Billings R E
J Pharmacol Exp Ther. 1983 Jun;225(3):630-6.
Phenytoin (DPH) is metabolized in isolated hepatocytes from male rats by hydroxylation to 5-(4-hydroxyphenyl)-5-phenylhydantoin, 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin (dihydrodiol) and a catecholic metabolite, 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin, which is further metabolized by methylation of one of the phenolic hydroxyl groups. Isolated hepatocytes from female rats convert DPH to the initial metabolites, but only trace amounts of the catechol are formed. Similar results were obtained in vivo and with liver homogenate preparations. Incubation of possible precursor metabolites to the catechol indicate that the sex difference in catechol formation is due to differences in 5-(4-hydroxyphenyl)-5-phenylhydantoin hydroxylation rather than to differences in oxidation of the dihydrodiol metabolite. It is postulated that different isozymes of cytochrome P-450 catalyze the hydroxylation of DPH and its p-phenol metabolite because sex differences are observed only in the second hydroxylation step. Furthermore, the sex difference may be due to lower activity of one or more cytochrome P-450 isozymes in female rats than in male rats. These results may have important implications in the pharmacological activity and toxicity of DPH.
苯妥英（DPH）在雄性大鼠的离体肝细胞中通过羟基化代谢为5-（4-羟基苯基）-5-苯基乙内酰脲、5-（3,4-二羟基-1,5-环己二烯-1-基）-5-苯基乙内酰脲（二氢二醇）和一种儿茶酚代谢物5-（3,4-二羟基苯基）-5-苯基乙内酰脲，后者通过其中一个酚羟基的甲基化进一步代谢。雌性大鼠的离体肝细胞将DPH转化为初始代谢物，但仅形成痕量的儿茶酚。在体内和肝脏匀浆制剂中也获得了类似的结果。对儿茶酚可能的前体代谢物进行孵育表明，儿茶酚形成的性别差异是由于5-（4-羟基苯基）-5-苯基乙内酰脲羟基化的差异，而不是二氢二醇代谢物氧化的差异。据推测，细胞色素P-450的不同同工酶催化DPH及其对苯酚代谢物的羟基化，因为仅在第二步羟基化中观察到性别差异。此外，性别差异可能是由于雌性大鼠中一种或多种细胞色素P-450同工酶的活性低于雄性大鼠。这些结果可能对DPH的药理活性和毒性具有重要意义。
