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Inhibitory Effects of Cedrol, β-Cedrene, and Thujopsene on Cytochrome P450 Enzyme Activities in Human Liver Microsomes
Abstract
Cedrol, β-cedrene, and thujopsene are bioactive sesquiterpenes found in cedar essential oil and exert antiseptic, anti-inflammatory, antispasmodic, tonic, astringent, diuretic, sedative, insecticidal, and antifungal activities. These compounds are used globally in traditional medicine and cosmetics. The aim of this study was to investigate the inhibitory effects of cedrol, β-cedrene, and thujopsene on the activities of eight major human cytochrome P-450 (CYP) enzymes using human liver microsomes to assess potential β-cedrene-, cedrol-, and thujopsene–drug interactions. Cedrol, β-cedrene, and thujopsene were found to be potent competitive inhibitors of CYP2B6-mediated bupropion hydroxylase with inhibition constant (K i) values of 0.9, 1.6, and 0.8 μM, respectively, comparable with that of a selective CYP2B6 inhibitor, thioTEPA (K i, 2.9 μM). Cedrol also markedly inhibited CYP3A4-mediated midazolam hydroxylation with a K i value of 3.4 μM, whereas β-cedrene and thujopsene moderately blocked CYP3A4. Cedrol, β-cedrene, and thujopsene at 100 μM negligibly inhibited CYP1A2, CYP2A6, and CYP2D6 activities. Only thujopsene was found to be a mechanism-based inhibitor of CYP2C8, CYP2C9, and CYP2C19. Cedrol and thujopsene weakly inhibited CYP2C8, CYP2C9, and CYP2C19 activities, but β-cedrene did not. These in vitro results indicate that cedrol, β-cedrene, and thujopsene need to be examined for potential pharmacokinetic drug interactions in vivo due to their potent inhibition of CYP2B6 and CYP3A4.
... Moreover, four constituents such as cedrol, geranylgeraniol, sclareol, and ethyl linoleate were shown to have definite pharmacological activities. Cedrol, a kind of sesquiterpene alcohols, expresses various activities such as anticancer, [11,12] anti-inflammatory, [13] sedative, [14] and antifungal. [15][16][17] Zhang [12] investigated that cedrol can inhibit cell proliferation, induce apoptosis in A549 cells via mitochondrial and PI3K/Akt signaling pathways and pro-death autophagy by increasing intracellular production of reactive oxygen species. ...
... [15][16][17] Zhang [12] investigated that cedrol can inhibit cell proliferation, induce apoptosis in A549 cells via mitochondrial and PI3K/Akt signaling pathways and pro-death autophagy by increasing intracellular production of reactive oxygen species. Moreover, Jeong et al. [13] found that cedrolcan inhibited the activity of cytochrome P450 enzyme in human liver microsomes. Geranylgeraniol, an important biosynthetic precursor of multiple biochemical products including terpenes, carotenoids, steroids, cholesterol, and paclitaxel, is a straight chain diterpene possessing extensive physiological activities such as anticancer, antivirus, and so on. ...
... In our study, we demonstrated the high antimicrobial activity of strain LGMF1254 against the phytopathogen P. citricarpa because of the production of volatile compounds inhibiting mycelium growth and pycnidia formation. Among the major compounds produced by strain LGMF1254, the amounts of trans-a-bergamotene [31], cedrene [26], thujopsene [26], and a-himachalene [6] [4,5,65]. Phytosanitary restrictions on the export of fruits with CBS signs, the absence of an effective treatment, and restrictions on the presence of fungicide residues in fruits [51] highlight the importance of alternative strategies for the treatment of CBS, such as biological control. ...
... In our study, we demonstrated the high antimicrobial activity of strain LGMF1254 against the phytopathogen P. citricarpa because of the production of volatile compounds inhibiting mycelium growth and pycnidia formation. Among the major compounds produced by strain LGMF1254, the amounts of trans-a-bergamotene [31], cedrene [26], thujopsene [26], and a-himachalene [6] [4,5,65]. Phytosanitary restrictions on the export of fruits with CBS signs, the absence of an effective treatment, and restrictions on the presence of fungicide residues in fruits [51] highlight the importance of alternative strategies for the treatment of CBS, such as biological control. ...
The citrus industry is among the most important worldwide, but citrus plants are affected by a large number of diseases, such as Citrus Black Spot (CBS), caused by the fungus Phyllosticta citricarpa. To identify alternative methods for CBS control, endophytic fungi were isolated by our group from healthy citrus plants in Brazil. Over 400 fungal isolates were obtained, and isolate LGMF1254 was selected based on its inhibitory effect on the growth of P. citricarpa because of the production of volatile organic compounds (VOCs). This isolate was identified as Muscodor sp. by morphological examination and phylogenetic analysis using the internal transcribed spacer (ITS) region: High similarity with M. sutura, M. vitigenus, and M. equiseti was observed. We also sequenced the RPB2 gene, and isolate LGMF1254 showed 99% similarity with M. sutura. To identify this isolate at the species level, the main VOCs were determined, and according to this analysis, LGMF1254 may be classified as an M. sutura strain; however, sequences from regions other than ITS and RPB2 are necessary for conclusive genotyping. The VOCs produced by strain LGMF1254 can be considered an alternative way to control P. citricarpa during the transport of fruits and to prevent the development of CBS signs.
... As such, more studies that involve other PAHs are required as well as elucidation of the mechanisms underlying the protective effects of these therapeutic agents. In addition, more therapeutic agents especially from natural products that have the potentials to inhibit the activities of cytochrome P450 enzymes need to be screened for their ameliorative potentials against PAH-induced toxicity in humans and other animals (Jeong et al. 2014). ...
Polycyclic aromatic hydrocarbons (PAHs) are legacy pollutants of considerable public health concern. Polycyclic aromatic hydrocarbons arise from natural and anthropogenic sources and are ubiquitously present in the environment. Several PAHs are highly toxic to humans with associated carcinogenic and mutagenic properties. Further, more severe harmful effects on human- and environmental health have been attributed to the presence of high molecular weight (HMW) PAHs, that is PAHs with molecular mass greater than 300 Da. However, more research has been conducted using low molecular weight (LMW) PAHs). In addition, no HMW PAHs are on the priority pollutants list of the United States Environmental Protection Agency (US EPA), which is limited to only 16 PAHs. However, limited analytical methodologies for separating and determining HMW PAHs and their potential isomers and lack of readily available commercial standards make research with these compounds challenging. Since most of the PAH kinetic data originate from animal studies, our understanding of the effects of PAHs on humans is still minimal. In addition, current knowledge of toxic effects after exposure to PAHs may be underrepresented since most investigations focused on exposure to a single PAH. Currently, information on PAH mixtures is limited. Thus, this review aims to critically assess the current knowledge of PAH chemical properties, their kinetic disposition, and toxicity to humans. Further, future research needs to improve and provide the missing information and minimize PAH exposure to humans.
... In addition, as of today there is no contribution of olive oil or its constituents in potential DFIs. On the other hand, for some terpenes with PAF action, i.e., cedrol, inhibiting properties against human P450 have been described in vitro and further studies are needed to clarify potential DFIs [130]. Regarding potential PD-DFIs of PAF modulators with anti-platelet medications, there are not any reports suggesting potential contribution in DFIs. ...
There is a growing interest among people in western countries for adoption of healthier lifestyle habits and diet behaviors with one of the most known ones to be Mediterranean diet (Med-D). Med-D is linked with daily consumption of food products such as vegetables, fruits, whole grains, seafood, beans, nuts, olive oil, low-fat food derivatives and limited consumption of meat or full fat food products. Med-D is well-known to promote well-being and lower the risk of chronic conditions such as cardiovascular diseases, diabetes, and metabolic syndrome. On the other hand bioactive constituents in foods may interfere with drugs’ pharmacological mechanisms, modulating the clinical outcome leading to drug-food interactions (DFIs). This review discusses current evidence for food products that are included within the Med-Dand available scientific data suggest a potential contribution in DFIs with impact on therapeutic outcome. Most cases refer to potential modulation of drugs’ absorption and metabolism such as foods’ impact on drugs’ carrier-mediated transport and enzymatic metabolism as well as potential synergistic or antagonistic effects that enhance or reduce the pharmacological effect for some drugs. Adherence to Med-D can improve disease management and overall well-being, but specific foods should be consumed with caution so as to not hinder therapy outcome. Proper patient education and consultation from healthcare providers is important to avoid any conflicts and side effects due to clinically significant DFIs.
... This solubility is influenced by the nature and polarity of the solvent (Wright and Marangoni, 2006). A few of the compounds such as thujopsene and alpha cedrol have been noted to have therapeutic activities, which include anti-inflammatory, antispasmodic, tonic, astringent, diuretic, sedative, insecticidal and antifungal activities (Jeong et al., 2014). Terpinolene has some anticancer effect (Okumura et al., 2012). ...
Essential oils are one of the most popular natural products, with broad applications in dermatology. Hair loss is a disorder in which the hair falls out from skin areas where they are usually present, such as the scalp and the body.
The aim of the work was to formulate oleogels containing two essential oils (Cedarwood and Rosemary) singly and in combination and evaluate their hair growth enhancing effect on an animal model. Oleogels were formed using beeswax as the organogelator with concentrations of 10 % for the oils when used singly or 5 % each for the oils when formulated in combination. Characterization of oleogels were done using spreadability, oil binding capacity (OBC), gas chromatography (GC) and differential scanning calorimetry (DSC). Hair growth evaluation was carried out in 18 albino rats in six groups of threes. A hair removal cream was applied on the experimental animals and the Oleogel applied for six-weeks.
GC analysis of the oils revealed the presence of thujopsene, alpha-pinene, beta-pinene, pentane, alpha cedrenea, beta cedrenea, alpha cedrol, gamma-terpene, acetonitrite, atlantone, terpinolene in cedarwood oil while rosemary oil contained 1-8 cineole, camphor, alpha-pinene, beta-pinene, camphene, p-cymene, alpha-terpinene, gamma terpinene, gamma-humulene, beat-bisabolene, genaniol and terpinolene. DSC thermogram of the oleogel formulations showed varying degrees of amorphicity.
Spreadability results showed that the oleogels containing cedarwood oil were more spreadable. Conversely, oil binding capacity values were higher with Rosemary oil than Cedar wood oil with values ranging from 91 % (for the oleogel containing 10 % rosemary oil) to 81 % for the bland oleogel (no essential oil). Hair growth evaluation revealed that the oleogel containing rosemary oil (10 %) had similar effects as the positive control (Minoxidil, 2 %) at the end of the six-week period.
Oleogels made from cedar wood and rosemary oils have hair growth enhancing effects.
... In line with this mechanism, another terpenoid compound, namely α-humulene, which was anti-proliferative, pro-apoptotic, and had a strong anti-cancer effect when combined with 5-Fu and oxaliplatin (Ambrož et al., 2019;Chen et al., 2019). The cytotoxicity of VO was also due to the presence of biphenylene, β-cedrene, 2-carene, ledane, and propanedinitrile (Pojarová et al., 2007a;Jeong et al., 2014;Batra et al., 2016;Salim et al., 2016;Elshamy et al., 2017). The results of this study revealed various potential effects associated with the inhibition or killing of cancer cells. ...
Objective:
To investigate vetiver oil (VO) selectivity effects on several cancer cell types and identify the β-caryophyllene role and mechanisms to prevent cancer development.
Methods:
Cytotoxic effects of VO on three types of cancer cells (WiDr, 4T1, T47D) were determined using MTT assay. VO's effects on the cell cycle and apoptosis were analyzed using flow cytometry. Intracellular Reactive Oxygen Species (ROS) of cells after treatment with VO was observed with DCFDA staining. Bioinformatics study and molecular docking were used to determine the molecular targets of VO.
