Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G, two lignan analogs derived from Schisandra chinensis.
Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G, two lignan analogs derived from Schisandra chinensis.
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gomisin C 和 gomisin G（两种源自五味子的木脂素类似物）对人 CYP3A4 和 CYP3A5 酶的抑制。
DOI：
10.1016/j.fitote.2017.03.010
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发表时间：
2017-06
期刊：
影响因子：
3.4
通讯作者：
Yin J
中科院分区：
文献类型：
--
作者：
Zhao J;Sun T;Wu JJ;Cao YF;Fang ZZ;Sun HZ;Zhu ZT;Yang K;Liu YZ;Gonzalez FJ;Yin J
五味子丙素（GC）和五味子庚素（GG）是从中药五味子中分离得到的两种木脂素类似物，五味子具有多种药理活性。然而，这些木脂素通过抑制人细胞色素P450 3A4（CYP3A4）和CYP3A5与其他药物之间潜在的草药 - 药物相互作用（HDI）仍不明确。在本研究中，对GC和GG对CYP3A4和CYP3A5的抑制作用进行了研究。结果表明，GC和GG均强烈抑制CYP3A介导的咪达唑仑1'-羟基化、硝苯地平氧化以及睾酮6β - 羟基化。值得注意的是，当以咪达唑仑和硝苯地平为底物时，GC对CYP3A4的抑制强度强于对CYP3A5的抑制强度。而当以睾酮为底物时，GC对CYP3A5的抑制作用弱于对CYP3A4的抑制作用。相比之下，GG对CYP3A5的抑制活性强于对CYP3A4的抑制活性，且不存在底物依赖性。此外，对接模拟表明，CYP3A4与GC之间的π - π相互作用以及CYP3A5与GG之间的氢键相互作用，可能导致它们产生不同的抑制作用。此外，据估计，在存在GC和GG的情况下，由CYP3A代谢的药物的血药浓度 - 时间曲线下面积（AUC）分别增加8% - 321%和2% - 3190%。这些研究结果有力地表明，GC和GG具有较高的HDI潜力，且亚甲二氧基的位置决定了它们对CYP3A4和CYP3A5的不同抑制作用，这对于含五味子草药的应用具有重要意义。
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.
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影响因子：
30.8
作者：
Kuehl, P;Zhang, J;Schuetz, E
通讯作者：
Schuetz, E
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作者：
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作者：
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作者：
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3.9
作者：
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Greenblatt, DJ