DNA single-strand breaks and toxicity induced by 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone or N-nitrosodimethylamine in hamster and rat liver

Syrian golden hamsters and F344 rats display contrasting susceptibilitiesto hepatocarcinogenesis induced by the tobacco-specific nitrosamine4-(methylnitrosamino)-1-(3-pyri-dyl)-1-butanone (NNK) and N-nitrosodimethylamine(NDMA). In this study, the time courses of DNA single-strandbreaks (SSB) and toxicity induced by NNK and NDMA in hamsterand rat liver were compared. DNA SSB reached a maximum 12 hafter carcinogen treatment, partially correlating with previousreports on time courses of DNA methyiation. The persistenceof DNA SSB up to 2–3 weeks after NNK or NDMA treatmentreflects a deficient repair of some DNA lesions. No significantspecies differences in the kinetics of DNA SSB induction andrepair were observed following NNK or NDMA (0.39 mmol/kg) treatment.However, NNK induced slightly more DNA SSB than NDMA in bothspecies. This could reflect the formation of intermediates withmore DNA-damaging capacity or inhibiting DNA processes. A significanthepatoxic effect of NNK, evaluated by plasma markers of liverinjury, was observed in rats and hamsters 12–24 h post-treatment.In contrast, NDMA induced earlier (<12 h) enzyme elevations.Maximum hepatotoxic effects were observed 24 h (NNK-treatedhamsters and rats, NDMA-treated rats) or 2 weeks (NDMA-treatedhamsters) after carcinogen administration. Three weeks aftertreatment, hepatotoxicity of NNK and NDMA was still detectedin hamsters, but not in rats. These results suggest that thetoxic effects of NNK and NDMA initiate a regenerative processthat occurs faster in rat than in hamster liver. Since hepatocarcinogenesisoccurs in NNK- but not in NDMA-treated rats, promutagenic lesionsgenerated from NNK might be fixed preferentially during cellproliferation.