Ethenobases are promutagenic
DNA adducts formed by some
environmental carcinogens and products of endogenous lipid peroxidation. Mutation spectra in
tumors induced in mice by
urethane or its metabolite
vinyl carbamate (Vcar) are compatible with
1,N(6)-ethenoadenine (epsilonA) being an initiating lesion in the development of these
tumors. As alkylpurine-
DNA-N-glycosylase (APNG) releases epsilonA from
DNA in vitro, wild-type and APNG-/- C57Bl/6J mice were treated with Vcar and levels of epsilonA and
3,N(4)-ethenocytosine (epsilonC), which is not a substrate of APNG, were analyzed in liver and lung
DNA. At 6 h after the last dose, levels of epsilonA were 1.6-fold higher in
DNA from APNG-/- mice and subsequently persisted at higher levels for longer than in
DNA from wild-type animals, confirming that epsilonA is released by APNG in vivo. In contrast, approximately 14-fold lower levels of epsilonC were induced by Vcar, and the kinetics of formation and persistence of epsilonC was similar in the two mouse strains. The carcinogenicity of Vcar was compared in APNG-/- and wild-type suckling mice given a single dose of Vcar (30 or 150 nmol/g). After 1 year, only mice in the high-dose group developed
hepatocellular carcinoma; however, the incidence was not higher in APNG-/- mice. Although higher levels and increased persistence of epsilonA was observed in hepatic
DNA from APNG-/- mice at 150 nmol/g Vcar, apoptosis and cell proliferation levels were similar in both strains of mice. This may explain why differences in epsilonA formation/persistence observed here did not result in higher susceptibility of APNG-/- mice to hepatocarcinogenesis.