Role of etheno DNA adducts in carcinogenesis induced by vinyl chloride in rats

Vinyl chloride, a hepatocarcinogen in humans and rodents, can form promutagenic etheno bases in DNA after metabolic activation. The formation of 1,N6-ethenoadenine (epsilon A) and 3,N4-ethenocytosine (epsilon C) was measured in adult Sprague-Dawley rats by immunoaffinity purification and 32P-postlabelling. A highly variable background was found in all tissues from untreated animals: the mean molar ratios of epsilon A:A and epsilon C:C in DNA ranged from 0.043 x 10(-8) to 31.2 x 10(-8) and from 0.062 x 10(-8) to 20.4 x 10(-8), respectively. After exposure to 500 ppm vinyl chloride by inhalation (4 h/day, 5 days/week for 8 weeks), increased levels of epsilon A were found in the liver, lung, circulating lymphocytes and testis, the mean (+/- SD) of induced levels (treated-control values) being (4.1 +/- 1.5) x 10(-8) for these tissues. No increase in the epsilon A:A ratio was observed in kidney, brain or spleen. The levels of epsilon C increased in all the tissues examined except the brain. The mean value of the induced epsilon C:C ratios was (7.8 +/- 1.2) x 10(-8) for the liver, kidney, lymphocytes and spleen, and these ratios were higher in the lung (28 x 10(-8)) and testis (19 x 10(-8)). The results suggest a variable repair capacity for epsilon A or epsilon C in different tissues. The results are discussed in relation to published studies on the accumulation and persistence of etheno bases in the liver during and after exposure to vinyl chloride and on mutation spectra in the ras and p53 genes in liver tumours induced by vinyl chloride. In addition, we show that the linear relationship established for monofunctional alkylating agents between their carcinogenic potency in rodents and their covalent binding index for promutagenic bases in hepatic DNA holds for vinyl chloride. It is concluded that etheno bases are critical lesions in hepatocarcinogenesis induced by vinyl chloride. For a better understanding of the mechanism of action of this compound, further work is needed on the role of DNA repair pathways and of endogenous lipid peroxidation products in the formation and persistence of etheno bases in vivo.