Results:
VO contained various essential oils in which β-caryophyllene was the most abundant. 4T1 cells performed the lowest IC50 value. WiDr and 4T1 cells showed an arrest in the G2/M phase, while T47D showed an increase of sub G1 population after VO treatment. On the other hand, apoptosis was only observed in WiDr and T47D cells. ROS levels were increased significantly in WiDr and T47D cells but not in 4T1 cells. Cannabinoids CB2 receptor (CNR2) was highly expressed in 4T1 cells and commonly exhibited a low survival rate on Triple Negative Breast Cancer (TNBC) patients. CNR2 was the notable target of β-caryophyllene and performed agonistic interaction, which might have contributed to its cytotoxic activity against 4T1 cells.
Conclusion:
The molecular interaction of VO cannabinoid agonists and the CNR2 receptor was the underlying cause of VO cytotoxicity, which is a VO distinction on TNBC. Therefore, VO is better suited for use as an anti-cancer agent in TNBC cells.
... Moreover, CEO has been documented as possessing antifungal activities including against Gloeophyllum trabeum, Oligoporus placenta, Trametes versicolor, Coniophora puteanai Candida albicans and Trichophyton mentagrophytes (Fidah et al., 2016;Orchard et al., 2019). The antifungal potency of CEO might be related to its main constituents such as cedrol, βcedrene and thujopsene (Jeong et al., 2014;Powers et al., 2018). These volatile compounds interrupt the balance in the lytic and synthesis enzyme such as chitin synthase leading to the cessation of hyphal extension (Fidah et al., 2016). ...
A novel formulation of composite coating comprising 0.8% chitosan (Chi) incorporating 0.025% CuO nanoparticles (CuO) and 0.5% Indonesian cedarwood essential oil (CEO) was fabricated by casting method. FTIR, CLSM, and SEM analyses were employed to characterize the biocompatibility of each formulation. Additionally, the physico-chemically properties of the composite coatings were characterized. The colour (L*), light transmission, zeta potential, and roughness of Chi were significantly (P < 0.05) altered negatively by the presence of CuO or CEO; the colour (a*, b*, and ∆E), apparent viscosity, and transparency also changed positively as a consequence of CuO and CEO incorporation. The antifungal features of a pure Chi coating against Penicillium italicum and Penicillium digitatum were improved synergistically by CuO and CEO, confirmed by in vitro and in vivo assays. Composite coatings obtained in this work may have potential applications for active primary food packaging, particularly for fresh postharvest commodities.
... M.Roem. extracts inhibit SARS-CoV replication (Jeong et al., 2014). Glycyrrhizin inhibits the replication of SARS-CoV after viral entrance into Vero cells, inhibiting virus attachment and entry (Shen et al., 2005). ...
Severe acute respiratory syndrome–related coronavirus-2 (SARS-CoV-2), a β-coronavirus, is the cause of the recently emerged pandemic and worldwide outbreak of respiratory disease. Researchers exchange information on COVID-19 to enable collaborative searches. Although there is as yet no effective antiviral agent, like tamiflu against influenza, to block SARS-CoV-2 infection to its host cells, various candidates to mitigate or treat the disease are currently being investigated. Several drugs are being screened for the ability to block virus entry on cell surfaces and/or block intracellular replication in host cells. Vaccine development is being pursued, invoking a better elucidation of the life cycle of the virus. SARS-CoV-2 recognizes O-acetylated neuraminic acids and also several membrane proteins, such as ACE2, as the result of evolutionary switches of O-Ac SA recognition specificities. To provide information related to the current development of possible anti–SARS-COV-2 viral agents, the current review deals with the known inhibitory compounds with low molecular weight. The molecules are mainly derived from natural products of plant sources by screening or chemical synthesis via molecular simulations. Artificial intelligence–based computational simulation for drug designation and large-scale inhibitor screening have recently been performed. Structure–activity relationship of the anti–SARS-CoV-2 natural compounds is discussed.
... Additionally, this compound was found to be a potent competitive inhibitor of CYP2B6-mediated bupropion hydroxylase comparable with that of a selective CYP2B6 inhibitor, thioTEPA. Thujopsene was found to be a mechanism-based inhibitor of CYP2C8, CYP2C9, and CYP2C19 (Jeong et al., 2014). 2-Pentylfuran is a volatile compound occurring in fungi such as Aspergillus fumigatus, A. niger, A. flavus, and Fusarium spp. ...
Codonopsis pilosula (Franch.) Nannf. is a species whose radix has long been used in traditional folk medicine in China, Japan and Korea. Codonopsis Radix is obtained from cultivations mainly in Gansu, Shanxi, Sichuan, and Guizhou Provinces of China. This study describes an efficient protocol for genetic transformation of C. pilosula by Rhizobium rhizogenes and the obtainment of transformed roots of this species with valuable medicinal properties. It was found that both the bacterial strain (A4 and ATCC 15834) and acetosyringone (AcS) addition influenced the efficiency of transformation. The highest frequency of root induction (69 %) was observed on the Murashige and Skoog (MS) agar medium supplemented with AcS after transformation with A4 strain. The transformation was confirmed by PCR analysis. Of the tested media (MS, Schenk and Hildebrandt - SH, Gamborg - B5, and Woody Plant - WPM) those with full macro- and microsalt concentrations elicited significantly greater C. pilosula transformed root (CP2) biomass accumulation than the half-strength media, apart from MS medium. The greatest CP2 root biomass was observed in SH medium (1.65 g flask⁻¹ DW). Among the tested sucrose concentrations (10−70 g L⁻¹), the best result was obtained by using 30 g L⁻¹ sucrose. Essential oils isolated by hydrodistillation from CP2 transformed roots and commercially available raw material, C. pilosula roots, had very similar qualitative composition. The most important group of common constituents of both oils were sesquiterpene hydrocarbons. The main among twenty two compounds in this group possessed skeletons of barbatane, thujopsane and bisabolane; the predominant ones being α- and β-barbatene, followed by β-chamigrene and thujopsene. This study presented that C. pilosula transformed roots can be a potential source for the industrial production of the raw material from species of the genus Codonopsis used in traditional Chinese medicine.
... Additionally, the majority of analyses of essential oil of P. amalago leaves showed the prevalence of sesquiterpene hydrocarbons such as bicyclogermacrene, β-phellandrene and germacrene D, with substantial amounts of monoterpene hydrocarbons, such as α-pinene, and some sesquiterpenoids such as spathulenol (Salehi et al., 2019). The essential oil played important biological roles, such as antimicrobial (Moqrich et al., 2005;Santos et al., 2016) anti-inflammatory (Jeong et al., 2014;Bahi et al., 2014;Passos et al., 2014;Carneiro et al., 2017) antioxidant (Nogueira Neto et al., 2013;Santos et al., 2016;Oliveira et al., 2016), and antihyperalgesic (Carneiro et al., 2017). ...
Piper amalago L. is a medicinal plant traditionally used as a healing agent for wounds, burns, abscesses, boils, and insect bites. The current study aimed to evaluate the possible effects of the aqueous crude extract obtained from P. amalago leaves, in different concentrations and in different incubation times, using the in vitro model of mouse fibroblasts (3T3). The extract was tested in different concentrations at the 24 h incubation time for analysis of cell viability, cytotoxicity, proliferation, cell morphology, immunostaining, adhesion and cell spreading assays, as well as to determine the hydroxyproline concentration and activity of the metalloproteinase MMP2. Morphologically, after exposure to the concentrations of 15 and 150 µg/mL, the cells maintained the morphology, yet a greater number of cells with more expansions of the cell body and larger than the control cells were observed. The treated cell culture also showed a greater number of cells, larger cells, a greater expansion of the cell body, adherent cells spread over the substrate, and a more juxtaposed, central and spherical nucleus. The treatment induced greater cell adhesion to the polymer, fibronectin, and collagen I. Biochemical results showed a significant increase in the hydroxyproline amino acid after exposure for 96 h. The extract did not induce loss of cell viability until the concentration reached 150 µg/mL, positively modulating proliferation, morphology, adhesion, degree of spreading, and organization of microfilaments. The extract also promoted a significant increase in the hydroxyproline amino acid.
... 14-day administration of cedrol significantly reduced the IL-6 and TNF-α level, in the spinal cord of animals subjected to nerve injury. Previous studies showed, Cedar oil and its major constituents, β-cedrene, cedrol, and thujopsene, display many biological activities, such as anti-inflammatory, antispasmodic, sedative, and sedative effects (Jeong et al. 2014;Kim et al. 2013). Plateletactivating factor receptor is the key mediator in the signal transduction pathways leading to inflammation (Elovitz et al. 2003). ...
Injured somatosensory nervous system cause neuropathic pain which is quite difficult to treat using current approaches. It is therefore important to find new therapeutic options. We have analyzed cedrol effect on chronic constriction injury (CCI) induced neuropathic pain in rats. The mechanical and thermal hypersensitivity were evaluated using the von Frey filament, radiant heat and acetone drop methods. The changes in the levels of biomarkers of oxidative stress including malondialdehyde (MDA) and total thiol (SH), as well as inflammatory mediators including Tumour Necrosis Factor alpha (TNF-α) and Interleukin 6 (IL-6) were estimated in the lumbar portion (L4–L6) of neuropathic rats. Administration of cedrol attenuated the CCI-induced mechanical and thermal hypersensitivity. CCI produced an increase in MDA along with a reduction in SH levels in the spinal cord of the CCI rats. Reduced levels of SH were restored by cedrol. Also, the levels of MDA were reduced in the cedrol-treated CCI rats compared to the untreated CCI rats. Besides, level of TNF-α and IL-6 increased in the spinal cord of CCI group and cedrol could reverse it. The current study showed that cedrol attenuates neuropathic pain in CCI rats by inhibition of inflammatory response and attenuation of oxidative stress.
... Compound (88) is the active component in the hiba essential oil responsible for its significant antimicrobial properties (Matsuura, Yamaguchi, Zaike, Yanagihara, & Ichinose, 2014). Other potential effects of (88) including anti-inflammatory, diuretic, and anti-spasmodic effects have also been reported (Jeong, Kwon, Kong, Kim, & Lee, 2014). Compound (89) was described to have a strong woody odor (Jirovetz et al., 2003). ...
Grapes are an important global horticultural product, and are mainly used for winemaking. Typically, grapes and wines are rich in various phytochemicals, including phenolics, terpenes, pyrazines, and benzenoids, with different compounds responsible for different nutritional and sensory properties. Among these compounds, sesquiterpenes, a subcategory of the terpenes, are attracting increasing interest as they affect aroma and have potential health benefits. The characteristics of sesquiterpenes in grapes and wines in terms of classification, biosynthesis pathway, and active functions have not been extensively reviewed. This paper summarizes 97 different sesquiterpenes reported in grapes and wines and reviews their biosynthesis pathways and relevant bio‐regulation mechanisms. This review further discusses the functionalities of these sesquiterpenes including their aroma contribution to grapes and wines and potential health benefits, as well as how winemaking processes affect sesquiterpene concentrations.
... α-Cedrene in essential oil of C. lanceolata shows antimite activity [23]. Jeong et al. [29] reported that thujopsene exhibited antiinflammatory, antispasmodic, tonic, astringent, diuretic, sedative, insecticidal, and antifungal activities. Not only does thujopsene have the potential to be developed into botanical drugs, it can provide a fragrant and healthy living environment. ...
