Cytochrome P450 metabolism of estradiol in hamster liver and kidney.
Estradiol induces kidney tumors in Syrian hamsters. The elevated conversion of estradiol to 4-hydroxylated metabolites in kidney compared to the predominant 2-hydroxylation in liver and other organs, where tumors are not induced by this treatment, has been proposed to be the basis of estrogen-induced carcinogenesis. In this study, we examined the hepatic and renal enzymes catalyzing the formation of catecholestrogens to understand the differences in estrogen metabolism in these organs. In liver, 2-hydroxylation of estradiol is the major metabolic pathway with 4-hydroxylation a minor by-product and with the formation of both catechols responding coordinately to the same inhibitors. Western blot analysis and inhibition studies suggest that the major form catalyzing hepatic estrogen 2-hydroxylation is a member of the CYP3A family, as previously observed with rat liver microsomes, and that 4-hydroxylation is a by-product of this metabolism. In the kidney, 4-hydroxylation of estradiol appears to be catalyzed by more than one enzyme according to the Eadie-Hofstee analysis. Both 2- and 4-hydroxylation in the kidney are affected differentially by inhibitors and are induced by beta-napthoflavone. Western blots of renal microsomes reveal that CYP1A2 is induced whereas CYP1A1 is detectable in kidney, but not induced by this treatment. Finally, a part of the 2-hydroxylation and a small part of the 4-hydroxylation by kidney microsomes may be catalyzed by a member of the CYP3A family, since these reactions are partially inhibited by CYP3A inhibitors such as progesterone and other progestins, although renal enzyme levels are much lower than those in the liver as revealed by Western blot. Our data suggest that estrogen 2-hydroxylation in the hamster kidney is catalyzed by members of the CYP1A and CYP3A families, which also contribute to 4-hydroxylation. The majority of 4-hydroxyestradiol formation in the hamster kidney may be catalyzed by a form(s) of the newly discovered CYP1B family that has yet to be characterized.
Hammond
D K
DK
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031, USA.
Zhu
B T
BT
Wang
M Y
MY
Ricci
M J
MJ
Liehr
J G
JG
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015153:Blotting, Western; D006224:Cricetinae; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D006900:Hydroxylation; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D012984:Software; D013250:Steroid Hydroxylases / Q000378:metabolism; D019324:beta-Naphthoflavone / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity
D004791:Enzyme Inhibitors; D004958:Estradiol; D009249:NADP; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C585499:Cyp1b1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; C020120:estrogen 2-hydroxylase