中国药理学与毒理学杂志2001，Vol.15Issue(6)：413-417,5.
山冈橐吾碱在雌性大鼠肝微粒体内的代谢
Metabolism of clivorine in female rat liver microsomes
摘要
Abstract
The metabolism of clivorine, an othonecine-type hepatotoxic pyrrolizidine alkaloid, was investigated in female rat liver microsomes. The major in vitro metabolites of clivorine found in the incubation mixture are two non-pyrrolic metabolites(M1 and M2) and the formation of hepatotoxic pyrrolic metabolites from clivorine is only the minor in vitro metabolic pathway of clivorine in female rats. It suggests that the major in vitro metabolic pathway of clivorine in female rats is different from that in male rats. Selective CYP450 inhibitors pilocarpine(Pil, CYP2A1), diethyldithiocarbamate (DDC, CYP2E1), sulfaphenazole (Sul, CYP2C) and ketoconazole (Ket, CYP3A) had no significant effects on the formation of M1 and M2. Selective flavin-containing monooxygenase(FMO) inhibitor methimazole could inhibit the formation of M2, but had no inhibitory effect on the formation of M1 and the formation of M1 was NADPH independent. The above results suggests that the hydrolase and FMO in microsomes are involved in the formation of M1 and M2 respectively. On the other hand, Selective CYP450 inhibitors Pil, DDC, Sul had no significant effects on the formation of pyrrolic metabolites from clivorine,but selective CYP3A inhibitor Ket could significantly inhibited the formation of pyrrolic metabolites of clivorine whereas clivorine was not metabolized by recombinant rat CYP2C12 and CYP2E1, but could be metabolized by recombinant rat CYP3A1 and CYP3A2 to produce its corresponding hepatotoxic pyrrolic metabolites. The above results indicate that rat CYP3A1 and CYP3A2 are the primary CYP450 involved in the formation of hepatotoxicpyrrolic metabolites. The difference in clivorine-induced toxicity can be partly attributed to this metabolic difference in sex.关键词
山冈橐吾碱/微粒体,肝/代谢分类
医药卫生引用本文复制引用
柳晓泉,林鸽,王广基,钱之玉..山冈橐吾碱在雌性大鼠肝微粒体内的代谢[J].中国药理学与毒理学杂志,2001,15(6):413-417,5.基金项目
国家自然科学基金资助项目 (39970862) （39970862）
国家973计划资助项目 (G1998051119). （G1998051119）
