Conversion of estradiol-17 beta to reactive embryotoxic intermediates by cytochrome P-450-dependent bioactivating systems.
P-450-dependent enzyme systems added to media of cultured rat embryos markedly increased the embryotoxicity of estradiol-17 beta. Increases were markedly attenuated by omission of NADPH, omission of enzyme, substitution of female for male rat liver as enzyme source, d) replacement of N2 with CO or replacement of estradiol-17 beta with diethylstilbestrol. Embryotoxicity correlated well (r = 0.84) with catecholestrogen generating activities. Addition of a catechol-methylating system failed to modify embryotoxicity even though large quantities of methoxyestrogens were formed. The results document that endogenous estrogen can be converted by P-450 to embryotoxic intermediates and suggest that reactive proximate metabolites are precatechols, perhaps epoxyenones.
D000818:Animals; D001711:Biotransformation; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004054:Diethylstilbestrol / Q000378:metabolism; D004622:Embryo, Mammalian / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism* / Q000633:toxicity; D004967:Estrogens / Q000633:toxicity*; D002393:Estrogens, Catechol / Q000633:toxicity; D005260:Female; D008099:Liver / Q000378:metabolism; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats
D004967:Estrogens; D002393:Estrogens, Catechol; D004958:Estradiol; D004054:Diethylstilbestrol; D003577:Cytochrome P-450 Enzyme System; D002394:Catechol O-Methyltransferase