Peterson L A, Carmella S G, Hecht S S
Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, NY 10595.
Carcinogenesis. 1990 Aug;11(8):1329-33. doi: 10.1093/carcin/11.8.1329.
Levels of DNA and/or hemoglobin pyridyloxobutylation were compared in A/J mice or F344 rats treated with a single dose of [5-3H]4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone ([5-3H]NNK), [5-3H]4-hydroxy-1-(3-pyridyl)-1-butanone ([5-3H]4-HPB) or [5-3H]4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone ([5-3H]NNKOAc), a compound that generates the proposed pyridyloxobutylating agent in situ upon esterase hydrolysis. The lung and liver DNA samples isolated from A/J mice treated with the various compounds were subjected to acid hydrolysis and the hydrolysates were analyzed for the presence of [5-3H]4-HPB. No detectable levels were found in the lung DNA isolated from [5-3H]4-HPB-treated animals, whereas significant amounts of [5-3H]4-HPB were released from lung and liver DNA isolated from [5-3H]NNK- and [5-3H]NNKOAc-treated mice. The levels of total binding and [5-3H]4-HPB released from the globin isolated from these animals showed a similar trend. That is, low binding levels were detected in the globin isolated from [5-3H]4-HPB-treated animals and significantly higher levels of binding were detected in the globin from the [5-3H]NNKOAc- and [5-3H]NNK-treated animals. Comparable findings were obtained in the rat experiments. These studies clearly demonstrate that methyl hydroxylation of NNK leads to a species that is capable of reacting covalently with nucleophiles in DNA and protein. Thus, the levels of 4-HPB released from DNA and globin can be attributed to the activation of NNK and not to the direct binding of 4-HPB.
在接受单剂量[5-³H]4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮([5-³H]NNK)、[5-³H]4-羟基-1-(3-吡啶基)-1-丁酮([5-³H]4-HPB)或[5-³H]4-(乙酰氧基甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮([5-³H]NNKOAc，一种经酯酶水解后可原位生成拟吡啶氧基丁基化剂的化合物)处理的A/J小鼠或F344大鼠中，对DNA和/或血红蛋白吡啶氧基丁基化水平进行了比较。从用各种化合物处理的A/J小鼠中分离出的肺和肝DNA样本进行酸水解，并对水解产物分析[5-³H]4-HPB的存在情况。在用[5-³H]4-HPB处理的动物分离出的肺DNA中未发现可检测到的水平，而在用[5-³H]NNK和[5-³H]NNKOAc处理的小鼠分离出的肺和肝DNA中释放出了大量的[5-³H]4-HPB。从这些动物分离出的球蛋白中释放出的总结合水平和[5-³H]4-HPB呈现出相似的趋势。也就是说，在用[5-³H]4-HPB处理的动物分离出的球蛋白中检测到低结合水平，而在用[5-³H]NNKOAc和[5-³H]NNK处理的动物的球蛋白中检测到显著更高的结合水平。在大鼠实验中也获得了类似的结果。这些研究清楚地表明，NNK的甲基羟基化产生了一种能够与DNA和蛋白质中的亲核试剂发生共价反应的物质。因此，从DNA和球蛋白中释放出的4-HPB水平可归因于NNK的活化，而不是4-HPB的直接结合。
