanol absorption rates in five male subjects and utilized these measurements to evaluate first-pass metabolism. Gastric emptying of ethanol (0.15 g/kg) was determined via a gamma camera and gastric absorption from the ratio of gastric ethanol to [14C]polyethylene glycol. Gastric absorption accounted for 30% and 10% of ethanol administered with food and water, respectively. With food, estimated gastric mucosal ethanol concentrations fell from 19 to 5 mM over 2 h. Calculations using these concentrations and kinetic data for gastric alcohol dehydrogenase showed <2% of the dose underwent gastric metabolism. Application of observed ethanol absorption rates to a model of human hepatic ethanol metabolism indicated that only 30% and 4% of the dose underwent first-pass metabolism when administered with food and water, respectively. We conclude that virtually all first-pass ethanol metabolism occurs in the liver and first-pass metabolism accounts for only a small fraction of total clearance.
High-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS) was used to study flavonol aglycones and glycosides in berries. For the identification of aglycones, photodiode-array detection (DAD) was also used. The HPLC-ESI-MS technique is highly valuable in the identification of flavonol aglycones and glycosides from berry extracts. This ionization technique provides information on the structure of the aglycones and glycosides without time-consuming pre-purification or derivatization steps. Quercetin aglycone was identified with both ESI-MS and DAD in all of the berries studied. Myricetin aglycone was identified with both techniques in three berries. Hexose, deoxyhexose-hexose and pentose derivatives of quercetin were the most abundant flavonol glycosides identified. Two glycosides of myricetin and one glycoside of kaempferol were identified in blackcurrant. To confirm the data obtained using the HPLC-ESI-MS procedure, fractions of the glycosides from four berries were separated, hydrolyzed, silylated and the sugars were analyzed using gas chromatography-mass spectrometry.
Previous studies have shown that high concentrations of ethanol (>/=40%) cause functional damage of the gastrointestinal epithelial barrier by direct cytotoxic effect on the epithelial cells. The effects of lower noncytotoxic doses of ethanol on epithelial barrier function are unknown. A major function of gastrointestinal epithelial cells is to provide a barrier against the hostile substances in the gastrointestinal lumen. The apicolaterally located tight junctions (TJs) form a paracellular seal between the lateral membranes of adjacent cells and act as a paracellular barrier. In this study, we investigated the effects of lower doses of ethanol on intestinal epithelial TJ barrier function using filter-grown Caco-2 intestinal epithelial monolayers. The Caco-2 TJ barrier function was assessed by measuring epithelial resistance or paracellular permeability of the filter-grown monolayers. Ethanol (0, 1, 2.5, 5, 7.5, and 10%) produced a dose-related drop in Caco-2 epithelial resistance and increase in paracellular permeability. Ethanol also produced a progressive disruption of TJ protein (ZO-1) with separation of ZO-1 proteins from the cellular junctions and formation of large gaps between the adjacent cells. Ethanol, at the doses used (</=10%), did not cause cytotoxicity (lactate dehydrogenase release) to the Caco-2 cells. Ethanol produced a disassembly and displacement of perijunctional actin and myosin filaments from the perijunctional areas. On ethanol removal, actin and myosin filaments rapidly reassembled at the cellular borders. Ethanol stimulated the Caco-2 myosin light chain kinase (MLCK) activity but did not affect the MLCK protein levels. Specific MLCK inhibitor ML-7 inhibited both ethanol increases in MLCK activity and TJ permeability without affecting the MLCK protein levels. Consistent with these findings, metabolic inhibitors sodium azide and 2,4-dinitrophenol significantly prevented ethanol-induced increase in Caco-2 TJ permeability, whereas cycloheximide or actinomycin D had no effect. The results of this study indicate that ethanol at low noncytotoxic doses causes a functional and structural opening of the Caco-2 intestinal epithelial TJ barrier by activating MLCK.