Volatile organic compounds (VOCs) released from Chamaecyparis formosensis, Cryptomeria japonica, Cunninghamia lanceolata, Chamaecyparis obtusa var. formosana, and Taiwania cryptomerioides five major building and interior decoration timbers and their essential oil components were analyzed using GC–MS and TD/GC–MS/FID. Results showed that C. obtusa var. formosana had the highest yield of essential oil (3.42%), followed by C. formosensis (3.14%), while C. japonica had the lowest yield (0.95%). Moreover, oxygenated sesquiterpene was the highest relative content in all five essential oils and their main constituents were trans-myrtanol (18.04%), 1-epi-cubenol (15.99%), cedrol (62.26%), α-cadinol (26.42%), and α-cadinol (27.98%), respectively. In terms of emission quantity of top VOC, the results showed the decreasing order of C. formosensis (myrtenal, 74.21 mg/m2) > T. cryptomerioides (thujopsene, 12.00 mg/m2) > C. lanceolata (α-cedrene, 10.27 mg/m2) > C. obtusa var. formosana (α-pinene, 8.05 mg/m2) > C. japonica (α-cedrene, 4.25 mg/m2). C. formosensis had a greater amount of VOCs emitted and hence gave off more fragrance than C. obtusa var. formosana initially. However, after indoor exposure of 24 weeks, the VOC emission quantity of C. obtusa var. formosana exceeded that of C. formosensis. α-Cedrene and thujopsene were the top two major VOCs of both C. lanceolata and T. cryptomerioides. However, they both showed a trend of decrease in emission with prolonged exposure. All five plantation timbers showed good antifungal, antimicrobial, antibacterial, and antitermitic properties, making them ideal materials for interior decoration. Not only do they have strong bioactivities, they can also provide a fragrant and healthy living environment.
... For instance, caryophyllene, one of the bicyclic sesquiterpenes has potential antioxidant, anti-inflammatory, and antimicrobial activities (Sharma et al., 2016). Another compounds such as cedrol (a sesquiterpene alcohol), cedrene, and thujopsene possess inhibitory effects against cytochrome P450 (CYP) enzyme (CYP2B6 and CYP3A4) in human liver microsomes in vitro as well as anti-inflammatory, antifungal, insecticidal, diuretic, antispasmodic, astringent, sedative and antiseptic properties (Jeong et al., 2014). All phytochemicals detected in the ethyl acetate extracts of M. micrantha in present study was reported for the first time, except α-Longipinene, β-Himachalene, β-Cubebene, and α-Zingiberene, which were also reported in the previous study of the essential oil composition of M. micrantha from China (Zhang et al., 2004). ...
Mikania micrantha is commonly consumed as traditional medicine in some countries, including Malaysia. Little is known about the antioxidant properties and phytochemicals of M. micrantha. This study was aimed to investigate the total phenolic content (TPC), total flavonoid content (TFC) and antioxidant capacities of the leaves and stems of M. micrantha of hot water, cold water, 70% ethanol, ethyl acetate, and hexane extracts. Folin-Ciocalteu and aluminium chloride colorimetric assays were used to determine the TPC and TFC, respectively. The antioxidant capacities were determined using rapid, inexpensive and small-scale microplate of five different antioxidant assays. Gas chromatography-mass spectrometry (GC-MS) was used to chemically profile and characterize the phytochemicals. In comparison with different solvents, the ethyl acetate stems (EAS) and leaves (EAL) extracts of M. micrantha had the significantly greatest TPC (141 ± 0.51 mg gallic acid equivalent/g) and TFC (70.1 ± 0.92 catechin equivalent/g), respectively. Moreover, EAS extract had the significantly greatest antioxidant capacities using DPPH (EC50 = 324 ± 61.4 μg/mL), ABTS (0.53 ± 0.01 mmol trolox equivalent/g), FRAP (1.28 ± 0.05 mmol Fe 2+ /g), phosphomolybdenum antioxidative power (219 ± 7.03 mg ascorbic acid equivalent/g), and β-carotene bleaching (108 ± 2.23%) assays. GC-MS analysis of EAS showed the presence of sesquiterpenes (30.46%), phenol (16.38%), and alkane hydrocarbons (10.45%), which may contribute to its antioxidant capacities. These findings suggest the stems extract of M. micrantha using ethyl acetate as the potential source of natural antioxidant agents and its utilization to prevent oxidative damage-related diseases could be further explored.
... Chemical profiling of J. excelsa might help in its usage as a possible source of therapeutic agents, especially in traditional medicine. As an example, α-pinene and cedrol rich oil could be effectively used as a local antiseptic(32). Moreover, J. excelsa oils could be used as naturally derived preservatives due to the limonene-rich content. ...
Leaves and cones of the genus Juniperus, regularly used as a spice, could be a candidate for new food preservative with significant nutraceutical qualities. The main goal of this study was to evaluate the bioactivity and chemical profiling of the Juniperus excelsa leaves and cones in order to support its usage as a health–promoting food additive. The content of 44 phenolics was determined using LC–MS/MS, with catechin and quercitrin being the most dominant especially in leaves (234 and 142 mg/g of leaves dry weight, respectively). GC–MS analysis showed a simple terpene composition both in leaves and cones, with α–pinene (31 and 77%), cedrol (37 and 8%) and limonene (15 and 6%) as the most abundant compounds, respectively. J. excelsa showed a noteworthy antioxidant effect comparable with BHA, especially leaves extract towards HO• and lipid peroxidation inhibition, which is particularly important in food quality maintenance. Essential oil of leaves showed significant anti–inflammatory activity by means of inhibition of eicosanoids production and considerable antimicrobial activity against the clinically relevant and/or foodborne illness-causing bacteria. Due to its considerable bioactivity and high content of phenolics with proven health benefits, usage of J. excelsa as a food additive with valuable nutraceutical properties should be supported.
... Another sesquiterpene alantolactone showed a potent inhibitory effect on CYP3A4 activity with IC50 value of 3.6 µM in human liver microsomes [25]. Cedrol, β-cedrene and thujopsene, bioactive sesquiterpenes found in cedar essential oil, showed significant inhibition of several CYP isoforms in human liver microsomes [26]. ...
Sesquiterpenes, 15-carbon compounds formed from three isoprenoid units, are the main components of plant essential oils. Sesquiterpenes occur in human food, but they are principally taken as components of many folk medicines and dietary supplements. The aim of our study was to test and compare the potential inhibitory effect of acyclic sesquiterpenes, trans-nerolidol, cis-nerolidol and farnesol, on the activities of the main xenobiotic-metabolizing enzymes in rat and human liver in vitro. Rat and human subcellular fractions, relatively specific substrates, corresponding coenzymes and HPLC, spectrophotometric or spectrofluorometric analysis of product formation were used. The results showed significant inhibition of cytochromes P450 (namely CYP1A, CYP2B and CYP3A subfamilies) activities by all tested sesquiterpenes in rat as well as in human hepatic microsomes. On the other hand, all tested sesquiterpenes did not significantly affect the activities of carbonyl-reducing enzymes and conjugation enzymes. The results indicate that acyclic sesquiterpenes might affect CYP1A, CYP2B and CYP3A mediated metabolism of concurrently administered drugs and other xenobiotics. The possible drug?sesquiterpene interactions should be verified in in vivo experiments.
... thunbergianum [10]. β-Cedrene is a bioactive sesquiterpene which exerts antiseptic, anti-inflammatory, antispasmodic, tonic, astringent, diuretic, sedative, insecticidal, and antifungal activities [11]. This compound is used in traditional medicine and in cosmetic products. ...
Premna microphylla Turczaninow, an erect shrub, was widely used in Chinese traditional medicine to treat dysentery, appendicitis, and infections. In this study, the essential oil from P. microphylla Turcz. was obtained by hydrodistillation and analyzed by GC (Gas Chromatography) and GC-MS (Gas Chromatography-Mass Spectrometer). Fifty-six compounds were identified in the oil which comprised about 97.2% of the total composition of the oil. Major components of the oil were blumenol C (49.7%), ß-cedrene (6.1%), limonene (3.8%), a-guaiene (3.3%), cryptone (3.1%), and a-cyperone (2.7%). Furthermore, we assessed the in vitro biological activities displayed by the oil obtained from the aerial parts of P. microphylla, namely the antioxidant, antimicrobial, and cytotoxic activities. The antioxidant activity of the essential oil was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity. For this, the IC50 value was estimated to be 0.451 mg/mL. The essential oil of P. microphylla exhibited considerable antibacterial capacity against Escherichia coli with an MIC (Minimum Inhibitory Concentration) value of 0.15 mg/mL, along with noticeable antibacterial ability against Bacillus subtilis and Staphylococcus aureus with an MIC value of 0.27 mg/mL. However, the essential oil did not show significant activity against fungus. The oil was tested for its cytotoxic activity towards HepG2 (liver hepatocellular cells) and MCF-7 Cells (human breast adenocarcinoma cell line) using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, and exerted cytotoxic activity with an IC50 of 0.072 and 0.188 mg/mL for 72 h. In conclusion, the essential oil from P. microphylla is an inexpensive but favorable resource with strong antibacterial capacity as well as cytotoxic activity. Thus, it has the potential for utilization in the cosmetics and pharmaceutical industries.
Traditional medicine, 'LuRu', is a commonly used Tibetan medicine for clearing away heat and detoxifying. Dried products of Pedicularis flava and Pedicularis muscicola are often used as 'LuRu' in the market. This study aims to compare the chemical constituents of P. flava and P. muscicola using GC-MS and UPLC-TOF-MS, and confirm which plant species is more suitable to be used as 'LuRu'. A total of 46 and 68 compounds were identified from the volatile and non-volatile components, respectively. Out of these, 17 and 37 volatile and non-volatile components, respectively, had pharmacological activities. P. flava showed a higher content of the same active components than P. muscicola. Good biological activities are only observed in the unique components in P. flava, and not in P. muscicola. The two herbs should not be mixed in clinical medication. Our study shows that P. flava is better suited as a high-quality herb for the Tibetan medicine, 'LuRu'.
This research studied the effects of cadmium on kidney function of the freshwater turtles Mauremys reevesii. Turtles were injected intraperitoneally with 0, 7.5, 15, and 30 mg kg⁻¹ cadmium separately for once. The samples were gathered to check the kidney index, the contents of TP in kidney tissue, and the levels of CRE and BUN in the plasma of the turtles. Results showed that the concentration of TP was overall decreased with the extension of cadmium exposure time and the increasing of the exposure dose of cadmium. The CRE content in the plasma of each treatment group increased with the prolongation of exposure time in a dose-dependent, and the BUN levels of all poisoned groups showed a trend of increasing. The kidney index of treated turtles increased. In summary, cadmium could induce the increase of turtle kidney index, the content of CRE and BUN in plasma, and the decrease of TP content in the kidney.
Background: The antioxidant, hypoglycemic, and insulin-enhancing effects of ginger and cinnamon were previously confirmed in experimental and human studies, while the combined effect of ginger and cinnamon was not thoroughly investigated until now.
Objectives: This study was designed to assess the antidiabetic effect of combined administration of ginger ( Zingiber officinale Roscoe) and cinnamon ( Cinnamomum cassia L.) in streptozotocin (STZ)-induced diabetic rats compared to metformin and to explain the mechanism behind this effect.
Materials and methods: STZ was utilized to induce diabetes mellitus in male Sprague–Dawley rats. Assessments of fasting blood glucose level (BGL), the total antioxidant capacity (TAC), serum insulin, HOMA-IR, and HOMA–β cells were performed. Pancreatic gene expression of β-catenin and p53 was assessed using RT-PCR. Assessment of histopathological alterations of pancreatic islet cells was performed using routine and immunohistochemical techniques.
Results: BGL significantly decreased ( p = 0.01), while serum insulin and TAC significantly increased ( p < 0.001) in both metformin- and ginger plus cinnamon–treated groups compared to the untreated diabetic group. HOMA–β cell index significantly increased ( p = 0.001) in ginger plus cinnamon, indicating their enhancing effect on insulin secretion in diabetic conditions. p53 gene expression was significantly upregulated ( p < 0.001), while β-catenin was insignificantly downregulated ( p = 0.32) in ginger plus cinnamon–treated groups. Insulin immunoexpression in β cells significantly increased ( p = 0.001, p = 0.004) in metformin- and ginger plus cinnamon–treated groups, respectively.
Conclusions: The combined administration of ginger and cinnamon has a significant hypoglycemic and antioxidant effect in STZ-induced diabetes mostly through enhancing repair of islet cells mediated via upregulation of pancreatic p53 expression. Therefore, testing this effect in diabetic patients is recommended.
