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目的:鉴定中国成人肝微粒体中介导氯胍(PG)活化为氯胍三嗪(CG)的细胞色素P450(CYP450).方法:分析中国成人(n=6)肝微粒体中PG活化为CG的酶促动力学,各种CYP450抑制剂对该代谢的作用及其与S-美芬妥英4′-羟化的关系.结果:6个标本中,除一个外(两酶米氏模型),PG活化为CG的酶促动力学符合米氏一酶模型;CYP3A4和CYP2E1的选择性抑制剂醋竹桃霉素(81.1％)和二乙二硫基苯甲酸(47.23％)可抑制CG生成,其它抑制剂没有明显作用;在低PG浓度时,PG的环化与S-美芬妥英4′-羟化显著相关(r=0.805,P<0.05),高浓度时相关性明显减小.结论:在中国成人肝微粒体中CYP2C19和CYP3A4参与了PG活化为CG.
PURPOSE: To identify cytochrome P450s (CYP450) that mediate the induction of proguanil (PG) into proglucagon (CG) in adult human liver microsomes.Methods: The PG activities in Chinese adult (n = 6) CG enzymatic kinetics, the effect of various CYP450 inhibitors on the metabolism and its relationship with S-mephenytoin 4’-hydroxylation.Results: Among 6 specimens, except one, ). The enzymatic kinetics of PG activation to CG was in line with the Mie-I enzyme model. The selective inhibitor of CYP3A4 and CYP2E1, rebaudioside (81.1%) and diethyldithiobenzoic acid (47.23%), inhibited CG (P <0.05). At low concentrations of PG, the cyclization of PG was significantly correlated with the 4’-hydroxylation of S-mephenytoin (r = 0.805, P <0.05) Conclusions: CYP2C19 and CYP3A4 are involved in the activation of PG in Chinese adult human liver microsomes.