Intestinal glucose uptake is mainly performed by the sodium-dependent glucose transporter, SGLT1. The transport activity of SGLT1 was markedly inhibited by green tea polyphenols, this inhibitory activity being most pronounced in polyphenols having galloyl residues such as epicatechin gallate (ECg) and epigallocatechin gallate (EGCg). Experiments using brush-border membrane vesicles obtained from the rabbit small intestine demonstrated that ECg inhibited SGLT1 in a competitive manner, although ECg itself was not transported via SGLT1. The present results suggest that tea polyphenols such as ECg interact with SGLT1 as antagonist-like molecules, possibly playing a role in controlling the dietary glucose uptake in the intestinal tract.
A structure-activity study on the quinone/quinone methide chemistry of a series of 3',4'-dihydroxyflavonoids was performed. Using the glutathione trapping method followed by HPLC, (1)H NMR, MALDI-TOF, and LC/MS analysis to identify the glutathionyl adducts, the chemical behavior of the quinones/quinone methides of the different flavonoids could be deduced. The nature and type of mono- and diglutathionyl adducts formed from quercetin, taxifolin, luteolin, fisetin, and 3,3',4'-trihydroxyflavone show how several structural elements influence the quinone/quinone methide chemistry of flavonoids. In line with previous findings, glutathionyl adduct formation for quercetin occurs at positions C6 and C8 of the A ring, due to the involvement of quinone methide-type intermediates. Elimination of the possibilities for efficient quinone methide formation by (i) the absence of the C3-OH group (luteolin), (ii) the absence of the C2=C3 double bond (taxifolin), or (iii) the absence of the C5-OH group (3,3',4'-trihydroxyflavone) results in glutathionyl adduct formation at the B ring due to involvement of the o-quinone isomer of the oxidized flavonoid. The extent of di- versus monoglutathionyl adduct formation was shown to depend on the ease of oxidation of the monoadduct as compared to the parent flavonoid. Finally, unexpected results obtained with fisetin provide new insight into the quinone/quinone methide chemistry of flavonoids. The regioselectivity and nature of the quinone adducts that formed appear to be dependent on pH. At pH values above the pK(a) for quinone protonation, glutathionyl adduct formation proceeds at the A or B ring following expected quinone/quinone methide isomerization patterns. However, decreasing the pH below this pK(a) results in a competing pathway in which glutathionyl adduct formation occurs in the C ring of the flavonoid, which is preceded by protonation of the quinone and accompanied by H(2)O adduct formation, also in the C ring of the flavonoid. All together, the data presented in this study confirm that quinone/quinone methide chemistry can be far from straightforward, but the study provides significant new data revealing an important pH dependence for the chemical behavior of this important class of electrophiles.
Flavonoids may exert their health benefit in cardiovascular disease by modulating monocyte adhesion in the inflammatory process of atherosclerosis. Most in vitro studies used forms of flavonoids present in food rather than forms that appear in plasma after ingestion.
We tested the effects of plasma metabolites of (+)-catechin and quercetin on the modulation of monocyte adhesion to human aortic endothelial cells (HAEC) and on the production of reactive oxygen species (ROS).
Plasma extracts of flavonoid metabolites were prepared after intragastric administration of pure compounds to rats. The plasma preparations contained sulfate or glucuronide conjugates or both and methylated forms. We measured adhesion of U937 monocytic cells to HAEC and the production of ROS in HAEC when cells were pretreated with either pure compounds or plasma extracts from control or treated rats. Adhesion assays were performed with HAEC stimulated with interleukin (IL)-1 beta or U937 cells activated with phorbol myristyl acetate; ROS were measured after challenging HAEC with IL-1 beta or hydrogen peroxide.
Pretreatment of HAEC with (+)-catechin metabolites inhibited U937 cell adhesion to IL-1 beta-stimulated cells, whereas pretreatment with intact (+)-catechin had no effect. Generation of ROS in hydrogen peroxide-stimulated HAEC was inhibited by (+)-catechin, its metabolites, and control plasma extract, whereas ROS generation in IL-1 beta-stimulated HAEC was inhibited by (+)-catechin metabolites only. In contrast, quercetin inhibited U937 cell adhesion to IL-1 beta-stimulated HAEC, whereas its metabolites were not effective.
Metabolic conversion of flavonoids such as (+)-catechin and quercetin modifies the flavonoids' biological activity. Metabolites of flavonoids, rather than their intact forms, may contribute to the reported effects of flavonoids on reducing the risk of cardiovascular disease.
