COPPER-DEPENDENT FORMATION OF MISCODING ETHENO-DNA ADDUCTS IN THE LIVER OF LONG-EVANS CINNAMON (LEC) RATS DEVELOPING HEREDITARY HEPATITIS AND HEPATOCELLULAR-CARCINOMA

Formation of etheno-DNA adducts in the liver was investigated in Long Evans cinnamon (LEC) rats, a Long Evans strain with hereditary abnorma l copper metabolism, which develop spontaneous hepatitis and later hep atocellular carcinoma. Using an ultrasensitive immunoaffinity/P-32-pos tlabeling assay (J. Nair et al., Carcinogenesis, 16: 613-617, 1995), t he etheno adducts 1,N-6-ethenodeoxyadenosine (epsilon dA) and 3,N-4-et henodeoxycytidine (epsilon dC) were measured in the liver of 7-, 18-, 30-, and 87-week-old LEC rats, Levels mere highest in the liver of 18- week-old rats 85 +/- 17 (epsilon dA) and 85 +/- 30 (epsilon dC) adduct s per 10(9) parent nucleotides, and the increase in the levels of both etheno adducts was age dependent. Age-matched Long Evans agouti rats, a tumor-free sibling line of LEC rats, had much lower levels of ethen o adducts. Etheno adduct levels in LEC rats were well correlated with the hepatic copper levels, and peak adduct levels coincided with the a ge of commencement of fulminant hepatitis. Our results demonstrate for the first time a copper- and age-dependent formation of highly miscod ing etheno-DNA adducts in the liver of LEC rats. These adducts are for med from lipid peroxidation products (F. El-Ghissassi et al., Chem, Re s, Toxicol., 8: 273-283, 1995) and thus could arise in the liver of LE C rats from oxygen radicals generated by copper-catalyzed Fenton-type reactions, Etheno-DNA adducts along with other oxidative DNA base dama ges may thus be involved in liver carcinogenesis in LEC rats.