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Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G two lignan analogs derived from Schisandra chinensis

机译：五味子C和五味子G对人CYP3A4和CYP3A5酶的抑制作用这是五味子的两种木脂素类似物

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摘要

Gomisin C (GC) and gomisin G (GG) are two lignan analogs isolated from the Traditional Chinese Medicine Schisandra chinensis which possesses multiple pharmacological activities. However, the potential herb-drug interactions (HDI) between these lignans and other drugs through inhibiting human cytochrome P450 3A4 (CYP3A4) and CYP3A5 remains unclear. In the present study, the inhibitory action of GC and GG on CYP3A4 and CYP3A5 were investigated. The results demonstrated that both GC and GG strongly inhibited CYP3A-mediated midazolam 1′-hydroxylation, nifedipine oxidation and testosterone 6β-hydroxylation. Notably, the inhibitory intensity of GC towards CYP3A4 was stronger than CYP3A5 when using midazolam and nifedipine as substrates. While inhibition of GC towards CYP3A5 was weaker than CYP3A4 when using testosterone as substrate. In contrast, GG showed a stronger inhibitory activity on CYP3A5 than CYP3A4 without substrate-dependent behavior. In addition, docking simulations indicated that the π–π interaction between CYP3A4 and GC, and hydrogen-bond interaction between CYP3A5 and GG might result in their different inhibitory actions. Furthermore, the AUC of drugs metabolized by CYP3A was estimated to increase by 8%–321% and 2%–3190% in the presence of GC and GG, respectively. These findings strongly suggested that GC and GG showed high HDI potentials, and the position of methylenedioxy group determined their different inhibitory effect towards CYP3A4 and CYP3A5, which are of significance for the application of Schisandra chinensis-containing herbs.
机译：Gomisin C（GC）和gomisin G（GG）是从中药五味子中分离得到的两种木脂素类似物，具有多种药理活性。但是，这些木脂素与其他药物之间通过抑制人细胞色素P450 3A4（CYP3A4）和CYP3A5的潜在药草相互作用（HDI）尚不清楚。在本研究中，研究了GC和GG对CYP3A4和CYP3A5的抑制作用。结果表明，GC和GG均强烈抑制CYP3A介导的咪达唑仑1'-羟基化，硝苯地平氧化和睾酮6β-羟基化。值得注意的是，当使用咪达唑仑和硝苯地平作为底物时，GC对CYP3A4的抑制强度要比CYP3A5强。当使用睾丸激素作为底物时，对CYP3A5的GC抑制作用比CYP3A4弱。相反，GG对CYP3A5的抑制作用强于没有底物依赖性行为的CYP3A4。此外，对接模拟表明CYP3A4和GC之间的π-π相互作用以及CYP3A5和GG之间的氢键相互作用可能导致它们的不同抑制作用。此外，在存在GC和GG的情况下，经CYP3A代谢的药物的AUC估计分别增加了8％–321％和2％–3190％。这些发现强烈表明GC和GG显示出高的HDI电位，并且亚甲基二氧基的位置决定了它们对CYP3A4和CYP3A5的不同抑制作用，这对于含五味子的中草药的应用具有重要意义。

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