SEMV CELL-CULTURES - A MODEL FOR STUDIES OF PROSTAGLANDIN-H SYNTHASE-MEDIATED METABOLISM AND GENOTOXICITY OF XENOBIOTICS

Many xenobiotics and carcinogens are oxidized in vitro by prostaglandin-H synthase (PHS) in the presence of arachidonic acid or lipid peroxides. PHS has been suggested to serve as an alternative metabolic activation enzyme to the cytochrome P-450 isoenzymes, particularly in tissues low in monooxygenase activity. This article briefly describes PHS-catalyzed oxidations and reviews methods available for investigating the involvement of PHS in mediating the toxicity of certain chemicals. Since in vivo systems impose certain limitations on such studies, particular emphasis is placed on a specialized cell system which can serve as a model for investigating the PHS-dependent bioactivation of xenobiotics, its determinants and toxicological significance. This is exemplified by experiments conducted with the carcinogenic estrogen diethylstilbestrol (DES) in cell cultures derived from ram seminal vesicles which express PHS but lack monooxygenase activity. DES is oxidized by PHS in seminal vesicle (SEMV) cells and DES can induce micronuclei in this model; both processes are inhibited by indomethacin. These data support the hypothesis that PHS-dependent oxidation of DES plays a role in its genotoxicity.