Regulation of cytochrome P-450-dependent catechol estrogen formation in rat liver microsomes. Evidence for involvement of estrogen receptors.
Experiments were conducted to evaluate whether estrogen 2-hydroxylase activity in liver microsomes, the main pathway for oxidative metabolism of estrogens in the rat, is regulated by administration of synthetic estrogens. Ovariectomized rats were treated with ethinylestradiol (EE), 100 micrograms s.c. for 3 days. Liver microsomes from EE-treated animals showed a 2-fold increase over control in estrogen 2-hydroxylase activity measured over a substrate concentration range of 0.5 to 50 microM. Double-reciprocal plots of enzyme activity as a function of substrate concentration were linear; apparent Vmax values were 2-fold greater in microsomes from EE-treated animals while apparent Km values for control and EE preparations were not different. Administration of the triphenylethylene antiestrogen tamoxifen (TAM), 100 micrograms s.c. for 3 days, did not affect microsomal catechol estrogen formation activity, and apparent Km and Vmax values were comparable with controls. When EE and TAM were co-administered, no increase in microsomal estrogen 2-hydroxylase was observed, and apparent Km and Vmax values were not different from either control of TAM-treated preparations. Thus, acute administration of EE was associated with a specific increase in the apparent Vmax of estrogen 2-OHase activity, and this effect was not observed when TAM was co-administered with the estrogen.
D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D002393:Estrogens, Catechol / Q000096:biosynthesis*; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013250:Steroid Hydroxylases / Q000032:analysis; D013629:Tamoxifen / Q000494:pharmacology
D002393:Estrogens, Catechol; D013629:Tamoxifen; D004997:Ethinyl Estradiol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C020120:estrogen 2-hydroxylase