Mechanism of inhibition of estrogen-induced renal carcinogenesis in male Syrian hamsters by vitamin C

Abstract

Dietary supplementation of vitamin C to diethylstilbestrol (DES)- or estradiol-treated male Syrian hamsters is known to inhibit renal carcinogenesis by ∼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″-qulnone 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″-qulnone to cis- and trans-dlethylstllbestrol in a dose-dependent fashion. Changes in activities of quinone reductase, catalase, superoxide dismutase and of glutathione metabolizing enzymes (glutathione peroxidase, glutathione reductase, -γ-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 estrogeninduced carcinogenesis by reducing concentrations of estrogen quinone metabolites and their DNA adducts.