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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    • "Based on the results, the activities of the CYP1A2, CYP2C9, and CYP3A4 enzymes were inhibited by RG product intake, whereas CYP2C19 and CYP2D6 were not affected[22,23]. A previous conventional in vitro study obtained similar results, asserting that ginsenosides Rb1, Rb2, Rc, Re, and Rg1 did not affect CYP enzyme activity but that their metabolites ginsenoside Rh2, compound K, PPD, and PPT did inhibit CYP1A2, CYP2C9, and CYP3A4, with no effect on CYP2C19 and CYP2D6[4,5,10,24]. However, in this study, administration of the ginseng product at its recommended daily allowance resulted in a small inhibition of CYP1A2, CYP2C9, and CYP3A4 activities, such that even if the drug was administered in combination with CYP substrates, the effect was unlikely to be clinically meaningful. "
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    ABSTRACT: We evaluated the drug interaction profile of Red Ginseng (RG) with respect to the activities of major cytochrome P450 (CYP) enzymes and the drug transporter P-glycoprotein (P-gp) in healthy Korean volunteers.
    Full-text · Article · Jan 2016 · Journal of ginseng research
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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.
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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.
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