Hecht S S, Trushin N
American Health Foundation, Valhalla, NY 10595.
Carcinogenesis. 1988 Sep;9(9):1665-8. doi: 10.1093/carcin/9.9.1665.
Alkylation of DNA and hemoglobin was compared in male F344 rats given a single s.c. injection of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), or its major metabolite formed by carbonyl reduction, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In hepatic DNA, levels of 7-methylguanine and O6-methylguanine formed from NNK 1-48 h after treatment were similar to those formed from NNAL. In nasal mucosa and lung DNA, levels of 7-methylguanine and O6-methylguanine were somewhat higher after treatment with NNK than with NNAL. Acid hydrolysis of hepatic DNA, isolated from rats treated with either [5-3H]NNK or [5-3H]NNAL, gave 180 +/- 48 or 120 +/- 23 mumol/mol guanine, respectively, of 4-hydroxy-1-(3-pyridyl)-1-butanone. Basic hydrolysis of globin isolated from rats treated with either [5-3H]NNK or [5-3H]NNAL gave 4.1 +/- 0.7 or 2.0 +/- 0.1 pmol/mg, respectively of 4-hydroxy-1-(3-pyridyl)-1-butanone. These results indicate that NNAL is not a detoxification product of NNK, since treatment of rats with NNAL results in modifications of DNA which are qualitatively and quantitatively similar to those observed upon treatment with NNK. Alkylation of DNA and globin by NNAL may result mainly from its metabolic reconversion to NNK.
在给雄性F344大鼠单次皮下注射烟草特异性亚硝胺4-(甲基亚硝氨基)-1-(3-吡啶基)-1-丁酮（NNK）或其通过羰基还原形成的主要代谢产物4-(甲基亚硝氨基)-1-(3-吡啶基)-1-丁醇（NNAL）后，对DNA和血红蛋白的烷基化情况进行了比较。在肝脏DNA中，处理后1 - 48小时由NNK形成的7-甲基鸟嘌呤和O6-甲基鸟嘌呤水平与由NNAL形成的相似。在鼻黏膜和肺DNA中，用NNK处理后的7-甲基鸟嘌呤和O6-甲基鸟嘌呤水平比用NNAL处理后的略高。从用[5-³H]NNK或[5-³H]NNAL处理的大鼠中分离出的肝脏DNA经酸水解后，分别产生180±48或120±23μmol/mol鸟嘌呤的4-羟基-1-(3-吡啶基)-1-丁酮。从用[5-³H]NNK或[5-³H]NNAL处理的大鼠中分离出的球蛋白经碱水解后，分别产生4.1±0.7或2.0±0.1 pmol/mg的4-羟基-1-(3-吡啶基)-1-丁酮。这些结果表明，NNAL不是NNK的解毒产物，因为用NNAL处理大鼠会导致DNA发生定性和定量上与用NNK处理时相似的修饰。NNAL对DNA和球蛋白的烷基化可能主要源于其代谢再转化为NNK。