Plant VOCs are signaling compounds that attract pollinators, protect plants from stress, disease and predation, have allelopathic effects and play a role in plant growth and development. The purpose of this review was to evaluate pollinator plants for secondary metabolite VOCs such as monoterpenes and sesquiterpenes for their potential medicinal value to pollinating insects. To address disease pathogens impacting native pollinators and honeybees, plants with medicinal VOCs can be selected for prairie strips and pollinator gardens as agricultural best management practices. Eight flowering plants - bee balm, echinacea, catmint, prairie rose, lavender, thyme, oregano and red clover contain VOCs in their nectars and pollens such as caryophyllene, myrcene, germacrene, cymene, thymol, cineol, carvacrol, borneol, nonanal, linalool and terpineol that offer antimicrobial, antifungal, anti-inflammatory, antioxidant benefits and some are acaricides that may aid in controlling the Varroa destructor mite (=jacobsoni).
Cedarwood essential oil (CEO) has the effect of anti-inflammatory and anti-bacteria. However, the application of this essential oil is limited due to its strong volatility and poor water solubility. To address this issue, two types of oil-in-water CEO emulsions including CEO nanoemulsion (CEO-NE) and CEO Pickering emulsion (CEO-PE) were prepared. CEO-NE with 5% surfactant, had a smaller particle size (135.14 ± 1.1 nm) and higher absolute zeta potential value (32.75 mV) compared with CEO-PE (1% starch) which particle size was 626.21 ± 6.05 nm, zeta potential was 27.58 mV. The stability of CEO-NE and CEO-PE were tested by multiple light scattering, results showed that Turbiscan Stability Index (TSI) value of CEO-NE was much lower than that of CEO-PE. CEO-NE and CEO-PE exerted higher free radical scavenging activities, iron reducing power and antibacterial ability than CEO itself. These results indicated that emulsification is a feasible method to extend application of CEO.
Cytochrome P450 enzymes (P450 enzymes) are the most common and important phase I metabolic enzymes and are responsible for the majority of the metabolism of clinical drugs and other xenobiotics. Drug-drug interactions (DDIs) can occur when the activities of P450 enzymes are inhibited. In particular, irreversible inhibition of P450 enzymes may lead to severe adverse interactions, compared to reversible inhibition. Many natural products have been shown to be irreversible inhibitors of P450 enzymes. The risks for intake of naturally occurring irreversible P450 enzyme inhibitors have been rising due to the rapid growth of the global consumption of natural products. Irreversible inhibition is usually called mechanism-based inactivation, which is time-, concentration- and NADPH- dependent. Generally, the formation of electrophilic intermediates is fundamental for the inactivation of P450 enzymes. This review comprehensively classifies natural P450 enzyme inactivators, including terpenoids, phenylpropanoids, flavonoids, alkaloids, and quinones obtained from herbs or foods. Moreover, the structure − activity correlations according to the IC50 (or Ki ) values reported in the literature as well as the underlying mechanisms based on metabolic activation are highlighted in depth.
Antagonism of plant pathogenic fungi by endophytic fungi is a well-known phenomenon. In plate assays, the antagonism could be due to mycoparasitism, competition for space or antibiosis, involving a chemical diffusate, or a volatile organic compound (VOC). In this study, we demonstrate that besides mycoparasitism, VOCs play a major role in antagonism of pathogenic fungi by four endophytic fungi belonging to the genus Trichoderma. Using a double-plate assay, we show that all the four endophytic Trichoderma species significantly inhibited mycelial growth of three of the four pathogens, (Sclerotinia sclerotiorum-TSS, Sclerotium rolfsii-CSR and Fusarium oxysporum-CFO), while that of Macrophomina phaseolina-CMP was not affected. GC-MS analysis of the pure cultures of one of the endophytic fungi studied, namely, Trichoderma longibrachiatum strain 2 (Acc. No. MK751758) and the pathogens, F. oxysporum-CFO and M. phaseolina-CMP revealed the presence of several VOCs including hydrocarbons, alcohols, ketones, aldehydes, esters, acids, ethers and different classes of terpenes. In mixed double plates, where the endophyte was grown along with either of the two plant pathogens, F. oxysporum-CFO or M. phaseolina-CMP, there was an induction of a number of new VOCs that were not detected in the pure cultures of either the endophyte or the pathogens. Several of these new VOCs are reported to possess antifungal and cytotoxic activity. We discuss these results and highlight the importance of such interactions in endophyte-pathogen interactions.
Occasionally, the symbiosis of the fungus-growing ants is threatened by ascomycetous fungi mainly by species in the genus Escovopsis. GC-MS analyses were conducted to investigate the volatile organic compounds (VOCs) produced by Escovopsis and the mutualistic Leucocoprinus gongylophorus during dual-culture. In dual-culture Escovopsis' development was faster. Hexadecanoic acid (palmitic acid) and VOCs such as the sesquiterpenes α-cedrene, β-cedrene, thujopsene, α-santalene, α-selinene, cedrene, (+)-cuparene and δ-cadinene secreted by L. gongylophorus may be responsible for speeding the germination of Escovopsis’ conidia as well as for the faster hyphal development. Based on this study and available literature we infer that the relationship between these two species is mediated by hyphal interference (HI). Additional studies should unveil if the biological activity of some compounds produced by these fungi is attractive, repellent or toxic to the ants and inhibitory to other fungi.
Glioblastoma (GBM) is a common and aggressive brain tumor with a median survival of 12-15 months. Temozolomide (TMZ) is a first-line chemotherapeutic agent used in GBM therapy, but the occurrence of drug resistance limits its antitumor activity. The natural compound cedrol has remarkable antitumor activity and is derived from Cedrus atlantica. In this study, we investigated the combined effect of TMZ and cedrol in GBM cells in vitro and in vivo. The TMZ and cedrol combination treatment resulted in consistently higher suppression of cell proliferation via regulation of the AKT and MAPK signaling pathways in GBM cells. The combination treatment induced cell cycle arrest, cell apoptosis, and DNA damage better than either drug alone. Furthermore, cedrol reduced the expression of proteins associated with drug resistance, including O6-methlyguanine-DNA-methyltransferase (MGMT), multidrug resistance protein 1 (MDR1), and CD133 in TMZ-treated GBM cells. In the animal study, the combination treatment significantly suppressed tumor growth through the induction of cell apoptosis and decreased TMZ drug resistance. Moreover, cedrol-treated mice exhibited no significant differences in body weight and improved TMZ-induced liver damage. These results imply that cedrol may be a potential novel agent for combination treatment with TMZ for GBM therapy that deserves further investigation.
Cedrus deodara is a cedar plant from the Pinaceae family. Because Cedrus is widely used in health care products, cosmetics, medicine, and insecticides, the essential oils of Cedrus deodara (CDEOs) are gaining increasing levels of attention. However, there have only been a few studies on the anti-inflammatory effects of CDEOs. This study aimed to systematically study the composition and biological effects of CDEOs, in line with this, the study assessed the chemical composition of CDEOs and evaluated their anti-inflammatory mechanisms in mice. Gas chromatography-mass spectrometry (GC-MS) was used to determine and analyze a total of 41 compounds from CDEOs. It was found that the major components of CDEOs are thujopsene (28.23%), α-cedrene (17.01%), and cedrol (15.55%); moreover, our results showed that the active ingredients in CDEOs have anti-inflammatory and antioxidant effects and that the active ingredients in CDEOs can be used as an antioxidant, as an important biological resource in functional food, and as ingredients in cosmetics and pharmaceuticals. Taken together, these CDEOs serve as ideal additives for anti-inflammatory drugs.
Due to the rapidly increasing global interest in the use of herbs, phytomedicines and other natural products as medical or complementary remedies, concerns about the clinical medication safety have drawn much attention worldwide. Particularly, many natural ingredients exhibit inhibitory effects on cytochrome P450 (CYP) enzymes, which are the most important Phase I metabolism enzymes in liver. CYP2C9 is one of the most abundant CYP enzymes and responsible for the metabolism of over 15% clinical drugs, including oral sulfonylurea hypoglycemics, nonsteroidal anti-inflammatory agents, selective cyclooxygenase-2 inhibitors, antiepileptics, angiotensin II receptor inhibitors and anticoagulants. Diclofenac (4’-hydroxylase) and tolbutamide (methylhydroxylation) are widely used as probe substrates for CYP2C9. To date, numerous natural products have been reported to have the capabilities of inhibiting the catalytic activity of CYP2C9 and further influencing the pharmacokinetic and pharmacodynamic behaviors of drugs that are mainly metabolized by CYP2C9, leading to potential herb-drug interactions. Moreover, some fatal adverse interactions may occur for drugs with a narrow therapeutic window when they are coadministered with a CYP2C9 inhibitor, especially irreversible inactivators. For the purpose of better understanding the interactions of natural products with CYP2C9, we comprehensively reviewed the characteristics of CYP2C9, the natural ingredients that inhibit CYP2C9, the related research approaches and strategies, the types of inhibition and the underlying mechanisms.
The first total synthesis of juniperanol, the tricyclic sesquiterpenoid enantiomer of α-cedrol is described. The synthesis relies on stereoselective gold-catalyzed Ohloff-type propargylic ester rearrangement performed on a 10 g scale, and a carbocationic cascade in the presence of acetyl methanesulfonate. The ability of juniperanol to interfere in glucose processes in different cell types is described.
Cedrol is an extremely versatile sesquiterpene alcohol that was approved by the Food and Drug Administration of the United States as a flavoring agent or adjuvant and has been commonly used as a flavoring ingredient in cosmetics, foods and medicine. Furthermore, cedrol possesses a wide range of pharmacological properties including sedative, anti-inflammatory and cytotoxic activities. Commercial production of cedrol relies on fractional distillation of cedar wood oils, followed by recrystallization, and little has been reported about its biosynthesis and aspects of synthetic biology. Here, we report the cloning and functional characterization of a cedrol synthase gene (Lc-CedS) from the transcriptome of the glandular trichomes of a woody Lamiaceae plant Leucosceptrum canum. The recombinant Lc-CedS protein catalyzed the in vitro conversion of farnesyl diphosphate into the single product cedrol, suggesting that Lc-CedS is a high-fidelity terpene synthase. Co-expression of Lc-CedS, a farnesyl diphosphate synthase gene and seven genes of the mevalonate (MVA) pathway responsible for converting acetyl-CoA into farnesyl diphosphate in Escherichia coli afforded 363 μg/L cedrol as the sole product under shaking flask conditions. Transient expression of Lc-CedS in Nicotiana benthamiana also resulted in a single product cedrol with a production level of 3.6 μg/g fresh weight. The sole production of cedrol by introducing of Lc-CedS in engineered E. coli and N. benthamiana suggests now alternative production systems using synthetic biology approaches that would better address sufficient supply of cedrol.
Phase‐I metabolism mediated by cytochrome P450 (CYP) enzymes represents a major route of elimination of many drugs that can compete for the same CYP enzyme. The bioactivity of essential oils (EOs) and their flavour and fragrance constituents have been known since ancient times, and like any other physiological process in the human body the activity of CYP enzymes can also be influenced (increased and/or decreased) by these natural compounds. This review discusses the effects of EO constituents on important drug‐metabolizing CYP enzymes. Exposure to EO constituents through commonly used products via cutaneous, oral, and inhalation routes is outlined, and the impact of some important EO constituents on CYP enzymes is described in more detail. In particular, the simultaneous application of EO constituents with drugs or the excessive use of EOs and their constituents can lead to unexpected adverse effects. Influence of Cytochrome P450 on the Metabolism of an Essential Oil Constituent.
