Inhibitory Effects of Triptolide on Human Liver Cytochrome P450 Enzymes and P-Glycoprotein
Inhibitory Effects of Triptolide on Human Liver Cytochrome P450 Enzymes and P-Glycoprotein
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DOI：
10.1007/s13318-016-0323-8
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发表时间：
2017-02-01
影响因子：
1.9
通讯作者：
Rui, Hongbing
中科院分区：
文献类型：
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作者：
Zhang, Hanhua;Ya, Guangkui;Rui, Hongbing
背景与目的雷公藤内酯醇是雷公藤的有效成分，具有多种药理活性。然而，雷公藤内酯醇如何影响人肝细胞色素P450（CYP）酶和P-糖蛋白（P-gp）的活性仍不清楚。结果雷公藤甲素对人肝微粒体细胞色素P450 1A 2、3A 4、2A 6、2 E1、2D 6、2C 9、2C 19、2C 8的活性有明显的抑制作用，对人肝微粒体细胞色素P450 1A 2、3A 4、2A 6、2 E1、2D 6、2C 9、2C 19、2C 8的活性无明显影响。50%抑制浓度（IC 50）值分别为14.18和8.36 μ M，但其它β-内酰胺酶同工型不受影响。酶动力学研究表明，雷公藤甲素不仅是一个非竞争性抑制剂的CYP 1A 2，但也是一个竞争性抑制剂的CYP 3A 4，抑制常数（Ki）值分别为7.32和5.67 μ M。此外，雷公藤内酯醇是CYP 1A 2的时间依赖性抑制剂，50%最大失活浓度（K-i）和最大失活浓度（K-inact）值分别为286.5 μ M和0.024 min（-1）。罗丹明-123摄取实验表明雷公藤甲素对P-gp活性无影响。结论雷公藤甲素与CYP 1A 2和CYP 3A 4代谢的P-gp和P-gp的体外研究表明，雷公藤甲素可能与其他合用药物发生药代动力学药物相互作用。需要进一步的临床研究来评估这种相互作用的意义。
Background and Objectives Triptolide is an active component derived from Tripterygium wilfordii and it possesses numerous pharmacological activities. However, it remains unclear how triptolide influences the activity of human liver cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp).Methods In this study, the inhibitory effects of triptolide on the eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes (HLMs), and the effects of triptolide on the activity of P-gp were investigated using a rhodamine-123 uptake assay.Results The results showed that triptolide inhibited the activity of CYP1A2 and CYP3A4, with 50 % inhibitory concentration (IC50) values of 14.18 and 8.36 mu M, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that triptolide was not only a non-competitive inhibitor of CYP1A2, but also a competitive inhibitor of CYP3A4, with inhibition constant (K-i) values of 7.32 and 5.67 mu M, respectively. In addition, triptolide is a time-dependent inhibitor for CYP1A2, and the concentration at 50 % maximum inactivation (K-i) and maximum inactivation (K-inact) values were 286.5 mu M and 0.024 min(-1), respectively. The rhodamine-123 uptake assay showed that triptolide could not affect the activity of P-gp.Conclusions The in vitro studies of triptolide with CYP isoforms and P-gp indicate that triptolide has the potential to cause pharmacokinetic drug interactions with other coadministered drugs metabolized by CYP1A2 and CYP3A4. Further clinical studies are needed to evaluate the significance of this interaction.