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研究了山冈橐吾碱 (clivorine)在雌性大鼠肝微粒体内的代谢 .山冈橐吾碱在雌性大鼠肝微粒体内的主要代谢物为两个非吡咯代谢物M1和M2 .与雄性大鼠不同 ,生成肝毒性的吡咯代谢物为其次要的代谢途径 .文献报道山冈橐吾碱在雄性大鼠肝微粒体内的主要代谢方式是形成相应的吡咯代谢物 .这提示山冈橐吾碱在雌雄大鼠肝微粒体内的主要代谢方式不同 .CYP4 5 0特异性抑制剂黄胺苯吡唑(CYP2C) ,毛果芸香碱 (CYP2A1) ,二乙基二硫代氨基甲酸钠 (CYP2E1)和酮康唑 (CYP3A)对M1和M2的形成无明显的影响 .黄素单氧化酶的特异性抑制剂甲巯咪唑可以显著地抑制M2 的形成 ,但对M1的形成无明显的抑制作用 ,且M1在肝微粒体中的形成为NADPH非依赖性 ,上述结果提示参与M1和M2代谢的酶分别为肝微粒体中的水解酶和黄素单氧化酶 .另一方面 ,毛果芸香碱 ,黄胺苯吡唑和二乙基二硫代氨基甲酸钠对山冈橐吾碱的吡咯代谢物的形成无明显的影响 ,而CYP3A的特异性抑制剂酮康唑可以显著地抑制吡咯代谢物的生成 ,且山冈橐吾碱在重组的大鼠肝CYP2C12 ,CYP2E1温孵液中无代谢 ,而在重组的大鼠肝CYP3A1和CYP3A2的温孵液中山冈橐吾碱被代谢成相应的吡咯代谢物 .这提示CYP3A作为主要的CYP4 5 0酶参与了山冈橐吾碱的肝毒性吡咯代谢物的形成 .山冈橐吾碱?
The metabolism of clivorine in liver microsomes of female rats was studied. The main metabolite of hillyoxine in liver microsomes of female rats was two non-pyrrole metabolites M1 and M2, which were different from those in male rats , Generating pyrrole metabolites of liver toxicity as its secondary metabolic pathways reported in the literature mountain hyaluridine in rat liver microsomal metabolism in the main form of the corresponding pyrrole metabolites.This suggests that hillside hyaluronate in male and female rats The main metabolic mechanisms of liver microsomes were different.CYP450 specific inhibitor CYP2C, pilocarpine (CYP2A1), diethyldithiocarbamate (CYP2E1) and ketoconazole (CYP3A) on M1 Had no obvious effect on the formation of M2.The single inhibitor of flavin monooxygenase methimazole significantly inhibited the formation of M2 but had no obvious inhibition on the formation of M1 and the formation of M1 in liver microsome was NADPH The above results suggest that the enzymes involved in M1 and M2 metabolism are hydrolase and flavin monooxygenase in liver microsome, respectively.On the other hand, pilocarpine, pyrantel and diethyl dithiocarbamate There was no significant effect on the formation of pyrrole metabolites in hilly guanamine, but ketoconazole, a specific inhibitor of CYP3A, could significantly inhibit the formation of pyrrole metabolites, and hyaluronan in the recombinant rat liver CYP2C12, CYP2E1 In warm incubation solution, there was no metabolism, but in the incubation of recombinant rat liver CYP3A1 and CYP3A2, kapokine was metabolized to the corresponding pyrrole metabolites, suggesting that CYP3A, as a major CYP450 enzyme, Alkaloid hepatotoxicity pyrrole metabolites formation.