呋喃二烯对肝脏细胞色素P450酶不同亚型的影响

Inhibitory and Inductive Effects of Furanodiene on Hepatic Cytochrome P450

目的考察呋喃二烯(furanodiene,FDE)对肝脏微粒体主要的细胞色素P450(CYP)酶活性的影响。方法采用探针底物法,考察FDE在体外孵育体系中对大鼠和人肝微粒体CYP1A、CYP2A、CYP3A、CYP2C、CYP2D、CYP2E1的抑制作用,并计算相应的IC50值;采用微粒体体外"鸡尾酒"孵育法(cocktail法),考察大鼠经低、高剂量FDE(40 mg·kg?1和160 mg·kg?1)连续灌胃7 d,其肝微粒体主要CYP酶活性的变化。结果 FDE对大鼠肝微粒体CYP2D1和CYP2C6/7有较弱的抑制作用,其IC50分别为15.8和23.8μmol·L?1;对人肝微粒体CYP2C9也有较弱的抑制作用,IC50为26.1μmol·L?1。与对照组比较,大鼠灌胃40 mg·kg?1 FDE,肝微粒体主要CYP酶活性无显著变化;灌胃160 mg·kg?1后,肝微粒体CYP2E1活性为对照组的164%。结论 FDE对大鼠和人肝微粒体CYP主要亚型的抑制作用较弱;40 mg·kg?1 FDE对大鼠肝微粒体主要CYP酶未显示明显诱导作用,160 mg·kg?1 FDE对肝微粒体CYP2E1有一定的诱导作用。

OBJECTIVE To study the inhibitive and inductive effect of furanodiene（FDE） on main cytochrome P450 isoforms（CYPs） in rat and human liver microsomes. METHODS Probe substrate method was used to evaluate the in vitro inhibitory effect of FDE on CYP1 A, CYP2 A, CYP3 A, CYP2 C, CYP2 D and CYP2E1 in rat and human liver microsomes. Rats were administered with FDE at a dosage of 40 mg·kg^-1 or 160 mg·kg^-1 by gastric lavage for successive 7 days, then the metabolic activities of main CYPs in liver microsomes were evaluated by cocktail-LC-MS/MS method. The inductive effect of FDE was evaluated by comparing the activities of main CYP450 isoforms in rat liver microsomes with or without treatment of FDE. RESULTS FDE inhibited the activities of CYP2D1 and CYP2C6/7 in rat liver microsomes, with the IC50 values of 15.8 and 23.8 μmol·L^-1, respectively. FDE also inhibited CYP2C9 activity in human liver microsomes with the IC50 of 26.1 μmol·L^-1. Compared with the vehicle group, 40 mg·kg^-1 FDE did not obviously change the activities of main CYPs in rat microsomes, while 160 mg·kg^-1 of FDE increased the activity of CYP2E1 to 164% of the vehicle group. CONCLUSION FDE has a negligible or weak inhibitory effect on main CYP450 in rat and human liver microsomes, FDE can not induce main CYP450 in rat liver microsomes at 40 mg·kg^-1 while induce CYP2E1 to some extent at 160 mg·kg^-1.