The vaporization enthalpies and vapor pressures of (+)-cedrol and nerolidol are reported at T = 298.15 K using a series of alcohols as standards by correlation gas chromatography. Vaporization enthalpies at T = 298.15 K of (88.3±1.5, 91.4±1.5, 92.7±1.6) kJ⋅mol⁻¹ were evaluated for (+)-cedrol, Z-nerolidol and E-nerolidol, respectively. Upon injection into the gas chromatograph, (+)-cedrol was partially converted to α- and β-cedrene, identified by GCMS and independent synthesis. Additionally, the vaporization enthalpy of 1-adamantanol evaluated as an unknown and then used as a standard, compared well to the value calculated from the sublimation, fusion and solid-solid phase transition enthalpies previously reported. Liquid vapor pressures of (+)-cedrol, Z-nerolidol, E-nerolidol and 1-adamantanol are also reported as a function of temperature. A vapor pressure of 187.9 kPa is estimated for 1-adamantanol at the fusion temperature and the vapor pressure of solid 1-adamantanol at T = 298.15 K is reproduced within a factor of two of the literature value.
The present study aims to determine the drug-drug interaction between urination treatment drug oleanolic acid and anti-HIV drug zidovudine (AZT). The inhibition of oleanolic acid towards in vitro glucuronidation metabolism of AZT was determined. The inhibition potential of oleanolic acid towards the glucuronidation metabolism of AZT was firstly investigated at 150 mu M of AZT; 50, 100, 150, and 200 mu M of oleanolic acid inhibited 14.6, 36.8, 56.4, and 70.4% of AZT glucuronidation activity. Furthermore, the half value (IC50) for the inhibition of oleanolic acid towards the glucuronidation of oleanolic acid was determined at multiple concentrations of AZT. The results showed that IC50 value was 102.5, 122.5, 130, and 140.2 mu M at 100, 150, 250, and 400 mu M of AZT, indicating that higher concentration of oleanolic acid was needed for attach the same inhibition potential with the increasing concentration of AZT. The present study demonstrated the inhibition of herbal ingredient oleanolic acid towards AZT glucuronidation, indicating possible drug-drug interaction between oleanolic acid and AZT.
During the last 10-15 years, cytochrome P450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed in human liver and is known to metabolize more than 100 drugs. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is increasing. Similarly, many drugs have been identified as CYP2C8 inhibitors or inducers. In vivo, already a small dose of gemfibrozil, i.e., 10% of its therapeutic dose, is a strong, irreversible inhibitor of CYP2C8. Interestingly, recent findings indicate that the acyl-β-glucuronides of gemfibrozil and clopidogrel cause metabolism-dependent inactivation of CYP2C8, leading to a strong potential for drug interactions. Also several other glucuronide metabolites interact with CYP2C8 as substrates or inhibitors, suggesting that an interplay between CYP2C8 and glucuronides is common. Lack of fully selective and safe probe substrates, inhibitors, and inducers challenges execution and interpretation of drug-drug interaction studies in humans. Apart from drug-drug interactions, some CYP2C8 genetic variants are associated with altered CYP2C8 activity and exhibit significant interethnic frequency differences. Herein, we review the current knowledge on substrates, inhibitors, inducers, and pharmacogenetics of CYP2C8, as well as its role in clinically relevant drug interactions. In addition, implications for selection of CYP2C8 marker and perpetrator drugs to investigate CYP2C8-mediated drug metabolism and interactions in preclinical and clinical studies are discussed.
Red ginseng (RG) is one of the top selling herbal medicines in Korea, but is not recommended in hypertensive patients. In this study, the pharmacokinetic (PK) interaction between RG and losartan, an antihypertensive drug, was examined. RG was orally administered for 2 wk to male Sprague-Dawley (S-D) rats at either control (0), 0.5, 1, or 2 g/kg/d for 2 wk. After the last administration of RG and 30 min later, all animals were treated with 10 mg/kg losartan by oral route. In addition, some S-D rats were administered RG orally for 21 d at 2 g/kg followed by losartan intravenously (iv) at 10 mg/kg/d. Post losartan administration, plasma samples were collected at 5, 15, and 30 min and 1, 1.5, 2, 3, 6, 12, and 24 h. Plasma concentrations of losartan and E-3174, the active metabolite of losartan, were analyzed by a high-pressure liquid chromatography-tandem mass spectrometer system (LC-MS/MS). Oral losartan administration showed dose-dependent pharmacokinetics (PK) increase with time to maximum plasma, but this was not significant between different groups. There was no significant change in tmax with E-3174 PK. With iv losartan, pharmacokinetics showed elevation of area under the plasma concentration-time curve from time zero extrapolated to infinitity. There was not a significant change in AUCinf with E-3174 PK. Therefore, RG appeared to interfere with biotransformation of losartan, as RG exerted no marked effect on E-3174 PK in S-D rats. Data demonstrated that oral or iv treatment with losartan in rats pretreated with RG for 2 wk showed that losartan PK was affected but E-3174 PK remained unchanged among different dose groups. These results suggested that RG induces negligible influence on losartan and E-3174 PK in rats.
Heartwood samples from Juniperus virginiana L. were extracted with liquid carbon dioxide, and the bioactivity of carbon dioxide-derived cedarwood oil (CWO) toward several species of ants and cedrol toward ticks was determined. Repellency was tested for ants, and toxicity was tested for ticks. Ants in an outdoor bioassay were significantly repelled by the presence of CWO on a pole leading to a sugar-water solution. Similarly, CWO was a significant repellent barrier to red imported fire ants and prevented them from finding a typical food source. Black-legged tick nymphs exhibited dosage-dependent mortality when exposed to cedrol and at the highest dosage (i.e., 6.3 mg/ml) tested, the cedrol killed 100% of the ticks. These repellency and toxicity results together demonstrate a clear potential for the use of CWO as a pest control agent.
Introduction:
Because 30 to 70% of tumour patients use complementary and alternative medicines; herb-drug combinations are particularly frequent in this population. Some of these combinations can critically alter exposure of anti-neoplastic and palliative treatment.
Areas covered:
This review summarises pharmacokinetic drug interactions caused by the herbal products most frequently used by tumour patients (garlic, ginkgo, ginseng, echinacea and St John's wort [SJW]).
Expert opinion:
Herb-drug interactions, in general, and some interactions in particular (e.g., transporters, Phase II metabolism enzymes) are still poorly investigated and are difficult to evaluate because mixtures are administered with variable and often unspecified amounts of ingredients. Current evidence suggests that garlic and ginkgo can be safely co-administered, whereas CYP2C9 substrates (e.g., warfarin) should be monitored closely when ginseng therapy is started. Echinacea can induce drug metabolism mediated by CYP3A, but most likely relevant when administered with substances with a narrow therapeutic index or low oral bioavailability. The most relevant herbal perpetrator drug is SJW, which has substantial impact on CYP3A4- and CYP2C9-mediated metabolism and P-glycoprotein-mediated transport. This may lower exposure of co-administered drugs by up to 70%. Such an interaction is expected to occur with most of the tyrosine kinase inhibitors, but current evidence is limited.
The present study was undertaken to evaluate the subacute toxicity of arsenic (As) and chlorpyrifos (CPF) alone or in combination. In addition, the ameliorative effect of ascorbic acid on As and/or CPF-induced hepatic microsomal xenobiotic metabolizing enzymes in rats was examined. Rats were divided into 9 groups of 6 animals each: control (deionized water), vehicle control (groundnut oil), ascorbic acid (100 mg/kg body weight), As (40 ppm in water), CPF (5 mg/kg body weight), As (40 ppm) + CPF (5 mg/kg body weight), As + ascorbic acid, CPF + ascorbic acid, and As + CPF + ascorbic acid. After 28 d of exposure, rats were sacrificed and liver was extracted for isolation of hepatic microsomes. Exposure to As or CPF alone as well as both of these in combination significantly altered microsomal proteins and activity of phase I and phase II xenobiotic-metabolizing enzymes. Cytochrome P-450 and cytochrome b 5 levels and activities of aniline p-hydroxylase (APH) and uridine diphosphate glucuronosyltransferase (UGT) were significantly decreased in groups treated with As, CPF, and As plus CPF, while glutathione S-transferase (GST) was not markedly altered. Enzymatic activity of aminopyrine N-demethylase (ANDM) was also significantly reduced in As- and CPF-only groups. Co-administration of ascorbic acid effectively countered the As- and CPF-induced alterations in xenobiotic-metabolizing enzymes.
Honokiol is a bioactive component isolated from the medicinal herbs Magnolia officinalis and Magnolia grandiflora that has antioxidative, anti-inflammatory, antithrombotic, and antitumor activities. The inhibitory potentials of honokiol on eight major human cytochrome P450 (CYP) enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4, and four UDP-glucuronosyltransferases (UGTs) 1A1, 1A4, 1A9, and 2B7 in human liver microsomes were investigated using liquid chromatography-tandem mass spectrometry. Honokiol strongly inhibited CYP1A2-mediated phenacetin O-deethylation, CYP2C8-mediated amodiaquine N-deethylation, CYP2C9-mediated diclofenac 4-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4-hydroxylation, and UGT1A9-mediated propofol glucuronidation with Ki values of 1.2, 4.9, 0.54, 0.57, and 0.3 μM, respectively. Honokiol also moderately inhibited CYP2B6-mediated bupropion hydroxylation and CYP2D6-mediated bufuralol 1'-hydroxylation with Ki values of 17.5 and 12.0 μM, respectively. These in vitro results indicate that honokiol has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, and UGT1A9.
Abstract Ginkgo biloba leaf extracts (GLEs) are popular herbal remedies for the treatment of Alzheimer's dementia, tinnitus, vertigo and peripheral arterial disease. As GLEs are taken regularly by older people who are likely to also use multiple other drugs for the treatment of, e.g. hypertension, diabetes, rheumatism or heart failure, potential herb-drug interactions are of interest. Preclinical studies of high doses/concentrations of GLEs of varying quality and standardization hinted at both an inhibition and induction of metabolic enzymes and transporters. However, in humans, positive in vitro-findings could not be replicated in vivo. At maximum recommended doses of 240 mg/day, a clinically relevant interaction potential of the standardized GLE EGb 761 could not be shown. GLE doses higher than the recommended ones led to a weak induction of the CYP2C19-mediated omeprazole 5-hydroxylation, and a weak inhibition of the CYP3A4-mediated midazolam 1'-hydroxylation, respectively. Also, the regular intake of a poorly characterized GLE at a dose of 360 mg/day slightly increased the bioavailability of talinolol, a substrate of P-glycoprotein and various organic anion-transporting polypeptides. Thus, regarding pharmacokinetic herb-drug interactions, the intake of the standardized GLE, EGb 761, together with synthetic drugs appears to be safe as long as daily doses up to 240 mg are consumed. If this applies to other extracts prepared according to the European Pharmacopoeia remains uncertain. Also, a relevant potential for drug interactions cannot be excluded for poorly standardized GLEs used in many food supplements.
Artemisinin-based combination therapy (ACT) is the recommended treatment of uncomplicated P.falciparum malaria by the World Health Organisation (WHO). Some artemisinin compounds and anti-retroviral drugs have been shown to be metabolized by CYP2B6. In the African clinical settings, the likelihood of co-administration of ACTs and antiretroviral drugs is higher than elsewhere, posing the risk of drug-drug interactions (DDIs). This study aimed to investigate whether artemisinin compounds inhibit CYP2B6 activity in vitro using recombinant CYP2B6 (rCYP2B6) and human liver microsomes (HLM). Values for IC50 and Ki were determined by kinetic analyses using non-linear regression. In vitro to in vivo extrapolations of the likelihood of DDIs where done using a static [I]/Ki approach. Artemisinin and artemether were shown to inhibit CYP2B6 in vitro through a partial mixed type of inhibition, while dihydroartemisinin did not inhibit the enzymatic activity. IC50 values for artemisinin were 9.5 and 9.1 µM for rCYP2B6 and HLM, respectively, after 30 min of incubation. Corresponding values for artemether were 7.5 and 5.4 µM. Artemisinin did not show any time-dependency or requirement of NADPH in its mechanism, indicating a reversible mode of inhibition. Based on the [I]/Ki approach using rCYP2B6, the risk of DDIs for artemisinin was indicated to be medium to high, while artemether had a low risk. The findings indicate a potential but moderate risk of DDIs in the co-administration of artemisinin or artemether with efavirenz in the co-treatment of malaria and HIV/AIDS.
