Induction by estrogens of lipid peroxidation and lipid peroxide-derived malonaldehyde-DNA adducts in male Syrian hamsters: role of lipid peroxidation in estrogen-induced kidney carcinogenesis.

Abstract

Estrogen-induced kidney carcinogenesis in male Syrian hamsters has previously been postulated to be mediated by free radicals generated by redox cycling of catecholestrogen metabolites. As part of our examination of this hypothesis, we have studied the induction of lipid peroxidation and lipid peroxide-derived malondialdehyde (MDA)-DNA adducts in kidney and liver of hamsters treated with single injections of diethylstilbestrol (DES) or with estradiol (E2) implants for various lengths of time. Treatment of hamsters with 50 and 100 mg/kg DES increased concentrations of both lipid hydroperoxides and of MDA-DNA adducts. In hamsters treated with E2 implants for up to 50 days, lipid peroxide levels in liver were double control values 3 h after hormone implantation, and then decreased to plateau values of 30% over controls. Those in kidney rose to 2- to 3-fold above controls 3 days after hormone implantation and then decreased to plateau values of 51% above controls. MDA-DNA adduct levels were two or three times higher than those of controls in liver and kidney of hamsters treated with hormone implants for 3 and 7 days. Renal lipid peroxide concentrations were raised by chronic treatment with E2, but not by weakly carcinogenic estrogens ethinylestradiol or 2-fluoroestradiol. In contrast, MDA-DNA adduct levels were raised by all three steroidal estrogens 3 days after estrogen implantation. The increases in lipid peroxides and in MDA-DNA adducts in estrogen-treated hamsters support a mechanism of carcinogenesis by free radical generation via redox cycling of catcholestrogen metabolites. Lipid peroxides are postulated to play a dual role in estrogen-induced carcinogenesis, (i) as cofactors for cytochrome P450-mediated formation of catecholestrogen metabolites and their redox cycling, and (ii) as precursors of MDA, a DNA adduct-forming endogenous electrophile.