Sex differences in rats in the metabolism of phenytoin to 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin.

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.