Lipid Hydroperoxide-Induced Endogenous DNA Adducts in Hamsters: Possible Mechanism of Lipid Hydroperoxide-Mediated Carcinogenesis

Abstract

DNA of livers or kidneys of rodents contain endogenously modified nucleotides of as yet unknown structure or function. As part of our examination of the origin of endogenous DNA modifications, we examined polar adducts of hamster liver and kidney DNA by 32P-postlabeling analysis (central and upper cuts) and compared them to adducts generated by incubation of DNA with [9Z,11E,(13S)]-13-hydroperoxyoctadecadienoic acid or with malondialdehyde. The central and upper cuts of DNA adduct maps of intact female retired breeder hamsters contained one and three adducts called C1, U1, U2, and U3, respectively, which cochromatographed with similar adducts in DNA incubated with the hydroperoxide or with malondialdehyde. Concentrations of adducts C1, U1, and U2 in organs of 1-month-old hamsters were lower than those in the 5-month-old female retired breeder hamsters. Adduct concentrations increased in tandem with lipid peroxide concentrations in livers and kidneys of hamsters treated with carbon tetrachloride compared to controls. A linear dependence of the concentrations of adducts on those of lipid peroxides was demonstrated independent of the treatment conditions or the organ examined. The polar endogenous adducts U1, U2, and U3 were identified by cochromatography in five different chromatographic systems with adducts induced by linoleic hydroperoxide or malondialdehyde. Adducts U1, U2, or U3 were also formed by incubating malondialdehyde with dAMP or with dGMP, respectively. The dependence of adduct concentrations in vivo on lipid peroxide levels are taken as evidence that decomposition products of lipid peroxides such as malondialdehyde induced endogenous DNA adducts in intact animals. Moreover, these adducts may mediate carcinogenic processes induced by chemicals which raise lipid peroxide levels.