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 susceptibilities to hepatocarcinogenesis induced by the tobacco-specific nitrosamine 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosodimethylamine (NDMA). In this study, the time courses of DNA single-strand breaks (SSB) and toxicity induced by NNK and NDMA in hamster and rat liver were compared. DNA SSB reached a maximum 12 h after carcinogen treatment, partially correlating with previous reports on time courses of DNA methylation. The persistence of DNA SSB up to 2-3 weeks after NNK or NDMA treatment reflects a deficient repair of some DNA lesions. No significant species differences in the kinetics of DNA SSB induction and repair were observed following NNK or NDMA (0.39 mmol/kg) treatment. However, NNK induced slightly more DNA SSB than NDMA in both species. This could reflect the formation of intermediates with more DNA-damaging capacity or inhibiting DNA processes. A significant hepatotoxic effect of NNK, evaluated by plasma markers of liver injury, 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-treated hamsters and rats, NDMA-treated rats) or 2 weeks (NDMA-treated hamsters) after carcinogen administration. Three weeks after treatment, hepatotoxicity of NNK and NDMA was still detected in hamsters, but not in rats. These results suggest that the toxic effects of NNK and NDMA initiate a regenerative process that occurs faster in rat than in hamster liver. Since hepatocarcinogenesis occurs in NNK- but not in NDMA-treated rats, promutagenic lesions generated from NNK might be fixed preferentially during cell proliferation.
Jorquera
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R
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec, Canada.
Castonguay
A
A
Schuller
H M
HM
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002273:Carcinogens / Q000633:toxicity*; D006224:Cricetinae; D004249:DNA Damage; D004260:DNA Repair; D004277:DNA, Single-Stranded / Q000187:drug effects*; D004128:Dimethylnitrosamine / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D009602:Nitrosamines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D004277:DNA, Single-Stranded; D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D004128:Dimethylnitrosamine