CONVERSION OF ESTRONE TO 2-HYDROXYESTRONE 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 activatio n of estrogens in the genesis of cancers such as estrogen-induced rena l tumors in hamsters, we have 1) determined steroid-17 beta-oxidoreduc tase activity of microsomes and cytosol prepared from hamster kidney a nd liver; 2) compared the rates of 2-, 4-, and 16 alpha-hydroxylations of estrone by microsomes from hamster kidney and liver; and 3) determ ined the rates of inactivation of 2- and 4-hydroxyestrone by catechol- O-methyltransferase from hamster kidney and by purified enzyme. Micros omal steroid-17 beta-oxidoreductase activity in hamster kidney and liv er was low and favored the conversion of estrone to estradiol. Cytosol ic steroid-17 beta-oxidoreductase activity was only barely detectable in both liver and kidney. Using hepatic microsomes, the rate of 2-hydr oxylation of estrone was comparable to that found previously using est radiol as substrate, whereas 4-hydroxylation of estrone was double tha t of estradiol. Using renal microsomes, the rates of 2- and 4-hydroxyl ation 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. Fa drozole hydrochloride was an equally good inhibitor of rates of 2- and 4-hydroxylation of estrone (20 mu M) by hepatic microsomes (ICS50 sim ilar to 25 mu M). Corresponding IC50 values with renal microsomes were less than 2 mu M, and 2-hydroxylation of estrone was inhibited by Fad rozole hydrochloride up to 15% more than 4-hydroxylation. Treatment of hamsters with estradiol for 2 months decreased rates of 2- and 4-hydr oxylation of estrone by renal microsomes by approximately 95%. The rat e of conversion of estrone to 16 alpha-hydroxyestrone by hepatic micro somes was 10-20% that of 2-hydroxylation. Renal microsomes catalyzed 1 6 alpha-hydroxylation of estrone at an even lower rate (similar to 5% of that of 2-hydroxylation). Rates of O-methylation of 2- and 4-hydrox yestrone by hamster kidney cytosol. were comparable to those of 2- and 4-hydroxyestradiol. In conclusion, conversion of estrone to its catec hol metabolites by microsomes of hamster kidney, a target organ of est rogen-induced carcinogenesis, is quantitatively more important than th e conversion to 16 alpha-hydroxyestrone. The findings are consistent w ith the postulated role of catechol estrogens generated in situ in est rone-induced carcinogenesis.