Conversion of estrone to 2- and 4-hydroxyestrone by hamster kidney and liver microsomes: implications for the mechanism of estrogen-induced carcinogenesis.
Conversion of estrone to 2- and 4-hydroxyestrone by hamster kidney and liver microsomes: implications for the mechanism of estrogen-induced carcinogenesis.
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DOI：
10.1210/endo.135.5.7956900
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发表时间：
1994-11
期刊：
影响因子：
4.8
通讯作者：
B. Zhu;Q. Bui;J. Weisz;J. G. Liehr
中科院分区：
文献类型：
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作者：
B. Zhu;Q. Bui;J. Weisz;J. G. Liehr
作为正在进行的雌激素代谢激活在癌症（如雌激素诱导的仓鼠肾肿瘤）发生中的作用研究的一部分，我们已经1)测定了从仓鼠肾脏和肝脏制备的微粒体和细胞质的类固醇-17 β -氧化还原酶活性；2)比较仓鼠肾脏和肝脏微粒体对雌酮的2-、4-和16 α -羟基化率；3)测定鼠肾儿茶酚- o -甲基转移酶和纯化酶对2-和4-羟孕酮的失活率。小鼠肾脏和肝脏微粒体类固醇-17 β -氧化还原酶活性较低，有利于雌酮向雌二醇的转化。细胞质类固醇-17 β -氧化还原酶活性仅在肝脏和肾脏中几乎检测不到。使用肝微粒体，雌酮的2-羟基化速率与先前使用雌二醇作为底物的速率相当，而雌酮的4-羟基化速率是雌二醇的两倍。使用肾微粒体，雌二醇的2-和4-羟基化率比使用雌二醇为底物的高10- 20倍，2-和4-羟基化的比例约为2:1。盐酸法唑对雌酮2-羟基化和4-羟基化（20微米）的抑制作用同样良好（IC50，约25微米）。与肾微粒体对应的IC50值小于2 microM，盐酸法唑对雌酮2-羟基化的抑制作用比4-羟基化的抑制作用强15%。用雌二醇治疗仓鼠2个月后，肾微粒体对雌二醇的2-羟基化和4-羟基化率降低了约95%。肝微粒体将雌酮转化为16 α -羟孕酮的速率是2-羟化的10-20%。肾微粒体以更低的速率催化雌酮的16 α -羟基化（约为2-羟基化的5%）。仓鼠肾细胞液中2-和4-羟孕酮的o -甲基化率与2-和4-羟孕酮的o -甲基化率相当。综上所述，雌激素诱导癌变的靶器官——仓鼠肾脏微粒体将雌酮转化为儿茶酚代谢物，在数量上比转化为16 α -羟孕酮更为重要。这些发现与在雌激素诱导的癌变中原位产生儿茶酚雌激素的假设作用一致。
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.