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Copper-dependent Formation of Miscoding Etheno-DNA Adducts in the Liver of Long Evans Cinnamon (LEC) Rats Developing Hereditary Hepatitis and Hepatocellular Carcinoma¹

German Cancer Research Center, DKFZ, Division 0325, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany [J. N., H. B.]; National Cancer Center Research Institute, Tokyo, Japan [H. S., M. N.]; and IARC, Lyon, France [A. B.]

Formation of etheno-DNA adducts in the liver was investigated in Long Evans cinnamon (LEC) rats, a Long Evans strain with hereditary abnormal copper metabolism, which develop spontaneous hepatitis and later hepatocellular carcinoma. Using an ultrasensitive immunoaffinity/³²P-postlabeling assay (J. Nair et al., Carcinogenesis, 16: 613–617, 1995), the etheno adducts 1,N⁶-ethenodeoxyadenosine (dA) and 3,N⁴-ethenodeoxycytidine (dC) were measured in the liver of 7-, 18-, 30-, and 87-week-old LEC rats. Levels were highest in the liver of 18-week-old rats 85 ± 17 (dA) and 85 ± 30 (dC) adducts per 10⁹ 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 etheno adducts. Etheno adduct levels in LEC rats were well correlated with the hepatic copper levels, and peak adduct levels coincided with the age of commencement of fulminant hepatitis. Our results demonstrate for the first time a copper- and age-dependent formation of highly miscoding etheno-DNA adducts in the liver of LEC rats. These adducts are formed from lipid peroxidation products (F. El-Ghissassi et al., Chem. Res. Toxicol., 8: 273–283, 1995) and thus could arise in the liver of LEC rats from oxygen radicals generated by copper-catalyzed Fenton-type reactions. Etheno-DNA adducts along with other oxidative DNA base damages may thus be involved in liver carcinogenesis in LEC rats.

¹ This work was supported in part by Grants EV5V-CT940409 and STEP-CT91-0145 from the Commission of the European Communities and a Grant-in-Aid from the Japanese Ministry of Health and Welfare for a comprehensive 10-year strategy for cancer control. Presented in part at the 7th Biennial Meeting of the International Society for Free Radical Research, Sydney, Australia, November 6–10, 1994.

² To whom requests for reprints should be addressed.

Received 8/22/95. Accepted 1/17/96.

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