Genetic variability in cytochrome P-450 (CYP) has the potential to modify pharmacological and toxicological responses to many chemicals. Both CYP2B6 and CYP2C19 are pharmacologically and toxicologically relevant due to their ability to metabolize multiple drugs and environmental contaminants, including the organophosphorus (OP) pesticide chlorpyrifos. The aim of this study was to determine the prevalence of CYP2B6 and CYP2C19 variants in an indigenous Egyptian population (n = 120) that was shown to be occupationally exposed to chlorpyrifos. Further, the genotyping data was compared for Egyptians with previously studied populations to determine between population differences. Allelic frequencies were CYP2B6 1459C > T (3.8%), CYP2B6 785A > G (30.4%), CYP2B6 516G > T (28.8%), CYP2C19 681G > A (3.8%), and CYP2C19 431G > A (0%). The most prevalent CYP2B6 genotype combinations were CYP2B6 *1/*1 (44%), *1/*6 (38%), *6/*6 (8%), and *1/*5 (6%). The frequency of the CYP2C19 genotype combinations were CYP2C19 *1/*1 (93%), *1/*2 (6%), and *2/*2 (1%). The frequency of the CYP2B6 516G > T and CYP2B6 785A > G polymorphisms in this Egyptian cohort is similar to that found North American and European populations but significantly different from that reported for West African populations, while that of CYP2B6 1459C > T is similar to that found in Africans and African Americans. The observed frequency of CYP2C19 681G > A in Egyptians is similar to that of African pygmies but significantly different from other world populations, while CYP2C19 431 G > A was significantly different from that of African pygmies but similar to other world populations.
Juniperus communis leaf oil, J. chinensis wood oil, and Cupressus funebris wood oil (Cupressaceae) from China were analyzed by gas chromatography and gas chromatography-mass spectrometry. We identified 104 compounds, representing 66.8-95.5% of the oils. The major components were: α-pinene (27.0%), α-terpinene (14.0%), and linalool (10.9%) for J. communis; cuparene (11.3%) and δ-cadinene (7.8%) for J. chinensis; and α-cedrene (16.9%), cedrol (7.6%), and β-cedrene (5.7%) for C. funebris. The essential oils of C. funebris, J. chinensis, and J. communis were evaluated for repellency against adult yellow fever mosquitoes, Aedes aegypti (L.), host-seeking nymphs of the lone star tick, Amblyomma americanum (L.), and the blacklegged tick, Ixodes scapularis Say, and for toxicity against Ae. aegypti larvae and adults, all in laboratory bioassays. All the oils were repellent to both species of ticks. The EC(95) values of C. funebris, J. communis, and J. chinensis against A. americanum were 0.426, 0.508, and 0.917 mg oil/cm(2) filter paper, respectively, compared to 0.683 mg deet/cm(2) filter paper. All I. scapularis nymphs were repelled by 0.103 mg oil/cm(2) filter paper of C. funebris oil. At 4 h after application, 0.827 mg oil/cm(2) filter paper, C. funebris and J. chinensis oils repelled ≥80% of A. americanum nymphs. The oils of C. funebris and J. chinensis did not prevent female Ae. aegypti from biting at the highest dosage tested (1.500 mg/cm(2) ). However, the oil of J. communis had a Minimum Effective Dosage (estimate of ED(99) ) for repellency of 0.029 ± 0.018 mg/cm(2) ; this oil was nearly as potent as deet. The oil of J. chinensis showed a mild ability to kill Ae. aegypti larvae, at 80 and 100% at 125 and 250 ppm, respectively.
Eupatilin and jaceosidin are bioactive flavones found in the medicinal herbs of the genus Artemisia. These bioactive flavones exhibit various antioxidant, antiinflammatory, antiallergic, and antitumor activities. The inhibitory potentials of eupatilin and jaceosidin on the activities of seven major human cytochrome P450 enzymes in human liver microsomes were investigated using a cocktail probe assay. Eupatilin and jaceosidin potently inhibited CYP1A2-catalyzed phenacetin O-deethylation with 50% inhibitory concentration (IC(50)) values of 9.4 microM and 5.3 microM, respectively, and CYP2C9-catalyzed diclofenac 4-hydroxylation with IC(50) values of 4.1 microM and 10.2 microM, respectively. Eupatilin and jaceosidin were also found to moderately inhibit CYP2C19-catalyzed [S]-mephenytoin 4'-hydroxylation, CYP2D6-catalyzed bufuralol 1'-hydroxylation, and CYP2C8-catalyzed amodiaquine N-deethylation. Kinetic analysis of human liver microsomes showed that eupatilin is a competitive inhibitor of CYP1A2 with a K(i) value of 2.3 microM and a mixed-type inhibitor of CYP2C9 with a K(i) value of 1.6 microM. Jaceosidin was shown to be a competitive inhibitor of CYP1A2 with a K(i) value of 3.8 microM and a mixed-type inhibitor of CYP2C9 with K(i) value of 6.4 microM in human liver microsomes. These in vitro results suggest that eupatilin and jaceosidin should be further examined for potential pharmacokinetic drug interactions in vivo due to inhibition of CYP1A2 and CYP2C9.
Ethyl acetate extracts from heartwood of seven western conifer trees and individual volatile compounds in the extracts were tested for antimicrobial activity against Phytophthora ramorum. Extracts from incense and western redcedar exhibited the strongest activity, followed by yellow-cedar, western juniper, and Port-Orford-cedar with moderate activity, and no activity for Douglas-fir and redwood extracts. Chemical composition of the extracts varied both qualitatively and quantitatively among the species with a total of 37 compounds identified by mass spectrometry. Of the 13 individual heartwood compounds bioassayed, three showed strong activity with a Log(10) EC(50) less than or equal to 1.0 ppm (hinokitiol, thymoquinone, and nootkatin), three expressed moderate activity ranging from 1.0-2.0 ppm (nootkatol, carvacrol, and valencene-11,12-diol), four compounds had weak activity at 2.0-3.0 ppm [alpha-terpineol, valencene-13-ol, (+)-beta-cedrene, (-)-thujopsene], and three had no activity [(+)-cedrol, delta-cadinene, and methyl carvacrol]. All of the most active compounds contained a free hydroxyl group, except thymoquinone. The importance of a free hydroxyl was demonstrated by the tremendous difference in activity between carvacrol (Log(10) EC(50) 1.81 +/- 0.08 ppm) and methyl carvacrol (Log(10) EC(50) >3.0 ppm). A field trial in California, showed that heartwood chips from redcedar placed on the forest floor for 4 months under Umbellularia californica (California bay laurel) with symptoms of P. ramorum leaf blight significantly limited the accumulation of P. ramorum DNA in the litter layer, compared with heartwood chips from redwood.
Woohwangcheongsimwon is a traditional medicine for treating hypertension, arteriosclerosis, coma, and stroke in China and Korea. To assess potential interactions of herb and drug metabolism, commercially available Woohwangcheongsimwon suspensions were examined for their potential to inhibit the activity of nine human cytochrome P450 enzymes. The Woohwangcheongsimwon suspensions showed strong inhibition of CYP2B6 activity. To identify individual constituents with inhibitory activity, the suspension was partitioned using hexane, ethyl acetate, and dichloromethane, and each fraction was tested for its inhibitory effect on CYP2B6-catalyzed bupropion hydroxylation. The hexane fraction possessed inhibitory activity, and gas chromatography/mass spectrometry analysis identified borneol and isoborneol as major constituents of the hexane fraction. These two terpenoids moderately inhibited CYP2B6-catalyzed bupropion hydroxylase activity in a competitive manner, with K(i) values of 9.5 and 5.9 microM, respectively, as well as efavirenz 8-hydroxylase activity, with K(i) values of 22 and 26 microM, respectively. Additionally, reconstituted mixtures of borneol and isoborneol, at the same concentrations as in the Woohwangcheongsimwon suspension, had comparable potency in inhibiting bupropion hydroxylation. These in vitro data indicate that Woohwangcheongsimwon preparations contain constituents that can potently inhibit the activity of CYP2B6 and suggest that these preparations should be examined for potential pharmacokinetic drug interactions in vivo.
Liquorice is the root of Glycyrrhiza uraleusis Fisch. or G. glabra L., Leguminosae. It is a widely used herbal medicine native to southern Europe and parts of Asia and has beneficial applications in both the medicinal and the confectionery sectors. Unlike its usage in Europe, liquorice in traditional Chinese medicine is commonly combined with other herbs in a single prescription, as a unique ''guide drug'' to enhance the effectiveness of other ingredients, to reduce toxicity, and to improve flavor in almost half of Chinese herbal formulas. A review on phytochemical and pharmacological research to explain this unique ''guide" effect is suggested for future investigations.
The information was collected from scientific journals, books, and pharmacopeia. The studies about the traditional uses, randomized controlled trials, chemical, pharmacological and pharmacokinetic data related to liquorice-herb/drug interaction or combination were included in the review.
According to recent reports, the "guide" effect of liquorice is partially through components transformed in liquorice-drug interaction; altering enzyme activity of P450 isoforms, as evidenced by induction of model probe substrates; and modulation of drug transporter proteins such as intestinal P-glycoprotein.
The overview and comparison of traditional uses of liquorice with recent pharmacological studies and randomized controlled trials provide new insights into this ancient drug for future investigations and clinical use, especially in drug combination.
Hypericum perforatum (HP) belongs to the Hypericaceae family and is one of the oldest used and most extensively investigated medicinal herbs. The medicinal form comprises the leaves and flowering tops of which the primary ingredients of interest are naphthodianthrones, xanthones, flavonoids, phloroglucinols (e.g. hyperforin), and hypericin. Although several constituents elicit pharmacological effects that are consistent with HP's antidepressant activity, no single mechanism of action underlying these effects has thus far been found. Various clinical trials have shown that HP has a comparable antidepressant efficacy as some currently used antidepressant drugs in the treatment of mild/moderate depression. Interestingly, low-hyperforin-content preparations are effective in the treatment of depression. Moreover, HP is also used to treat certain forms of anxiety. However, HP can induce various cytochrome P450s isozymes and/or P-glycoprotein, of which many drugs are substrates and which are the main origin of HP-drug interactions. Here, we analyse the existing evidence describing the clinical consequence of HP-drug interactions. Although some of the reported interactions are based on findings from in vitro studies, the clinical importance of which remain to be demonstrated, others are based on case reports where causality can, in some cases, be determined to reveal clinically significant interactions that suggest caution, consideration, and disclosure of potential interactions prior to informed use of HP. Copyright © 2013 John Wiley & Sons, Ltd.
Misclassification of Curcuma species (family Zingiberaceae) may lead to unwanted human exposure to Curcuma elata sesquiterpenes zederone and germacrone which have caused hepatotoxicity and changes in CYP expression in laboratory animals. We investigated how these compounds interact with the human cytochrome P450 (CYP) system, in order to evaluate their potential for human liver toxicity and herb-drug interactions. We found that both sesquiterpenes (1 - 30 μM) greatly induced expression of CYP2B6 and CYP3A4 but not CYP1A2 mRNAs in human primary hepatocytes (HPHs). This induction profile correlated with activation of constitutive androstane and pregnane X receptors. Cytotoxicity was also observed in exposed HPHs. CYP inhibition studies with pooled human liver microsomes (HLMs) indicated that zederone and germacrone moderately inhibited CYP2B6 and CYP3A4 activities in vitro, with IC50 values below 10 μM. When zederone was incubated with HLMs and NADPH, one di-epoxide metabolite was formed and by using glutathione trapping, five epoxide-derived conjugates were detected. Germacrone produced two oxidized metabolites and four glutathione conjugates. The results suggest that enzymes in HLMs convert sesquiterpenes into reactive, electrophilic compounds which may be causative for the reported liver injuries. These findings provide insight on the safety and drug-herb interactions of the Curcuma species.
