Modulation of estrogen-induced carcinogenesis by chemical modifications.
The mechanism of carcinogenesis by estrogens is still unknown. Uncontrolled stimulation of cell proliferation, an endocrine imbalance, or metabolic activation of estrogens to reactive intermediates capable of tissue injury have previously been proposed. In an attempt to gain insight into mechanistic details of estrogen-induced carcinogenesis in male Syrian hamsters, fluorine substituted estrogens, which were impaired in their capacity to be transformed into catechols, have been tested for their carcinogenic activity. 2-Fluoroestradiol was found to be non-carcinogenic in Syrian hamsters despite its estrogenic potency. In a second unrelated experiment, ascorbic acid, which reduced diethylstilbestrol quinone to cis- and trans-diethylstilbestrol in vitro, was administered to estradiol or diethylstilbestrol-treated hamsters. A lowered incidence of kidney tumors in vivo was found in animals receiving ascorbic acid vs estrogen-treated control animals. These results were taken as evidence for a role of estrogen metabolites (catechols formed from estradiol or quinone formed from diethylstilbestrol) in estrogen-induced tumorigenesis. A mechanistic model of metabolic activation of estrogens followed by damage to cellular macromolecules is proposed.
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001711:Biotransformation; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008297:Male; D008647:Mesocricetus; D013329:Structure-Activity Relationship
D004967:Estrogens; D004247:DNA; D001205:Ascorbic Acid