Jorquera R, Castonguay A, Schuller H M
Laboratory of Cancer Etiology and Chemoprevention, School of Pharmacy, Laval University, Quebec, Canada.
Carcinogenesis. 1994 Feb;15(2):389-94. doi: 10.1093/carcin/15.2.389.
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.
叙利亚金黄地鼠和F344大鼠对烟草特异性亚硝胺4-(甲基亚硝胺)-1-(3-吡啶基)-1-丁酮(NNK)和N-亚硝基二甲胺(NDMA)诱导的肝癌发生表现出相反的易感性。在本研究中，比较了NNK和NDMA在仓鼠和大鼠肝脏中诱导的DNA单链断裂(SSB)的时间进程和毒性。致癌物处理后12小时，DNA SSB达到最大值，这与先前关于DNA甲基化时间进程的报道部分相关。NNK或NDMA处理后长达2-3周DNA SSB的持续存在反映了某些DNA损伤修复不足。在NNK或NDMA(0.39 mmol/kg)处理后，未观察到DNA SSB诱导和修复动力学方面的显著物种差异。然而，在两个物种中，NNK诱导的DNA SSB略多于NDMA。这可能反映了具有更强DNA损伤能力或抑制DNA过程的中间体的形成。通过肝损伤血浆标志物评估，在治疗后12-24小时在大鼠和仓鼠中观察到NNK的显著肝毒性作用。相比之下，NDMA诱导酶升高的时间更早(<12小时)。在给予致癌物后24小时(NNK处理的仓鼠和大鼠、NDMA处理的大鼠)或2周(NDMA处理的仓鼠)观察到最大肝毒性作用。处理后三周，在仓鼠中仍检测到NNK和NDMA的肝毒性，但在大鼠中未检测到。这些结果表明，NNK和NDMA的毒性作用引发了一个再生过程，该过程在大鼠肝脏中比在仓鼠肝脏中发生得更快。由于肝癌发生在NNK处理而非NDMA处理的大鼠中，NNK产生的促诱变损伤可能在细胞增殖过程中优先被固定。
