Inhibition by 17-α-ethinyl estradiol of benzo[ a]pyrene metabolism in isolated adult rat hepatocytes

Abstract

The effects of 17-α-ethinyl estradiol [EE] were studied on benzo[ a]pyrene (BP) metabolism and covalent binding to DNA and on some enzymes involved in the activation/inactivation pathway. Suspensions of hepatocytes freshly isolated from adult rats either untreated or pretreated with phenobarbital or methylcholanthrene were used as an experimental model closer to the in vivo situation than subcellular fractions. The formation of water-soluble and of organic metabolites of benzo[ a]pyrene was inhibited by EE at 10 −4 M in hepatocytes from untreated rats and at 10 −3 M in those isolated from rats pretreated with phenobarbital. Dihydrodiols were the main class of metabolites affected by EE. The pretreatment of rats with 3-methylcholanthrene rendered hepatocytes insensitive to the effect of EE. The effect of EE on BP metabolism was well correlated to its inhibitory effect on BP metabolite binding to DNA in untreated and phenobarbital-treated rats. These data could not however be related to a quantitative decrease in cytochrome P-450 of hepatocytes incubated in the presence of EE. Epoxide hydratase, UDP-glucuronyl-transferase and glutathione S-transferase activities were lowerea by 36, 27 and 19% respectively in the presence of 10 −4 M EE. The impairment of BP metabolism by EE might be due to a functional alteration specific for cytochrome P-450, or to a non-destructive mechanism and/or to a competition of both chemical. for a number of enzymatic pathways common to their metabolism.