Abstract：
4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major nitrosamine formed in tobacco smoke, induces a high incidence of lung, liver, and nasal cavity tumors in rats. Since alpha-hydroxylation of NNK by target tissues can lead to the generation of a methylating agent, the formation and removal of 7-methylguanine and the promutagenic lesions O6-methylguanine (O6mGua) and O4-methyldeoxythymidine were determined over 12 days of NNK administration to rats (100 mg/kg/day). DNA alkylation was greatest in the nasal mucosa, followed by liver and lung after 1 dose of NNK. No DNA adducts were detected in kidney and brain under these conditions. The concentration of O6mGua increased steadily in lung throughout the treatment regimen, while O6-methylguanine-DNA methyltransferase decreased to less than 5% of control. The concentration of O4-methyldeoxythymidine in lung DNA reached a steady state after 4 days of carcinogen treatment. After NNK treatment was discontinued, O6mGua persisted, while O4-methyldeoxythymidine was removed rapidly in the lung, suggesting that different repair pathways exist for the removal of these adducts in vivo. In hepatocytes, nonparenchymal cells, and nasal mucosa, O6mGua concentrations were maximal after 1-2 days and declined by 50-80% during the remaining 10 days of treatment. The decrease in O6mGua levels in nasal mucosa paralleled a decline in O6-methylguanine-DNA methyltransferase activity and was associated with marked cytotoxicity to Bowman\'s glands, portions of the lateral nasal gland, and the olfactory and respiratory mucosa during carcinogen treatment. In contrast, the decline in O6mGua in hepatocytes was attributed to the induction of O6-methylguanine-DNA methyltransferase activity, since an 18-fold reduction in the ratio of O6mGua:7-methylguanine was observed over the 12 days of treatment. These studies have demonstrated a marked accumulation of promutagenic DNA adducts in target tissues during repeated exposure to NNK.
摘要：
4-(N-甲基-N-亚硝胺)-1-(3-吡啶基)-1-丁酮(NNK),烟草烟雾中形成的主要亚硝胺，诱导高发病率的肺，肝脏,和大鼠的鼻腔肿瘤。由于靶组织对NNK的α-羟基化可以导致甲基化剂的产生，在对大鼠施用NNK（100mg/kg/天）的12天内，确定了7-甲基鸟嘌呤的形成和去除以及致突变病变O6-甲基鸟嘌呤（O6mGua）和O4-甲基脱氧胸苷。DNA烷基化在鼻粘膜中最大，1剂NNK后依次为肝脏和肺。在这些条件下,在肾和脑中没有检测到DNA加合物。在整个治疗方案中，O6mGua在肺中的浓度稳步增加，而O6-甲基鸟嘌呤-DNA甲基转移酶降低至对照的5%以下。致癌物处理4天后，肺DNA中O4-甲基脱氧胸苷的浓度达到稳定状态。NNK治疗停止后，O6mGua坚持，虽然O4-甲基脱氧胸苷在肺中被迅速去除，这表明在体内存在不同的修复途径来去除这些加合物。在肝细胞中，非实质细胞,和鼻粘膜，O6mGua浓度在1-2天后达到最大，在剩余的10天治疗期间下降了50-80％。鼻粘膜中O6mGua水平的下降与O6-甲基鸟嘌呤-DNA甲基转移酶活性的下降平行，并与对Bowman腺体的显著细胞毒性有关，侧鼻腺的部分，以及致癌物治疗期间的嗅觉和呼吸道粘膜。相比之下,肝细胞中O6mGua的下降归因于O6-甲基鸟嘌呤-DNA甲基转移酶活性的诱导，因为在治疗的12天内观察到O6mGua:7-甲基鸟嘌呤的比例降低了18倍。这些研究已经证明,在反复暴露于NNK的过程中,在靶组织中促诱变DNA加合物的显著积累。
