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

Estrogen-induced kidney carcinogenesis in male Syrian hamstershas previously been postulated to be mediated by free radicalsgenerated by redox cycling of catecholestrogen metabolites.As part of our examination of this hypothesis, we have studiedthe induction of lipid peroxidation and lipid peroxide-derivedmalondialdehyde (MDA)-DNA adducts in kidney and liver of hamsterstreated with single injections of diethylstilbestrol (DES) orwith estradiol (E implants for various lengths of time. Treatmentof hamsters with 54) and 100 mg/kg DES increased concentrationsof both lipid hydroperoxides and of MDA-DNA adducts. In hamsterstreated with E Implants for up to 50 days, lipid peroxide levelsin liver were double control values 3 h after hormone implantation,and then decreased to plateau values of 30% over controls. Thosein kidney rose to 2- to 3-fold above controls 3 days after hormoneimplantation and then decreased to plateau values of 51% abovecontrols. MBA-DNA adduct levels were two or three times higherthan those of controls in liver and kidney of hamsters treatedwith hormone implants for 3 and 7 days. Renal lipid peroxideconcentrations were raised by chronic treat ment with E₂, butnot by weakly carcinogenic estrogens ethinylestradiol or 2-fluoroestradiol.In contrast, MDA- DNA adduct levels were raised by all threesteroidal estrogens 3 days after estrogen implantation. Theincreases in lipid peroxides and in MDA-DNA adducts in estrogen-treated hamsters support a mechanism of carcinogenesis by freeradical generation via redox cycling of catcholestrogen metabolites.Lipid peroxides are postulated to play a dual role in estrogen-inducedcarcinogenesis, (i) as cofactors for cytochrome P450-mediatedformation of catecholestrogen metabolites and their redox cycling,and (ii) as precursors of MDA, a DNA adduct-forming endogenouselectrophile.