Aim of this study was to evaluate the total antioxidant activity (TAA) of extra virgin olive oil (EVOO) and the effect of heating on the alpha-tocopherol content and TAA in relation to the presence of polyphenols, heating time, and temperature. Experiments included the measurement by ABTS decolorization assay of antioxidant capacity of alpha-tocopherol and 14 simple phenolic compounds present in EVOO, either dissolved in ethanol or added to refined olive oil, and the evaluation of TAA, total phenols, and alpha-tocopherol of six commercial EVOO and three olive oils. Finally, four experimental oils were prepared from refined olive oil containing a fixed amount (300 ppm) of alpha-tocopherol and increasing amounts of polyphenols (25, 125, 225, and 326 ppm) extracted from EVOO. The thermal stability of experimental oils under domestic heating conditions (heating time from 30 to 120 min, heating temperature from 160 to 190 degrees C) was studied by evaluating the loss of alpha-tocopherol and TAA according to a Latin square design. Results indicate that TAA of commercial oils is mainly due to their phenol and alpha-tocopherol content. Heating experiments suggest that polyphenols from EVOO are effective stabilizers of alpha-tocopherol during olive oil heating, thus contributing to the nutritional value of cooked foods.
The concentrations of three polyphenols ((+)-catechin, quercetin and trans-resveratrol) in blood serum, plasma and urine, as well as whole blood, have been measured after their oral and intragastric administration, respectively, to humans and rats. The method developed for this purpose utilized ethyl acetate extraction of 100 microl samples and their derivatization with bis(trimethylsilyl)trifluoroacetamide (BSTFA) followed by gas-chromatographic analysis on a DB-5 column followed by mass selective detection employing two target ions and one qualifier ion for each compound. Total run time was 17 min with excellent resolution and linearity. The limits of detection (LOD) and quantitation (LOQ) were an order of magnitude less than for any previously published method, being 0.01 microg/l and 0.1 microg/l, respectively, for all compounds. Recovery at 1 microg/l and 10 microg/l was >80% in all instances but one, and was >90% in 50%. Imprecision was acceptable at 0.25 and 1.0 microg/l, concentrations below the LOQ of previous methods. Aglycones released from conjugates after hydrolysis were easily measurable. Optimal conditions for hydrolysis were established. After oral administration of the three polyphenols to humans, their conjugates vastly exceeded the concentrations of the aglycones in both plasma and urine. Concentrations peaked within 0.5-1.0 h in plasma and within 8 h in urine. During the first 24 h, 5.1% of the (+)-catechin and 24.6% of the trans-resveratrol given were recovered in the urine (free plus conjugated). This method can be proposed as the method of choice to assay these polyphenols and their conjugates in biological fluids.
Dietary polyphenols, including anthocyanins, are suggested to be involved in the protective effects of red wine against cardiovascular diseases. Very little data are available concerning the bioavailability of anthocyanins, major sources of red pigmentation in red wine. The aim of this study was to compare changes in plasma malvidin-3-glucoside (M-3-G), a red wine anthocyanin, and its urinary excretion after ingestion of red wine, dealcoholized red wine and red grape juice.
Six healthy male subjects were studied in a randomized cross over setting in a human nutrition research unit under controlled conditions. All subject consumed 500 mL of each beverage on separate days providing the following M-3-G quantities: red wine 68 mg, dealcoholized red wine 58 mg, and red grape juice 117 mg. M-3-G was measured by HPLC and photodiode detection.
M-3-G was found in plasma and urine after ingestion of all the beverages studied. The aglycon, sulfate or glucuronate conjugates of M-3-G were not detected in plasma and urine. Increases in plasma M-3-G concentrations were not significantly different after the consumption of either red wine or dealcoholized red wine and were about two times less than those measured after consumption of red grape juice. This difference may be caused by the about two times higher M-3-G concentration determined in red grape juice. Area under the plasma concentration curves were as follows: 288 +/- 127 nmol x h/L (red wine), 214 +/- 124nmol x h/L (dealcoholized red wine) and 662 +/- 210 nmol x h/L (red grape juice) and showed a linear relationship with the amount of anthocyanin consumed (mean +/- SD).