Several isolated compounds from the wood part of Thujopsis dolabrata were evaluated for their inhibitory effects against antigen-induced mast cell degranulation and interleukin-4 (IL-4) secretion, as well as IL-4 mRNA and protein expression in immunoglobulin E (IgE)-sensitized RBL-2H3 cells. Among the five isolated compounds, (-)-elema-1,3,11(13)-trien-12-ol (1) and thujopsene (2) exhibited the potent inhibitory activity against mast cell degranulation measured by β-hexosaminidase release with IC values of 27.4 µM and 25.1 µM, respectively. These compounds also inhibited the release of IL-4 (IC values of 7.0, 6.7 µM, respectively), IL-4 mRNA expression (IC values of 16.5, 7.2 µM, respectively) and IL-4 protein expression (IC values of 17.0, 9.6 µM, respectively) in antigen-induced IgE-sensitized RBL-2H3 cells. These results suggested that (-)-elema-1,3,11(13)-trien-12-ol (1) and thujopsene (2) effectively inhibits mast cell degranulation as well as IL-4 production, suggesting that these compounds from Thujopsis dolabrata can be used as candidates for IgE-mediated allergic disorders.
Abstract Cytochrome P450 (CYP) 2B6 belongs to the set of important hepatic drug-metabolizing CYPs. It makes up roughly 3%-6% of total hepatic CYP content and metabolizes several pharmaceuticals including bupropion, efavirenz, cyclophosphamide, pethidine, ketamine and propofol. The enzyme is susceptible to drug-drug interactions by enzyme induction and inhibition. In addition to drugs, CYP2B6 is able to both detoxify and bioactivate a number of procarcinogens and environmental agents including pesticides and herbicides. There is an extensive interindividual variability in the expression of CYP2B6, which is in part explained by extensive genetic polymorphism. CYP2B6 is one of the most polymorphic CYP genes in humans with over 100 described SNPs, numerous complex haplotypes and distinct ethnic and racial frequencies. This review summarizes the basic properties of CYP2B6 and the main characteristics of clinical relevance.
This study investigated the chemical composition, anticancer, and antimicrobial activities in vitro of the essential oil isolated from the heartwood of Cunninghamia lanceolata var. konishii from Taiwan. The essential oil was isolated using hydrodistillation in a Clevenger-type apparatus, and characterized by GC-FID and GC-MS. Thirty-seven compounds were identified, representing 100% of the oil. The main components identified were cedrol (58.3%), alpha-cedrene (11.8%), alpha-terpineol (4.2%) and beta-cedrene (3.5%). The oil exhibited cytotoxic activity against human lung, liver and oral cancer cells. The active source compound was cedrol. The antimicrobial activity of the oil was tested by the disc diffusion and micro-broth dilution methods against ten microbial species. The oil exhibited strong growth suppression against Gram-positive bacteria and yeast with inhibition zones of 42-50 mm to MIC values of 31.25-62.5 microg/mL, respectively. For the antimicrobial activities of the oil, the active compound was determined to be cedrol.
The phenolic derivatives eugenol and isoeugenol, which are naturally found in essential oils of different spices, are commonly used as fragrances. Recently data demonstrated that growth suppression produced by these substances occurs in keratinocytes and that the effects may be mediated via aryl hydrocarbon receptor (AhR) interactions. In this study the effects of eugenol and isoeugenol were determined on intracellular localization of AhR, AhR target gene expression, AhR-dependent cell cycle regulation, and proliferation in HaCaT cells. Both compounds produced a rapid and marked translocation of AhR into the nucleus, induced the expression of the AhR target genes cytochrome P-450 1A1 (CYP1A1) and AhR repressor (AhRR), and inhibited proliferation of HaCaT cells. Among the G(1) phase cell cycle-related proteins, levels of the retinoblastoma protein (RB), which is known to interact with AhR, and levels of the cyclin dependent kinase (CDK) 6 were reduced by eugenol and isoeugenol, whereas steady-state levels of CDK2 and CDK4 remained unaffected. Protein levels of CDK inhibitor (CKI) p27(KIP1), known to be modulated in an AhR-dependent manner, were increased after treatment with both substances. In conclusion, data show that the antiproliferative properties of eugenol and isoeugenol in HaCaT cells are mediated through AhR, and thereby the molecular mechanisms of action in these cells were identified for the first time in this study.
Artemisinin drugs have become the first-line antimalarials in areas of multidrug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of cytochrome P450 (P450)-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism. To better understand the autoinduction and metabolic drug-drug interactions (DDIs), we evaluated the P450s (particularly CYP2B6 and CYP3A4) inhibited or induced by two artemisinin drugs, Qing-hao-su (QHS) and dihydroartemisinin (DHA) using human liver microsome, recombinant P450 enzymes, and primary human hepatocytes. The results suggested that QHS was a weak reversible inhibitor of CYP2B6 (K(i) 4.6 μM), but not CYP3A4 (IC₅₀ ∼ 50 μM) and did not show measurable time-dependent inhibition of either CYP2B6 or CYP3A4. DHA inhibited neither CYP2B6 nor CYP3A4 (IC₅₀ > 125 μM). In addition, it was found that QHS induced the activity of CYP3A4 (E(max) 3.5-fold and EC₅₀ 5.9 μM) and CYP2B6 (E(max) 1.9-fold and EC₅₀ 0.6 μM). Of the other P450s, UDP glucuronosyltransferases, and transporters studied, QHS and DHA had no significant effect except for minor induction of mRNA expression of CYP1A2 (E(max) 7.9-fold and EC₅₀ 5.2 μM) and CYP2A6 (E(max) 11.7-fold and EC₅₀ 4.0 μM) by QHS. Quantitative prediction of P450-mediated DDIs indicate autoinduction of QHS clearance with the AUC(i)/AUC ratio decreasing to 59%, as a result of a 1.9-fold increase in CYP3A4 and a 1.6-fold increase in CYP2B6 activity. These data suggest that QHS drugs are potential inducers of P450 enzymes, and the possible drug interactions (or lack thereof) with artemisinin drugs may be clinically relevant.
A previous study reported that when cedrol (odorant) is inhaled directly through the lower airway of the trachea, it decreases the sympathetic nervous activity and blood pressure in totally laryngectomized subjects (Umeno et al., 2008). In the present study, totally laryngectomized subjects were asked to inhale cedrol into the lower airway in the same manner and its effects on regional cerebral blood flow (rCBF) were analyzed. Our results indicated that hippocampal rCBF was bilaterally increased during cedrol inhalation as compared to the inhalation of blank air. These results provide the first evidence that an odorant in the lower airway modulates autonomic activity via the central nervous system.
A series of sesquiterpenes and hinokitiol-related compounds (1-15) was isolated from the essential oil of Thujopsis dolabrata Sieb. et Zucc. var. hondai Makino, and their structures were determined by combined spectroscopic analyses. The inhibitory effects of these compounds on microbial cell growth and Na(+)/K(+)-ATPase were evaluated in vitro. It was found that (-)-elema-1,3,11(13)-trien-12-ol (5), α,β,γ-costol (8), and chamigrenol (11) inhibit the activities of Na(+)/K(+)-ATPase, with IC(50) values of 11.2 ± 0.11, 12.2 ± 0.09, and 15.9 ± 0.54 μg/mL, respectively. Thujopsene (1), cedrol (9), γ-cuparenol (10), and chamigrenol (11) showed potent antibacterial activity, with MIC values in the range of 25-50 μg/mL, and β-thujaplicin (12) exhibited a broad spectrum of antibacterial and antifungal activity. These results indicate that these isolated compounds are promising candidates for the development of potent Na(+)/K(+) ATPase inhibitors and antimicrobial agents.
As the use of herbal medicines increases, the public health consequences of drug-herb interactions are becoming more significant. Herbal medicines share the same drug metabolizing enzymes and drug transporters, including cytochrome P450 enzymes (CYPs), glucuronosyltransferases (UGTs), and P-glycoprotein, with several clinically important drugs. Interactions of several commonly used herbal medicines, such as Ginko biloba, milk thistle, and St. John's wort, with therapeutic drugs including warfarin, midazolam, alprazolam, indinavir, saquinavir, digoxin, nifedipine, cyclosporine, tacrolimus, irinotecan, and imatinib in humans have been reported. Many of these drugs have very narrow therapeutic indices. As the herb-drug interactions can significantly alter pharmacokinetic and pharmacodynamic properties of administered drugs, the drugs interacting with herbal medicines should be identified by appropriate in vitro and in vivo methods. A good understanding of the mechanisms of herb-drug interactions is also essential for assessing and minimizing clinical risks. In vitro methods are useful for providing mechanistic information and evaluating multiple components in herbal medicines. This review describes major factors affecting the metabolism of herbal medicines, mechanisms of herb-drug interactions mediated by CYPs and UGTs, and several in vitro methods to assess the herb-drug interactions. Finally, drug interactions of Ginkgo biloba and St. John's wort, as representative herbal medicines, are described.
Botanicals fall under different regulations in different countries and are mostly consumed without the consultation of the healthcare professional. Over the last decade, utilization of herbal therapies has been extensively documented. The findings indicate the possibility of potential herb-drug interactions due to the concomitant administration of herbal extracts and prescription/over-the-counter drugs. Simultaneously, with the increasing public awareness and search for safer herbal remedies, the study on herbal-drug interactions has gained momentum through the study of drug metabolizing enzymes. Cytochrome P450 (CYP) inhibition or induction is probably the most common mechanism for the pharmacokinetic interactions of herbs and drugs. Any inhibition of CYP enzymes by herbal extracts may result in enhanced plasma and tissue concentration of drugs, leading to toxicity, while induction results in reduced drug concentration leading to decreased drug efficacy and treatment failure. Considering the rapidly growing herbal markets, these types of clinical interactions remain under-reported and unclear. With the increasing consumption of herbal extracts along with prescription medicines, the safety of herbs has become a concern. This article reviews the potential for drug interactions by herbal extracts through drug metabolizing enzymes.
A toxicologic and dermatologic review of cedrol when used as a fragrance ingredient is presented.
Curcuma species (Zingiberaceae) are used as both food and medicine in Asia. Ten sesquiterpenes (1-10) and two curcuminoids (11 and 12) were isolated from the rhizomes of Curcuma aromatica Salisb. and identified. The compounds were evaluated for their ability to inhibit cytochrome P450 (CYP). Among them, the sesquiterpene (4S,5S)-(+)-germacrone-4,5-epoxide (7) inhibited certain subtypes of CYP more potently than or at levels comparable to the curcuminoids curcumin (11) and demethoxycurcumin (12); 7 (IC(50) = 1.0 ± 0.2 μM) > 12 (IC(50) = 7.0 ± 1.7 μM) > 11 (IC(50) = 14.9 ± 1.4 μM) for CYP3A4 inhibition; 12 (IC(50) = 1.4 ± 0.2 μM) > 11 (IC(50) = 6.0 ± 1.4 μM) > 7 (IC(50) = 7.6 ± 2.5 μM) for CYP2C9 inhibition; and 7 (IC(50) = 33.2 ± 3.6 μM) = 12 (IC(50) = 34.0 ± 14.2 μM) > 11 (IC(50) > 100 μM) for CYP1A2 inhibition. These results suggest the possibility that Curcuma aromatica Salisb. may cause food-drug interactions via cytochrome P450 inhibition by sesquiterpene 7 and curcuminoids 11 and 12.
