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The carcinogenic activity of ethinyl estrogens is determined by both their hormonal characteristics and their
1Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031.
Abstract:
Estrogens induce kidney tumors in Syrian hamsters. The mechanism of carcinogenesis is unknown and has been investigated in this study using a weak carcinogen, 17 alpha-ethinyl estradiol (EE), and a strongly carcinogenic estrogen, 17 alpha-ethinyl-11 beta-methoxyestradiol [moxestrol (MOX)]. We investigated rates of conversion of estrogens to catechol metabolites and rates of their methylation to methyl ethers in order to examine the hypothesis that catechol metabolites mediate estrogen-induced carcinogenesis. Rates of conversion of MOX to catechol metabolites by hamster liver or kidney cortex microsomes were 40-50% of those with estradiol as substrate. However, the rate of catechol-O-methyltransferase-catalyzed methylation of 2-hydroxy-MOX was the least of the catechol metabolites examined when incubated with cytosol of hamster kidney. In contrast, EE was converted to catechol metabolites by hamster liver and kidney microsomes at rates 25-35% of those obtained with estradiol. These catechol metabolites of EE were methylated by catechol-O-methyltransferase of hamster kidney cytosol at rates slightly lower than those observed with catechols of estradiol. The progesterone receptor binding of EE and MOX was investigated, because progesterone is known to inhibit estrogen-induced carcinogenesis in the hamster kidney. Neither estradiol nor MOX inhibited the binding of progesterone to its receptor in hamster kidney cytosol. However, in the presence of 20 nM EE, the binding affinity of radiolabeled progesterone to receptor was inhibited (increase in Kd from 0.98 nM in controls to 3.02 nM in the presence of EE). Maximum binding values (5.0 fmol/mg protein in controls and 6.0 fmol/mg protein in the presence of EE) were not significantly altered. These results support the hypothesis that estrogen-induced carcinogenesis is mediated by catechol estrogen metabolites. The carcinogenic estrogen MOX is converted to catechol metabolites at lower rates than estradiol, but their methylation may be sterically hindered by the 11 beta-methoxy substituent. In contrast, the rates of conversion of the weakly carcinogenic EE to catechol metabolites are low, whereas their methylation rates are only marginally lower than those of 2- and 4-hydroxyestradiol. The decreased capacity of EE to form catechol metabolites in conjunction with its partial progestin agonist activity in the target organ of hamsters may contribute to the low tumor incidence.
Insights
Estrogen-induced kidney tumors in hamsters may be caused by specific metabolites. This study investigated how different estrogens convert to these compounds and interact with progesterone receptors, suggesting a mechanism for carcinogenesis.
Area of Science:
- Endocrinology
- Carcinogenesis
- Metabolism
Background:
- Estrogens are known to induce kidney tumors in Syrian hamsters.
- The precise mechanism behind estrogen-induced carcinogenesis remains unclear.
- Progesterone is known to inhibit estrogen-induced kidney carcinogenesis in hamsters.
Purpose of the Study:
- To investigate the hypothesis that catechol metabolites mediate estrogen-induced carcinogenesis.
- To compare the conversion rates of different estrogens (17 alpha-ethinyl estradiol and moxestrol) to catechol metabolites.
- To examine the interaction of these estrogens with the progesterone receptor.
Main Methods:
- Incubation of hamster liver and kidney microsomes with estrogens to determine catechol metabolite conversion rates.
- Assay of catechol-O-methyltransferase activity in hamster kidney cytosol for catechol metabolite methylation.
- Progesterone receptor binding assays in hamster kidney cytosol with and without the presence of estrogens.
Main Results:
- Moxestrol (MOX) conversion to catechol metabolites was lower than estradiol, and its catechol metabolite methylation was the slowest among those examined.
- 17 alpha-ethinyl estradiol (EE) conversion to catechol metabolites was also low, with marginally lower methylation rates compared to estradiol catechols.
- EE demonstrated partial progestin agonist activity by inhibiting progesterone binding to its receptor, while MOX did not.
Conclusions:
- The findings support the hypothesis that catechol estrogen metabolites mediate estrogen-induced carcinogenesis.
- The lower conversion and hindered methylation of MOX catechols may explain its strong carcinogenic potential, while EE's low catechol formation and partial progestin activity correlate with its weak carcinogenicity.
- Metabolic activation to catechol metabolites and interaction with the progesterone receptor are key factors in estrogen-induced kidney tumor development in hamsters.