M-3-G is poorly absorbed after a single ingestion of red wine, dealcoholized red wine, or red grape juice and seems to be differentially metabolized as compared to other red grape polyphenols. Our results suggest that not anthocyanins such as M-3-G themselves but rather not yet identified anthocyanin metabolites and/or other polyphenols in red wine might be responsible for the observed antioxidant and health effects in vivo in subjects consuming red wine.
Atherosclerosis may result partly from processes that occur following food consumption and that involve oxidized lipids in chylomicrons. We investigated reactions that could occur in the acidic pH of the stomach and accelerate the generation of lipid hydroperoxides and co-oxidation of dietary constituents. The ability of dietary polyphenols to invert catalysis from pro-oxidation to antioxidation was examined. The acidic pH of gastric fluid amplified lipid peroxidation catalyzed by metmyoglobin or iron ions. Metmyoglobin catalyzed peroxidation of edible oil, resulting in 8-fold increase of hydroperoxide concentration. The incubation of heated muscle tissue in simulated gastric fluid for 2 h enhanced hydroperoxides accumulation by 6-fold to 1200 microM. In the presence of catechin or red wine polyphenols, metmyoglobin catalyzed the breakdown of hydroperoxides to zero, totally preventing lipid peroxidation and beta-carotene cooxidation. We suggest that human gastric fluid may be an excellent medium for enhancing the oxidation of lipids and other dietary constituents. The results indicate the potentially harmful effects of oxidized fats intake in the presence of endogenous catalysts found in foods, and the major benefit of including in the meal plant dietary antioxidants.
The aim of this study was to investigate the effects of quercetin, a natural polyphenolic flavonoid, on voltage-dependent Ca2+ channels of smooth muscle cells freshly isolated from the rat tail artery, using either the conventional or the amphotericin B-perforated whole-cell patch-clamp method.
Quercetin increased L-type Ca2+ current [ICa(L)] in a concentration- (pEC50=5.09±0.05) and voltage-dependent manner and shifted the maximum of the current-voltage relationship by 10 mV in the hyperpolarizing direction, without, however, modifying the threshold and the equilibrium potential for Ca2+. Quercetin-induced ICa(L) stimulation was reversible upon wash-out. T-type Ca2+ current was not affected by quercetin.
Quercetin shifted the voltage dependence of the steady-state inactivation and activation curves to more negative potentials by about 5.5 and 7.5 mV respectively, in the mid-potential of the curves as well as increasing the slope of activation. Quercetin slowed both the activation and the deactivation kinetics of the ICa(L). The inactivation time course was also slowed but only at voltages higher than 10 mV. Moreover quercetin slowed the rate of recovery from inactivation.
These results prove quercetin to be a naturally-occurring L-type Ca2+ channel activator.
British Journal of Pharmacology (2002) 135, 1819–1827; doi:10.1038/sj.bjp.0704631
Despite their powerful biologic activities conducive to protection against atherosclerosis, cancer and inflammatory diseases demonstrated in vitro, there is considerable doubt whether the polyphenolic constituents present in red wine and other dietary components are effective in vivo.
We have tested the absorptive efficiency of three of these constituents (trans-resveratrol, [+]-catechin and quercetin) when given orally to healthy human subjects in three different media.
Twelve healthy males aged 25 to 45 were randomly assigned to three different groups consuming orally one of the following polyphenols: trans-resveratrol, 25 mg/70 kg; [+]-catechin 25 mg/70 kg; quercetin 10 mg/70 kg. Each polyphenol was randomly administered at 4-week intervals in three different matrices: white wine (11.5% ethanol), grape juice, and vegetable juice/homogenate. Blood was collected at zero time and at four intervals over the first four hours after consumption; urine was collected at zero time and for the following 24-h. The sums of free and conjugated polyphenols were measured in blood serum and urine by a gas-chromatographic method.
