Conversion of estrone to 2- and 4-hydroxyestrone by hamster kidney and liver microsomes: implications for the mechanism of estrogen-induced carcinogenesis.
As part of an ongoing investigation of the role of metabolic activation of estrogens in the genesis of cancers such as estrogen-induced renal tumors in hamsters, we have 1) determined steroid-17 beta-oxidoreductase activity of microsomes and cytosol prepared from hamster kidney and liver; 2) compared the rates of 2-, 4-, and 16 alpha-hydroxylations of estrone by microsomes from hamster kidney and liver; and 3) determined the rates of inactivation of 2- and 4-hydroxyestrone by catechol-O-methyltransferase from hamster kidney and by purified enzyme. Microsomal steroid-17 beta-oxidoreductase activity in hamster kidney and liver was low and favored the conversion of estrone to estradiol. Cytosolic steroid-17 beta-oxidoreductase activity was only barely detectable in both liver and kidney. Using hepatic microsomes, the rate of 2-hydroxylation of estrone was comparable to that found previously using estradiol as substrate, whereas 4-hydroxylation of estrone was double that of estradiol. Using renal microsomes, the rates of 2- and 4-hydroxylation of estrone were 10- to 20-fold higher than those with estradiol as substrate, and the ratio of 2- to 4-hydroxylation was about 2:1. Fadrozole hydrochloride was an equally good inhibitor of rates of 2- and 4-hydroxylation of estrone (20 microM) by hepatic microsomes (IC50, approximately 25 microM). Corresponding IC50 values with renal microsomes were less than 2 microM, and 2-hydroxylation of estrone was inhibited by Fadrozole hydrochloride up to 15% more than 4-hydroxylation. Treatment of hamsters with estradiol for 2 months decreased rates of 2- and 4-hydroxylation of estrone by renal microsomes by approximately 95%. The rate of conversion of estrone to 16 alpha-hydroxyestrone by hepatic microsomes was 10-20% that of 2-hydroxylation. Renal microsomes catalyzed 16 alpha-hydroxylation of estrone at an even lower rate (approximately 5% of that of 2-hydroxylation). Rates of O-methylation of 2- and 4-hydroxyestrone by hamster kidney cytosol were comparable to those of 2- and 4-hydroxyestradiol. In conclusion, conversion of estrone to its catechol metabolites by microsomes of hamster kidney, a target organ of estrogen-induced carcinogenesis, is quantitatively more important than the conversion to 16 alpha-hydroxyestrone. The findings are consistent with the postulated role of catechol estrogens generated in situ in estrone-induced carcinogenesis.
Zhu
B T
BT
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031.
Bui
Q D
QD
Weisz
J
J
Liehr
J G
JG
D000818:Animals; D002394:Catechol O-Methyltransferase / Q000032:analysis / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000473:pathology; D002849:Chromatography, Gas; D006224:Cricetinae; D004967:Estrogens / Q000009:adverse effects*; D004970:Estrone / Q000378:metabolism*; D006894:Hydroxyestrones / Q000378:metabolism*; D006900:Hydroxylation; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008647:Mesocricetus; D008861:Microsomes / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D039181:Steroid 16-alpha-Hydroxylase
D004967:Estrogens; D006894:Hydroxyestrones; D004970:Estrone; C026418:4-hydroxyestrone; D039181:Steroid 16-alpha-Hydroxylase; D002394:Catechol O-Methyltransferase; C024980:2-hydroxyestrone