Shen Guolin, Zhuang Xiaomei, Xiao Weibin, Kong Linglei, Tan Yan, Li Hua
Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China.
Food Chem Toxicol. 2014 Sep;71:90-6. doi: 10.1016/j.fct.2014.05.020. Epub 2014 Jun 6.
Triptolide (TP) is an active component of Tripterygium wilfordii Hook. F and widely used to treat autoimmune and inflammatory diseases. It has been demonstrated that cytochrome P450 (CYP) are involved in the metabolism of TP. However, the underlying mechanisms of TP-induced toxicity mediated by hepatic CYP have not been well delineated. In this study, rat liver microsomes (RLM) and sandwich-cultured rat hepatocytes (SCRH) were used to identify the mechanism involving the CYP3A inhibition by TP and to evaluate TP-induced liver damage after CYP3A modulation by the known inhibitor, ketoconazole, and the known inducer, dexamethasone. The results showed that TP itself had a time- and concentration-dependent inhibitory effect on CYP3A. When the CYP3A inhibitor and inducer were added, the enzyme activity and hepatotoxicity changed significantly. The enzyme inducer increased CYP3A activity and decreased the metabolic half life (t1/2) of TP when compared to the control group, while the enzyme inhibitor had an opposite effect. Our findings reveal that TP is a weak CYP3A inhibitor involving the time-dependent inhibition mechanism. The induction or inhibition of CYP3A played an important role in TP-induced hepatotoxicity. Clinicians should be aware of the metabolic characteristics of TP to maximize therapeutic efficacy and reduce TP-induced toxicity.
雷公藤甲素（TP）是雷公藤的一种活性成分，广泛用于治疗自身免疫性疾病和炎症性疾病。已有研究表明，细胞色素P450（CYP）参与了TP的代谢。然而，由肝脏CYP介导的TP诱导毒性的潜在机制尚未完全阐明。在本研究中，使用大鼠肝微粒体（RLM）和三明治培养的大鼠肝细胞（SCRH）来确定TP抑制CYP3A的机制，并评估已知抑制剂酮康唑和已知诱导剂地塞米松对CYP3A进行调节后TP诱导的肝损伤。结果表明，TP本身对CYP3A具有时间和浓度依赖性抑制作用。当加入CYP3A抑制剂和诱导剂时，酶活性和肝毒性发生显著变化。与对照组相比，酶诱导剂增加了CYP3A活性并缩短了TP的代谢半衰期（t1/2），而酶抑制剂则产生相反的效果。我们的研究结果表明，TP是一种涉及时间依赖性抑制机制的弱CYP3A抑制剂。CYP3A的诱导或抑制在TP诱导的肝毒性中起重要作用。临床医生应了解TP的代谢特征，以最大限度地提高治疗效果并降低TP诱导的毒性。