All three polyphenols were present in serum and urine predominantly as glucuronide and sulfate conjugates, reaching peak concentrations in the former around 30-min after consumption. The free polyphenols accounted for 1.7 to 1.9% (trans-resveratrol), 1.1 to 6.5% ([+]-catechin) and 17.2 to 26.9% (quercetin) of the peak serum concentrations. The absorption of trans-resveratrol was the most efficient as judged by peak serum concentration, area-under-the curve (4 h) and urinary 24-h excretion (16-17% of dose consumed). [+]-Catechin was the poorest by these criteria (urine 24-h excretion 1.2%-3.0% of dose consumed), with quercetin being intermediate (urine 24-h excretion 2.9%-7.0% of dose consumed). Some significant matrix effects were observed for the serum polyphenol concentrations, but in the case of urine no matrix promoted significantly higher excretion than the other two.
The absorption of these three polyphenols is broadly equivalent in aqueous and alcoholic matrices but, at peak concentrations of 10 to 40 nmol/L, is inadequate to permit circulating concentrations of 5 to 100 micromol/L consistent with in vitro biologic activity. The voluminous literature reporting powerful in vitro anticancer and antiinflammatory effects of the free polyphenols is irrelevant, given that they are absorbed as conjugates.
Sulfate conjugation by phenolsulfotransferase (PST) enzyme is an important process in the detoxification of xenobiotics and endogenous compounds. There are two forms of PST that are specific for the sulfation of small phenols (PST-P) and monoamines (PST-M). Phenoilc acids have been reported to have important biological and pharmacological properties and may have benefits to human health. In the present study, human platelets were used as a model to investigate the influence of 13 phenolic acids on human PST activity and to evaluate the relationship to their antioxidant activity. The results showed that chlorogenic acid, syringic acid, protocatechuic acid, vanillic acid, sinapic acid, and caffeic acid significantly (p < 0.05) inhibited the activities of both forms of PST by 21-30% at a concentration of 6.7 microM. The activity of PST-P was enhanced (p < 0.05) by p-hydroxybenzoic acid, gallic acid, gentisic acid, o-coumaric acid, p-coumaric acid, and m-coumaric acid at a concentration of 6.7 microM, whereas the activity of PST-M was enhanced by gentisic acid, gallic acid, p-hydroxybenzoic acid, and ferulic acid. The phenolic acids exhibited antioxidant activity as determined by the oxygen radical absorbance capacity (ORAC) assay and Trolox equivalent antioxidant capacity (TEAC) assay, especially gallic acid, p-hydroxybenzoic acid, gentisic acid, and coumaric acid, which had strong activity. The overall effect of phenolic acids tested on the activity of PST-P and PST-M was well correlated to their antioxidant activity of ORAC value (r = 0.71, p < 0.01; and r = 0.66, p < 0.01). These observations suggest that antioxidant phenolic acids might alter sulfate conjugation.
Two hypotheses on absorption mechanisms of flavonoid glucosides across the small intestine have been proposed: active uptake of the quercetin glucoside by the sodium-dependent glucose transporter (SGLT1) with subsequent deglycosylation within the enterocyte by cytosolic beta-glucosidase, or luminal hydrolysis of the glucoside by lactase phlorizin hydrolase (LPH) and absorption by passive diffusion of the released aglycone. To test the above hypotheses we employed phlorizin (as an inhibitor of SGLT1) and N-(n-butyl)-deoxygalactonojirimycin (as an inhibitor of the lactase domain of LPH) in a rat everted-jejunal sac model. Quercetin-4'-glucoside mucosal hydrolysis was 10 times greater than quercetin-3-glucoside hydrolysis in the absence of inhibitors (449 and 47 nmol g(-1) tissue, respectively), despite the similar amounts (13+/-4 and 9+/-1 nmol g(-1), respectively) being transferred to the serosal compartment during the 15 min incubation. Apical hydrolysis of both quercetin glucosides was significantly reduced in the presence of NB-DGJ (80%), and transfer of quercetin (measured as quercetin metabolites) to the serosal solution was also significantly reduced (40-50%). In the presence of phlorizin, transfer of metabolites to the serosal solution was only reduced in the case of quercetin-4'-glucoside. Evidently the mechanism of absorption of quercetin-4'-glucoside involves both an interaction with SGLT1 and luminal hydrolysis by LPH, whereas quercetin-3-glucoside appears to be absorbed only following hydrolysis by LPH.
