Oxidative metabolism of diethylstilbestrol by prostaglandin synthetase.

The cooxidative metabolism of the transplacental carcinogen, diethylstilbestrol (DES), was examined using ram seminal vesicle microsomes. The major extractable metabolite was beta-dienestrol (Z,Z-DIES) and represented about 35% of the added DES in 3-min incubations supplemented with arachidonic acid. Its formation was dependent upon the presence of arachidonic acid, whereas reduced nicotinamide adenine dinucleotide phosphate failed to elicit Z,Z-DIES above background. Indomethacin and 1-phenyl-3-pyrazolidone, known inhibitors of prostaglandin synthetase, blocked Z,Z-DIES formation, probably by inhibiting the cyclooxygenase and the hydroperoxidase activities, respectively. Hydrogen peroxide and 15-hydroperoxyarachidonic acid (cosubstrates of the prostaglandin synthetase-hydroperoxidase), when replacing arachidonic acid in incubations, also supported oxidative metabolism of DES catalyzed by ram seminal vesicle microsomes. 1-Phenyl-3-pyrazolidone, but not indomethacin, inhibited the 15-hydroxyperoxyarachidonic acid-dependent formation of Z,Z-DIES. Incubation conditions which supported efficient Z,Z-DIES formation also resulted in the formation of 3,3-di(p-hydroxyphenyl)hexan-4-one and the cis-isomer of DES as well as nonextractable, protein-associated radioactivity indicating the presence of reactive intermediates. The implications of the peroxidative metabolism of DES for its toxic activity are obvious.