Efficient syntheses of α-cedrene (1), α-pipitzol (2), and sec-cedrenol (3) were carried out using a new method, which was inspired by the proposed biosynthesis of the tricyclic skeleton of cedrol (12). The key transformation begins with the oxidative dearomatization of curcuphenol (5a) followed by an intramolecular [5 + 2] cycloaddition of the respective phenoxonium intermediate across the tethered olefin. The benzylic stereocenter effectively guides the formation of the first two stereocenters during the [5 + 2] reaction. The cascade then terminates with the selective incorporation of acetic acid to generate a third stereocenter, setting it apart from other previous cationic [5 + 2] reactions. The phenolic precursors (5a-h) are constructed from readily available salicylaldehydes, either as the racemate (one pot) or as a specific enantiomer (four pots) by a modification to our method for the generation of ortho-quinone methides (o-QMs).
Curcumenol, one of the major components of Zedoary turmeric oil, has been widely used to treat cancer and inflammation. As an antibiotic or anticancer drug, curcumenol is highly likely to be used in combination with various synthetic drugs in most cases, thus it is necessary to evaluate potential pharmacokinetic drug-drug interactions induced by curcumenol. In this study, the inhibitory effects of curcumenol on seven CYP isoforms were investigated, and the results demonstrated that only CYP3A4 was strongly inhibited (IC(50) = 12.6 +/- 1.3 microM). Kinetic analysis showed the inhibition type was competitive with K(i) value of 10.8 microM. Time- and NADPH-dependent inhibitions were also investigated to show curcumenol is not a mechanism-based inhibitor. Employing these in vitro data and maximum plasma concentration of curcumenol in human predicted from beagle dog's in vivo pharmacokinetic data, the change in AUC of victim drugs was predicted to be 0.4%, which suggested that curcumenol may be safely used without inducing metabolic drug-drug interaction through P450 inhibition. Nevertheless, due to the limited pharmacokinetic data available for curcumenol in humans, it is still not possible to evaluate its potential clinical effects on human patients from in vitro data. Thus, the magnitude of drug-drug interaction (DDI) induced by curcumenol warrants further investigation.
Silymarin, which is extracted from the milk thistle (Silybum marianum), has been used for centuries for treating hepatic disorders and its hepatoprotective effects have been known for hundreds of years. Silymarin is a mixture of polyphenoic flavonoids, which include silibinin (silybin A and silybin B), isosilyin A and B, silychristin A and B, silydianin and other phenol compounds. The pharmacokinetics of silibinin shows fast absorption and elimination. Silymarin undergoes phase I and phase II metabolism, especially phase II conjugation reactions, it undergoes multiple conjugation reactions, and is primarily excreted into bile and urine. Silymarin has a good safety profile, but little is known regarding its potential for drug interaction. Silymarin has limited effect on the pharmacokinetics of several drugs in vivo; despite silymarin decreasing the activity of cytochrome P-450 (CYPs) enzymes, UDP-glucuronosyltransferase (UGT) enzyme, and reducing P-glycoprotein (P-gp) transport. Health-care practitioners should caution patients against co-administration of silymarin and pharmaceutical drugs.
A toxicologic and dermatologic review of tricyclo[5.2.1.02,6]dec-4-en-8-yl acetate when used as a fragrance ingredient is presented.
(1) Shavings from the Eastern Red Cedar (Juniperus virginiana) were examined for three diverse biological properties, i.e. enzyme induction, procarcinogenicity and insecticidal activity. (2) The ability of a cedar environment to stimulate liver drug-metabolizing enzymes in mice was confirmed by lowered values for barbiturate sleeping time. (3) In susceptible strains of mice (C3H-Avy, C3H-AvyfB and CBA/J) the use of cedar shavings as bedding increased significantly the incidence of spontaneous tumors of the liver and mammary gland, and also reduced the average time at which tumors appeared. (4) Cedar and some of its derivatives (Oil of Cedarwood, cedrene, cedrol) disrupted the reproductive and developmental cycle of a number of insects, including the Peanut Trash Bug (Elasmolomus sordidus), the Indian Meal Moth (Plodia interpunctella) and the Forage Mite (Tyrophagus putrescentiae).
Five compounds including furanocoumarin monomers (bergamottin, 6', 7'-dihydroxybergamottin (DHB)), furanocoumarin dimers (4-¿¿6-hydroxy-71-¿(1-hydroxy-1-methyl)ethyl-4-methyl-6-(7-oxo-7H- furo¿3,2-g1benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimethyl- 2-octenyl]oxy]-7H-furo[3,2-g]¿1benzopyran-7-one (GF-I-1) and 4-¿¿6-hydroxy-7¿¿4-methyl-1-(1-methylethenyl)-6-(7-oxo-7H-furo¿3, 2-g1benzopyran-4-yl)-4-hexenylŏxy-3, 7-dimethyl-2-octenylŏxy-7H-furo¿3,2-g1benzopyran-7-one (GF-I-4)), and a sesquiterpene nootkatone have been isolated from grapefruit juice and screened for their inhibitory effects toward human cytochrome P450 (P450) forms using selective substrate probes. Addition of ethyl acetate extract of grapefruit juice into an incubation mixture resulted in decreased activities of CYP3A4, CYP1A2, CYP2C9, and CYP2D6. All four furanocoumarins clearly inhibited CYP3A4-catalyzed nifedipine oxidation in concentration- and time-dependent manners, suggesting that these compounds are mechanism-based inhibitors of CYP3A4. Of the furanocoumarins investigated, furanocoumarin dimers, GF-I-1 and GF-I-4, were the most potent inhibitors of CYP3A4. Inhibitor concentration required for half-maximal rate of inactivation (K(I)) values for bergamottin, DHB, GF-I-1, and GF-I-4 were calculated, respectively, as 40.00, 5. 56, 0.31, and 0.13 microM, whereas similar values were observed on their inactivation rate constant at infinite concentration of inhibitor (k(inact), 0.05-0.08 min(-1)). Apparent selectivity toward CYP3A4 does occur with the furanocoumarin dimers. In contrast, bergamottin showed rather stronger inhibitory effect on CYP1A2, CYP2C9, CYP2C19, and CYP2D6 than on CYP3A4. DHB inhibited CYP3A4 and CYP1A2 activities at nearly equivalent potencies. Among P450 forms investigated, CYP2E1 was the least sensitive to the inhibitory effect of furanocoumarin components. A sesquiterpene nootkatone has no significant effect on P450 activities investigated except for CYP2A6 and CYP2C19 (K(i) = 0.8 and 0.5 microM, respectively).
It has been reported that cedarwood oil has sedative effects when inhaled. In this study, we evaluated sedative effects of inhaled cedrol, which is a major component of cedarwood oil. Accumulative spontaneous motor activity was significantly decreased in the cedrol-exposed Wistar rats. Similar results were confirmed in caffeine-treated Wistar rats, spontaneously hypertensive rats (SHR), and ddY mice. In addition, exposure to cedrol prolonged pentobarbital-induced sleeping time in Wistar rats. To investigate whether cedrol, which has a very faint aroma, affects the olfactory system, the nasal cavities of Wistar rats were treated with zinc sulfate to reduce olfactory function. Two days later, the pentobarbital-induced sleep time was measured as described above. Compared to intact rats, the sleep prolongation effect was decreased in a lavender-roman chamomile mixed oil exposure positive control group, indicating that olfactory function was impaired. In contrast, prolongation of the sleeping time did not change in the cedrol exposure group. The above findings indicate that cedrol inhalation had marked sedative effects regardless of the animal species or the functional state of the autonomic nerves, suggesting that the mechanism of action is via a pathway other than the olfactory system.
It is well known that odors affect behaviors and autonomic functions. Previous studies reported that some compounds in cedar wood essence induced behavioral changes including sedative effects. In the present study, we analyzed cardiovascular and respiratory functions while subjects were inhaling fumes of pure compound (Cedrol) which was extracted from cedar wood oil. Vaporized Cedrol (14.2+/-1.7 microg/l, 5 l/min) and blank air (5 l/min) were presented to healthy human subjects (n=26) via a face mask, while ECGs, heart rate (HR), systolic blood pressure (SBP), diastolic BP (DBP), and respiratory rates (RR) were monitored. Statistical analyses indicated that exposure to Cedrol significantly decreased HR, SBP, and DBP compared to blank air while it increased baroreceptor sensitivity. Furthermore, respiratory rate was reduced during exposure to Cedrol. These results, along with the previous studies reporting close relationship between respiratory and cardiovascular functions, suggest that these changes in respiratory functions were consistent with above cardiovascular alterations. Spectral analysis of HR variability indicated an increase in high frequency (HF) component (index of parasympathetic activity), and a decrease in ratio of low frequency to high frequency components (LF/HF) (index of sympathovagal balance) during Cedrol inhalation. Furthermore, Cedrol inhalation significantly decreased LF components of both SBP and DBP variability, which reflected vasomotor sympathetic activity. Taken together, these patterns of changes in the autonomic parameters indicated that Cedrol inhalation induced an increase in parasympathetic activity and a reduction in sympathetic activity, consistent with the idea of a relaxant effect of Cedrol.
To clarify the influences of ethnic and regional characteristics, and differences in perception on the cedrol effect on autonomic nerve activity, we compared women in their 20s-40s in Norway, Thailand, and Japan. A questionnaire survey of sense of stress and sleep conditions was performed at the same time. The degree of perceived stress, using a 30-item checklist, was highest in Japanese women. The mean stress score exceeded 5.0 in Japanese women, significantly higher than in Thai women (p<0.05) and Norwegian women (p<0.01). Sleeping time was shortest in Japanese women in all generations among the three countries. As the index of autonomic nervous activity, the miosis rate (ratio of pupil-diameter variation after light stimulus to initial pupil diameter) in pupillary light reflex was measured before and after cedrol inhalation. The miosis rate significantly increased after cedrol exposure compared to that before exposure in all three countries, suggesting that the parasympathetic nervous system became dominant. These findings suggested that cedrol produces a sedative effect in people of the three countries despite differences in the ethnic and living environments.
The epimeric tricyclic sesquiterpenoid alcohols globulol, epiglobulol, cedrol, epicedrol, longifolol, and isolongifolol were investigated in their ability to inhibit the recombinant human UDP-glucuronosyltransferase (UGT) 2B7. The stereoisomers displayed rapidly reversible competitive inhibition, which was substrate-independent. Longifolol and its stereoisomer isolongifolol displayed the lowest competitive inhibition constants (K(ic)) of 23 and 26 nM, respectively. The K(ic) values of cedrol and its epimer epicedrol were 0.15 and 0.21 microM, those of globulol and epiglobulol were 5.4 and 4.0 microM, respectively. The diastereomeric alcohols exhibited nearly identical affinities toward UGT2B7 indicating that the spatial arrangement of the hydroxy group had no influence on the dissociation of the enzyme-terpenoid complex. The high affinities stemmed presumably from mere hydrophobic interactions between the hydrocarbon scaffold of the terpenoid alcohol and the binding site of the enzyme. Glucuronidation assays revealed that there were large differences in the rates at which the epimeric alcohols were conjugated. Therefore, the spatial arrangement of the hydroxy group controlled the rate of the UGT2B7-catalyzed reaction. The introduction of a methyl group into the side chain of isolongifolol and longifolol increased the steric hindrance. As a result, the rate of the UGT2B7-catalyzed reaction was decreased by more than 88%. The findings indicated that the rate of the UGT2B7-catalyzed glucuronidation is significantly controlled by stereochemical and steric factors. Considering the high inhibition levels exerted by the tricyclic sesquiterpenoid alcohols, these compounds might serve as valuable lead structures for the design of potent inhibitors for UGT2B7.
To date, several clinically important drugs have been identified that interact with commonly used herbs. These drugs include (among others) warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). Because drug-herb interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of drugs that interact with commonly used herbal medicines has important implications in drug development. In silico, in vitro, animal and human studies are often used to identify drug interactions with herbs. We propose that drug-herb and herb-CYP interaction studies should be incorporated into drug development.