Oxidation of flavonoids with a catechol structural motif in their B ring leads to formation of flavonoid quinone/quinone methides, which rapidly react with GSH to give reversible glutathionyl flavonoid adducts. Results of the present study demonstrate that as a thiol-scavenging agent for this reaction Cys is preferred over GSH and N-acetylcysteine. The preferential scavenging by Cys over GSH reported in the present study appeared not to provide a basis for detection of thiol-based flavonoid conjugates in biological systems. This is because physiological concentrations of GSH are substantially higher than those of Cys, which was shown to shift the balance of thiol conjugate formation in favor of glutathionyl adduct formation. Furthermore, the cysteinyl quercetin adducts, although not showing the reversible nature of the glutathionyl conjugates, appeared nevertheless to be unstable. Thus, as a biomarker for formation of reactive quercetin quinone/quinone methides in biological systems, detection of the glutathionyl conjugates or the N-acetylcysteinyl conjugates derived from them should still be the method of choice. At GSH levels that dominate the level of other cellular thiol groups, covalent addition of the quinone to other cellular thiol groups may be efficiently prevented. However, various tissues are known to contain higher levels of protein-bound sulfhydryl moieties than of nonprotein sulfhydryl groups, the latter consisting of especially GSH. Thus, the results of the present study indicate that in biological systems covalent addition of quercetin quinone methide to tissue protein sulfhydryl groups can be expected. The transient nature of these adducts, as shown for all three types of thiol quercetin adducts in the present study, will, however, also result in a transient nature of the protein-bound quercetin adducts to be expected. Because stability of the various thiol quercetin adducts appeared a matter of minutes to hours instead of days, this rapid transient nature of possible quercetin quinone methide adducts may also restrict the ultimate toxicity to be expected from the quercetin quinone/quinone methides.
Quercetin is a typical flavonoid ubiquitously present in fruits and vegetables, and its antioxidant effect is implied to be helpful for human health. The bioavailability of quercetin glycosides should be clarified, because dietary quercetin is mostly present as its glycoside form. Although quercetin glycosides are subject to deglycosidation by enterobacteria for the absorption at large intestine, small intestine acts as an effective absorption site for glucose-bound glycosides (quercertin glucosides). This is because small intestinal cells possess a glucoside-hydrolyzing activity and their glucose transport system is capable of participating in the glucoside absorption. A study using a cultured cell model for intestinal absorption explains that the hydrolysis of the glucosides accelerates their absorption in the small intestine. Small intestine is also recognized as the site for metabolic conversion of quercetin and other flavonoids as it possesses enzymatic activity of glucuronidation and sulfation. Modulation of the intestinal absorption and metabolism may be beneficial for regulating the biological effects of dietary quercetin.
During red wine aging, there is a loss of anthocyanins and the formation of various other pigments, so-called vitisins A, which are formed through the chemical interaction of the original anthocyanins with pyruvic acid. The objective of this study was to investigate the antioxidant activities of the most abundant anthocyanins present in red wine (glycosides of delphinidin, petunidin, and malvidin) and their corresponding vitisins A. Anthocyanins exhibited a higher iron reducing as well as 2,2'-azinobis (3-ethyl-benzothiazoline-6-sulfonate) and peroxyl radical scavenging activity than their corresponding vitisins A. Delphinidin showed the highest antioxidant effect of the tested compounds in all of the assays used. Furthermore, we studied the effect of anthocyanins and vitisins A on platelet aggregation and monocyte and endothelial function. Anthocyanins and vitisins did not affect nitric oxide production and tumor necrosis factor-alpha (TNF-alpha) secretion in lipopolysaccharide plus interferon-gamma-activated macrophages. Furthermore, anthocyanins and vitisins did not change collagen-induced platelet aggregation in vitro. However, anthocyanins and to a lesser extent vitisins exhibited protective effects against TNF-alpha-induced monocyte chemoattractant protein production in primary human endothelial cells.
This work aimed to investigate, in the rat, the acute in vitro effect of red wine and the effect of chronic red wine ingestion on the intestinal absorption of thiamine and folate and to compare them with the effects of ethanol alone.
