普萘洛尔光学异构体在经不同诱导剂诱导的大鼠肝微粒体P450系统中的代谢特征

Metabolic characteristics of the optical isomers of propranolol in the cytochrome P450 of rat liver microsomes treated with different inducers 1

采用正常及β萘黄酮（ＢＮＦ）或苯巴比妥（ＰＢ）诱导的大鼠肝微粒体，研究了Ｒ（＋）和Ｓ（－）普萘洛尔代谢酶动力学参数及立体选择性．实验表明，３种微粒体酶的亲和力均无立体选择性，反应速度有较大差别，并表现出立体选择性．ＢＮＦ组对两种对映体的催化作用较对照组增强，并对Ｒ（＋）对映体有选择性；ＰＢ组的催化作用较对照组减弱，但对Ｓ（－）对映体有选择性．实验结果提示普萘洛尔经细胞色素Ｐ４５０代谢时，酶活性中心的结合基团无立体选择性。

R(+), S(-) Propranolol were metabolized in vitro by cytochrome P450 from normal and β naphthoflavone(BNF) or phenobarbital(PB) induced rats. A RP HPLC method was developed to determine propranolol concentration. The substrate concentration time curves and enzyme parameters (K m, V max and Cl int ) of each liver microsome to R(+) or S(-) propranolol were provided. The results showed that no stereoselectivity was observed in enzymatic affinity of three kinds of microsomes to enantiomers, while their catalytic abilities were quite different and had stereoselectivities. Compared with control microsome, BNF treated microsome showed stronger enzyme activities to propranolol enantiomers with the stereoselectivity of R(+) enantiomer, and PB treated microsome showed less enzyme activity to propranolol enantiomers with the stereoselectivity of S(-) enantiomer that is the same as control microsome. From the experiment it is concluded that the enzyme activity centers of three microsomes are quite different in composition and regioselectivity, and the stereoselectivities of propranolol cytochrome P450 metabolism in vitro in rat hepatic microsome are likely due to the stereoselectivities of the catalyzing function in enzyme while not of the binding function.