StructureActivity Relationship and Substrate-Dependent Phenomena in Effects of Ginsenosides on Activities of Drug-Metabolizing P450 Enzymes

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, People's Republic of China.
PLoS ONE (Impact Factor: 3.23). 07/2008; 3(7). DOI: 10.1371/journal.pone.0002697
Source: PubMed


Ginseng, a traditional herbal medicine, may interact with several co-administered drugs in clinical settings, and ginsenosides, the major active components of ginseng, may be responsible for these ginseng-drug interactions (GDIs). Results from previous studies on ginsenosides' effects on human drug-metabolizing P450 enzymes are inconsistent and confusing. Herein, we first evaluated the inhibitory effects of fifteen ginsenosides and sapogenins on human CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes by using commercially available fluorescent probes. The structure-activity relationship of their effects on the P450s was also explored and a pharmacophore model was established for CYP3A4. Moreover, substrate-dependent phenomena were found in ginsenosides' effects on CYP3A4 when another fluorescent probe was used, and were further confirmed in tests with conventional drug probes and human liver microsomes. These substrate-dependent effects of the ginsenosides may provide an explanation for the inconsistent results obtained in previous GDI reports.

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    • "Information on the metabolism of Panax notoginseng components is important for understanding the biological effects of Panax notoginseng. Some reports concerned the structure-activity relationship and substrate-dependent phenomena in effects of Ginsenosides on P450 Enzymes [15], [16]. Previously, we reported the pharmacokinetics of 25(R)-OCH3-PPD in rat. "
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    ABSTRACT: The present study characterized in vitro metabolites of 20(R)-25-methoxyl-dammarane-3β, 12β, 20-triol (20(R)-25-OCH3-PPD) in mouse, rat, dog, monkey and human liver microsomes. 20(R)-25-OCH3-PPD was incubated with liver microsomes in the presence of NADPH. The reaction mixtures and the metabolites were identified on the basis of their mass profiles using LC-Q/TOF and were quantified using triple quadrupole instrument by multiple reaction monitoring. A total of 7 metabolites (M1-M7) of the phase I metabolites were detected in all species. 25(R)-OCH3-PPD was metabolized by hydroxylation, dehydrogenation, and O-demethylation. Enzyme kinetic of 20(R)-25-OCH3-PPD metabolism was evaluated in rat and human hepatic microsomes. Incubations studies with selective chemical inhibitors demonstrated that the metabolism of 20(R)-25-OCH3-PPD was primarily mediated by CYP3A4. We conclude that 20(R)-25-OCH3-PPD was metabolized extensively in mammalian species of mouse, rat, dog, monkey, and human. CYP3A4-catalyzed oxygenation metabolism played an important role in the disposition of 25(R)-OCH3-PPD, especially at the C-20 hydroxyl group.
    PLoS ONE 04/2014; 9(4):e94962. DOI:10.1371/journal.pone.0094962 · 3.23 Impact Factor
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    • "Pharmacogenomic variations of CYP3A4 in humans have been indicated in many drug metabolism and drug-drug interactions. Because the effects on CYP3A4 might be substrate-dependent, as we found previously for the ginsenosides34, three fluorescent probes, Vivid CYP3A4 green, Vivid CYP3A4, red and Vivid CYP3A4 blue, were used to determine the effects of gingerols on CYP3A4. There was no significant difference in the inhibitory potency of these compounds. "
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    ABSTRACT: Aim: Ginger rhizome is used worldwide as a spicy flavor agent. This study was designed to explore the potential effects of pungent ginger components, 6-, 8-, and 10-gingerol, on human cytochrome P450 (CYP450) enzymes that are responsible for the metabolism of many prescription drugs. Methods: The activities of human CYP2C9, CYP2C19, CYP2D6, and CYP3A4 were analyzed using Vivid P450 assay kits. The mRNA expression of CYP3A4 in human hepatocellular carcinoma cell line HepG2 was measured using quantitative real-time PCR assay. Results: All three gingerols potently inhibited CYP2C9 activity, exerted moderate inhibition on CYP2C19 and CYP3A4, and weak inhibion on CYP2D6. 8-Gingerol was the most potent in inhibition of P450 enzymes with IC50 values of 6.8, 12.5, 8.7, and 42.7 μmol/L for CYP2C9, CYP2C19, CYP3A4, and CYP2D6, respectively. By comparing the effects of gingerols on CYP3A4 with three different fluorescent substrate probes, it was demonstrated that the inhibition of gingerols on CYP3A4 had no substrate-dependence. In HepG2 cells, 8-gingerol and 10-gingerol inhibited, but 6-gingerol induced mRNA expression of CYP3A4. Conclusion: 6-, 8-, and 10-gingerol suppress human cytochrome P450 activity, while 8- and 10-gingerol inhibit CYP3A4 expression. The results may have an implication for the use of ginger or ginger products when combined with therapeutic drugs that are metabolized by cytochrome P450 enzymes.
    Acta Pharmacologica Sinica 06/2013; 34(9). DOI:10.1038/aps.2013.49 · 2.91 Impact Factor
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    • ", B. Hao and co-workers (2008) [74], and C. Foti and co-workers (2012) [76] "
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    ABSTRACT: One of the major reasons for late-stage failure of drug candidates is due to problems uncovered in pharmacokinetics during clinical trials. There is now a general consensus for earlier consideration of these effects in the drug discovery process. Computer-aided design technology provides us with tools to develop predictive models for such pharmacokinetic properties. Among these tools, we focus on pharmacophore modeling techniques in this article. Pharmacophore models that are reported for various cytochrome P450 (CYP) enzymes are reviewed for the isoenzymes CYP1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4. In addition pharmacophore models for related metabolic processes through CYP19 (aromatase), CYP51 (14α-lanosterol demethylase), PXR (pregnane X-receptor), and finally for human intrinsic clearance are also reviewed. The models reported by various scientists are schematically represented in the figures in order to visually demonstrate their similarities and differences. The different models developed by different researchers or sometimes even by the same research group for different sets of ligands, provide a clear picture of the challenges in coming up with a single model with good predictive values. The main reason for this challenge is due to the relatively large size of the active sites and flexibility of the CYP isoenzymes, resulting with multiple binding sites. We propose development of multiple-diverse pharmacophore models for each binding mode (as opposed to a single predictive model for each CYP isoenzyme). After scoring and prioritization of the models, we propose the use of a battery of pharmacophore models for each CYP isoenzyme binding mode to computationally obtain a P450 interaction profile for drug candidates early in the drug development cycle, when decisions on their fate can be made before incurring cost of synthesis and testing.
    Current topics in medicinal chemistry 05/2013; 13(11). DOI:10.2174/15680266113139990037 · 3.40 Impact Factor
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