Mechanism of inhibition of estrogen-induced renal carcinogenesis in male Syrian hamsters by vitamin C.
Dietary supplementation of vitamin C to diethylstilbestrol (DES)- or estradiol-treated male Syrian hamsters is known to inhibit renal carcinogenesis by approximately 50%. To elucidate the mechanism of inhibition, the influence of administration of vitamin C on a series of previously described biochemical markers of kidney carcinogenesis was investigated. Hamsters were stratified into four groups: (i) untreated controls; (ii) vitamin C-treated; (iii) estrogen-treated; and (iv) estrogen plus vitamin C-treated animals. Concomitant administration of vitamin C and diethylstilbestrol (DES) decreased concentrations of the major DES-DNA adduct by 70-90% in liver, kidney and testis than those receiving DES only. Diethylstilbestrol-4',4"-quinone has previously been shown to be the genotoxic metabolite of DES responsible for DNA adduct formation in vivo. In vitro, vitamin C reduced diethylstilbestrol-4',4"-quinone to cis- and trans-diethylstilbestrol in a dose-dependent fashion. Changes in activities of quinone reductase, catalase, superoxide dismutase and of glutathione metabolizing enzymes (glutathione peroxidase, glutathione reductase, gamma-glutamyl transpeptidase and glucose-6-phosphate dehydrogenase) in response to vitamin C were not observed or not sufficiently large to account for the 50% decrease in tumor incidence. No differences were detected in indirect estrogen-induced kidney DNA adducts in response to vitamin C treatment. It is concluded that vitamin C inhibits estrogen-induced carcinogenesis by reducing concentrations of estrogen quinone metabolites and their DNA adducts.
Liehr
J G
JG
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77550-2774.
Roy
D
D
Gladek
A
A
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D006224:Cricetinae; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004054:Diethylstilbestrol / Q000378:metabolism; D004967:Estrogens; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008297:Male; D008647:Mesocricetus; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D004967:Estrogens; D004054:Diethylstilbestrol; D004247:DNA; D005954:Glucosephosphate Dehydrogenase; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D001205:Ascorbic Acid