There is a clear association between excessive exposure to estrogens and the development of cancer in several tissues including breast and endometrium. The risk factors for women developing these cancers are all associated with longer estrogen exposure; early menses, late menopause, and long term estrogen replacement therapy. The mechanism(s) of estrogen carcinogenesis is unknown. Estrogen metabolites can act as chemical carcinogens by binding to cellular proteins or DNA. The catechol metabolites of estrogens are oxidized to o-quinones which undergo redox cycling generating reactive oxygen species which can contribute to the carcinogenicity through oxidation of DNA. Our preliminary data also show that the o-quinones are converted to additional reactive alkylating agents, quinone methides. The focus of this proposal is the role of quinoid metabolites in estrogen carcinogenesis.
The specific aims are: 1. Establish the role of quinoids in the carcinogenic and cytotoxic effects of estrogens. The carcinogenic potential catechol estrogens will be studied in C3H 10T1/2 cells and their ability to act as tumor promoters will be examined in JB6 cells. The cytotoxicity of estrogens and catechol metabolites will be investigated in human ovarian and breast cancer cell lines. Biochemical parameters which serve as indicators of redox vs. alkylation mechanisms will be determined. 2. Determine the importance of quinoid formation to the metabolism of estrogens. The contribution of the o-quinone/p-quinone methide pathway to the biodegradation of estrogens will be determined. The ability of P450 to oxidize estrogens and their metabolites to o-quinones will be studied. Unsaturated estrogens which are components of the estrogen replacement drug, Premarin, will be investigated to probe electronic and steric effects on the biotransformation of estrogens to quinoids. 3. Investigate the effects of quinoid structure on electrophilic and/or redox reactivity. The electrophilicity of quinoids will be determined by measuring their rates of reaction with deoxynucleosides and by examining the extent of DNA alkylation. Their redox ability will be assessed by measuring reduction potentials, monitoring changes in NADPH and GSH levels in microsomal incubations, measuring reactive oxygen species, and examining autoxidation rates of the catechols. These data will determine the role of quinoids in the carcinogenic effects of estrogens and provide a basis for the development of estrogen replacement drugs devoid of carcinogenic activity.
| Peng, Kuan-Wei; Chang, Minsun; Wang, Yue-Ting et al. (2010) Unexpected hormonal activity of a catechol equine estrogen metabolite reveals reversible glutathione conjugation. Chem Res Toxicol 23:1374-83 |
