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目的 在体外研究山冈橐吾碱在人肝微粒体内的代谢及参与其代谢的主要的CYP4 5 0酶 ,探讨其代谢致毒机理。方法 采用人肝微粒体研究山冈橐吾碱的主要代谢方式和代谢物。在体外运用CYP4 5 0酶的选择性抑制剂和cDNA表达的人肝CYP4 5 0酶 ,探讨其对山冈橐吾碱的代谢及肝毒性的吡咯代谢物形成的影响及参与山冈橐吾碱代谢的主要的CYP4 5 0酶。结果 山冈橐吾碱在人肝微粒体内的主要代谢物为肝毒性的吡咯代谢物 :去氢倒千里光裂碱 ,7 谷胱甘肽基 去氢倒千里光裂碱 ,7,9 二谷胱甘肽基去氢倒千里光裂碱和山冈囊吾酸。CYP4 5 0特异性抑制剂α 萘黄酮 (抑制CYP1A2 )、黄胺苯吡唑 (抑制CYP2C)、奎尼丁 (抑制CYP2D6 )和二乙基二硫代氨基甲酸钠 (抑制CYP2E1)对山冈橐吾碱的代谢无明显的影响。但CYP3A的特异性抑制剂酮康唑和三乙酰竹桃霉素可以显著地抑制山冈橐吾碱的代谢及其吡咯代谢物和结合型吡咯物的形成。此外 ,在cDNA表达的人肝CYP3A4的温孵液中 ,山冈橐吾碱被代谢成相应的吡咯代谢物 ,而山冈橐吾碱在cDNA表达的人肝CYP1A2、CYP2C9、CYP2D6和CYP2E1温孵液中无代谢。结论 山冈橐吾碱在人肝微粒体内的主要代谢方式是形成肝毒性吡咯代谢物 ,CYP3A作为主要的CYP4 5 0酶参与了山冈橐吾碱的代谢及其肝毒性吡咯代谢?
OBJECTIVE: To study the metabolism of cyclopenthedrin in human liver microsomes and the major CYP450 enzyme involved in its metabolism in vitro, and to explore the mechanism of its metabolism. Methods Human liver microsomes were used to study the main metabolites and metabolites of Shanhaoxiujing. In vitro use of CYP450 enzyme selective inhibitors and cDNA expression of human liver CYP450 enzyme, to explore its metabolism and hepatotoxicity of pyrrolnitril pyrrole metabolites formed and the metabolism of the Hill Okamy The major CYP450 enzyme. Results The main metabolites of hyaluronan in human liver microsomes were hepatic toxic pyrrole metabolites: dehydroerithromycin, 7 glutathione dehydrogenolipine, 7,9 diamines Glycopeptide dehydrogenation Qianlian clenbuterol and Hill capsule acid. CYP450 specific inhibitors α-naphthoflavone (CYP1A2-inhibiting), pymetrozine (inhibiting CYP2C), quinidine (inhibiting CYP2D6) and sodium diethyldithiocarbamate (inhibiting CYP2E1) No significant effect on metabolism. However, the specific inhibitors of CYP3A, ketoconazole and oleandomycin, significantly inhibited the metabolism of hillyuprine and the formation of pyrrole metabolites and bound azole. In addition, in the incubation of cDNA-expressed human liver CYP3A4, hillyardine was metabolized to the corresponding pyrrole metabolite, while hillardine was incubated in cDNA-expressed human liver CYP1A2, CYP2C9, CYP2D6 and CYP2E1 warm incubations No metabolism. Conclusion The main metabolic pathway of hyaluronan in human liver microsomes is the formation of hepatotoxic pyrrole metabolites. CYP3A, as the major CYP450 enzyme, is involved in the metabolism of pyrrolnitin and pyrrole metabolism of hepatotoxicity.