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雷公藤内酯(triptolide,TP)是中药雷公藤的主要有效成分,但其严重的多器官毒性导致其治疗窗很窄。本文研究了雄性Wistar大鼠连续灌胃TP(0.05,0.3,0.6 mg.kg1.day1)以及TP(0.6 mg.kg1.day1)联用甘草次酸(glycyrrhetic acid,GA)(30 mg.kg1.day1)7天后,对大鼠肝脏4种细胞色素P450酶mRNA表达及酶活性的影响。结果表明,高剂量TP组CYP2E1,1A2,3A1以及2C11的mRNA表达水平较对照组显著上调,TP与GA联用组较TP高剂量组进一步上调了CYP3A1,2C11以及2E1的mRNA表达水平。同时,与对照组相比,高剂量TP组和TP与GA联用组均显著提高了CYP3A对睾酮6β-羟化反应的活性(分别为2.2倍与4.1倍)。由于TP在雄性大鼠体内中主要由CYP3A2代谢,因此本研究表明,TP诱导的CYP3A活性增加可能是TP在大鼠肝脏快速清除的重要原因,GA可通过促进TP的肝清除降低TP的肝毒性。此外,本研究还提示TP和GA与CYP3A底物药物共用时,可能发生药物相互作用。
Triptolide (TP) is the main active ingredient of Tripterygium wilfordii, but its severe multiple organ toxicity leads to narrow therapeutic window. In this study, male Wistar rats were treated with TP (0.05, 0.3, 0.6 mg.kg1.day1) and TP (0.6 mg.kg1.day1) in combination with glycyrrhetic acid (GA) (30 mg.kg1. day1) on the mRNA and proteinase activities of four cytochrome P450 enzymes in liver of rats. The results showed that mRNA expression levels of CYP2E1, 1A2, 3A1 and 2C11 were significantly up-regulated in high-dose TP group compared with control group. Compared with TP high-dose TP group, TP and GA increased the mRNA expression of CYP3A1, 2C11 and 2E1. Meanwhile, compared with the control group, high-dose TP group and combination of TP and GA significantly increased CYP3A activity of testosterone 6β-hydroxylation (2.2 times and 4.1 times, respectively). Since TP is mainly metabolized by CYP3A2 in male rats, this study suggests that increased TP-induced CYP3A activity may be an important reason for the rapid clearance of TP in rat liver. GA may reduce TP hepatotoxicity by promoting hepatic clearance of TP . In addition, this study also suggests that drug interactions may occur when TP and GA are co-administered with CYP3A substrate drugs.