The effects of red wine and of an ethanol solution (same ethanol concentration as that in the red wine, i.e., 12% [v/v]) on rat jejunal apparent permeability (Papp) to H-thiamine and H-folate in the mucosal-to-serosal direction were investigated. Red wine and ethanol were tested both chronically (21-day consumption) and acutely in vitro.
Acutely, both red wine and ethanol 12% (v/v) (both diluted 1:5) reduced (to 65 and 60% of control, respectively) the mucosal-to-serosal Papp to H-thiamine across rat jejunum. Chronic (21-day) ethanol (12% [v/v]) consumption also decreased the Papp to H-thiamine (to 33% of control), but red wine consumption for the same period did not change it. Mucosal-to-serosal Papp to H-folate across rat jejunum was not changed by chronic ingestion of red wine or ethanol. Similarly, it was not affected by acute exposition of the tissue to red wine or ethanol. Acute ethanol (0.05% [v/v]) did not affect the Papp to H-thiamine or H-folate in jejunal tissues obtained from control and red wine-treated rats, but it significantly increased the Papp to both H-thiamine and H-folate (to 183 and 197% of control, respectively) in tissues from chronically ethanol-treated rats.
Acute and chronic red wine or ethanol had no effect on the intestinal absorption of folate. However, ethanol, both acutely and chronically, decreased the jejunal absorption of thiamine, and red wine reduced the jejunal absorption of thiamine, but only when tested acutely. These findings show that it is not correct to extrapolate from results obtained with ethanol alone on intestinal permeability to the effect of alcoholic beverage consumption.
Quercetin is an abundant flavonoid in the human diet with numerous biological activities, which may contribute to the prevention of human disease but also may be potentially harmful. Quercetin is oxidized in cells to products capable of covalently binding to cellular proteins, a process that may be important for its biological activities. In the present study, using radiolabeled drug and quantifying the products after electrophoretic separation, proteins to which oxidized quercetin is binding irreversibly were identified. The binding of quercetin to human serum albumin (HSA) in human blood and the effect of stimulation of neutrophilic myeloperoxidase on this binding were also measured. The in vitro binding of quercetin to eight proteins in the presence of catalytic amounts of horseradish peroxidase and hydrogen peroxide was highly selective for HSA. For all proteins the binding was dramatically decreased by reduced L-glutathione. In the blood samples, the release of neutrophilic myeloperoxidase by phorbol ester caused a 3-fold increase in the binding of quercetin to HSA. This study shows that quercetin in the presence of peroxidase/hydrogen peroxide covalently links to proteins with a particularly high affinity for HSA and that this also may occur in vivo after exposure to quercetin. This provides further insights into the complex behavior of this major dietary flavonoid.
Royal Science of Chemistry; 8th Weurman Flavour Research Symposium Effects of quercetin and rutin on vascular preparations: a comparison between mechanical and electrophysiological phenom-ena
- U K Cambridge
- F Fusi
- S Saponara
- F Pessina
- B Gorelli
- G Sgaragli
Cambridge, U.K.: Royal Science of Chemistry; 8th Weurman Flavour Research Symposium. FUSI, F., SAPONARA, S., PESSINA, F., GORELLI, B. & SGARAGLI, G. (2003). Effects of quercetin and rutin on vascular preparations: a comparison between mechanical and electrophysiological phenom-ena. Eur. J. Nutr., 42, 10–17.
ECC Commission Regulation VO 2676/90 concerning the establishment of common analytical methods in the sector of wine
- ECC
ECC. (1990). ECC Commission Regulation VO 2676/90 concerning the
establishment of common analytical methods in the sector of wine.
Offic. J. Eur. Communities, 3, 1-192.
The impact of dealcoholization on the flavor of wineFrelating concentration of aroma compounds to sensory data using PLS analysis
- U Fisher
- R G Berger
- A Hakansson
- A C Nobel
FISHER, U., BERGER, R.G., HAKANSSON, A. & NOBEL, A.C. (1996).
The impact of dealcoholization on the flavor of wineFrelating
concentration of aroma compounds to sensory data using PLS
analysis. In: Flavour Science: Recent Developments. eds. Taylor,
A.J. & Mottram, D.S., pp. 335-338. Cambridge, U.K.: Royal
Science of Chemistry; 8th Weurman Flavour Research Symposium.