Carcinogenicity of catechol estrogens in Syrian hamsters

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Abstract

Estradiol and other estrogens induce renal carcinoma in male Syrian hamsters. The mechanism of carcinogenesis still remains unclear. Activation of estrogens to catechol metabolites has in the past been postulated to play a role in estrogen-induced carcinogenesis. Therefore, the carcinogenic activity of catechol estrogens was investigated. After 175 days of treatment, 4-hydroxyestradiol was found to be as carcinogenic as estradiol in male Syrian hamsters (45 and 45 animals with kidney tumors, respectively). Animals treated with 2-hydroxyestradiol (05) or 2-methoxyestradiol (06) did not develop renal carcinoma. The catechol estrogens failed to be mutagenic in the Ames test (reversions of his S. typhimurium to histidine prototrophy in the TA 100 strain). The lack of carcinogenic activity of 2-hydroxestradiol was not due to a failure to stimulate estrogen-dependent tumor growth. Growth of H-301 cells, an estrogen-dependent hamster kidney tumor cell line, was supported in vivo by estrogens in the following order: estradiol > 4-hydroxyestradiol > 2-hydroxyestradiol. Stimulation of tumor growth by 2-methoxyestradiol was not detected.

It was concluded that the carcinogenic activity of 4-hydroxyestradiol was consistent with a role of catechol metabolites in estrogen-induced carcinogenesis. However, the intrinsic carcinogenic or hormonal activity of 2-hydroxyestradiol probably can not be assessed accurately in vivo because of its rapid methylation and metabolic clearance.

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    With both endogenous estrogens and CEEs, the 4-hydroxylation pathway is predominately catalyzed by P4501B1/1A1 (Sissung et al., 2006; Spink et al., 2001). While 2-hydroxylation of endogenous estrogens is regarded as a benign metabolic pathway, 4-hydroxylation leads to cytotoxic and carcinogenic metabolites (Li and Li, 1987; Liehr et al., 1986; Newbold and Liehr, 2000). These electrophilic/redox-active quinones can cause damage within cells by alkylation and/or oxidation of cellular proteins and DNA in many tissues.

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