Prostaglandin H synthase (PHS) peroxidase dependent metabolic activation has been suggested to play a role in mediating adverse effects of various carcinogens. Recently, we derived a cell line from ram seminal vesicles (SEMV cells) to conduct studies on the PHS-mediated metabolism of estrogens and xenobiotics in intact cells with the goal of relating this to an endpoint for genotoxicity inducible in this in vitro model. The present paper describes the drug-metabolizing capability of SEMV cells which has been investigated using radiolabeled diethylstilbestrol (DES) and analysing culture extracts by means of reverse phase HPLC with on-line radioactivity detection and after enzymatic hydrolysis of conjugate fractions. The synthetic estrogen DES is converted to sulfate conjugates and to the oxidative metabolite Z,Z-dienestrol (Z,Z-DIES) in a time-dependent manner. Compounds expected to modulate PHS-dependent co-oxidation of DES increased (arachidonic acid) or inhibited (indomethacin) Z,Z-DIES formation of SEMV cells in culture. A comparison of rates of arachidonic acid turnover to prostaglandins on the one hand and DES oxidation on the other reveals that DES is oxidized despite the presence of competing endogenous cosubstrates of PHS peroxidase. The results clearly indicate that SEMV cells catalyze PHS-dependent oxidation of DES as well as carrying out phase II metabolism in the absence of detectable monooxygenase activity. These features and recent data showing that DES can induce micronuclei in SEMV cells makes them an attractive model for further investigations of the role of PHS in mediating the genotoxicity of DES and other xenobiotics.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.