Zhang Siyi, Wang Mingyao, Villalta Peter W, Lindgren Bruce R, Upadhyaya Pramod, Lao Yanbin, Hecht Stephen S
Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, MMC 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA.
Chem Res Toxicol. 2009 May;22(5):926-36. doi: 10.1021/tx900015d.
The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are potent pulmonary carcinogens in rats. NNK and NNAL require metabolic activation to express their carcinogenicity. Cytochrome P450-catalyzed alpha-hydroxylation at the methyl position of NNK or NNAL generates reactive intermediates, which alkylate DNA to form pyridyloxobutyl (POB)-DNA adducts or pyridylhydroxybutyl (PHB)-DNA adducts. NNK is metabolized to NNAL in a reversible and stereoselective manner, and the tissue-specific retention of (S)-NNAL is believed to be important to the carcinogenicity of NNK. In the present study, we investigated the formation of POB- and PHB-DNA adducts in extrahepatic tissues of F344 rats treated chronically with NNK and (R)- and (S)-NNAL (10 ppm in the drinking water, 1-20 weeks). POB- and PHB-DNA adducts were quantified in nasal olfactory mucosa, nasal respiratory mucosa, oral mucosa, and pancreas of treated rats. Adduct formation in the nasal respiratory mucosa exceeded that in the other tissues. O(2)-[4-(3-Pyridyl)-4-oxobut-1-yl]thymidine (O(2)-POB-dThd) or O(2)-[4-(3-pyridyl)-4-hydroxybut-1-yl]thymidine (O(2)-PHB-dThd) was the major adduct, followed by 7-[4-(3-pyridyl)-4-oxobut-1-yl]guanine (7-POB-Gua) or 7-[4-(3-pyridyl)-4-hydroxybut-1-yl]guanine (7-PHB-Gua). There was a remarkable similarity in adduct formation between the NNK and the (S)-NNAL groups, both of which were distinctively different from that in the (R)-NNAL group. For example, in the nasal olfactory mucosa, POB-DNA adduct levels in the NNK and (S)-NNAL groups were not significantly different from each other, while (R)-NNAL treatment generated 6-33 times lower amounts of POB-DNA adducts than did NNK treatment. In contrast, (R)-NNAL treatment produced significantly higher levels of PHB-DNA adducts than did NNK or (S)-NNAL treatment. Similar trends were observed in the nasal respiratory mucosa, oral mucosa, and pancreas. These results suggest extensive retention of (S)-NNAL in various tissues of NNK-treated rats and support a mechanism in which the preferential metabolism of NNK to (S)-NNAL, followed by sequestration of (S)-NNAL in the target tissues and reoxidation to NNK, is important to NNK tumorigenesis.
烟草特异性亚硝胺4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮(NNK)及其代谢产物4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁醇(NNAL)是大鼠体内强效的肺致癌物。NNK和NNAL需要代谢活化才能表现出致癌性。细胞色素P450催化的NNK或NNAL甲基位置的α-羟基化产生反应性中间体，该中间体使DNA烷基化形成吡啶氧基丁基(POB)-DNA加合物或吡啶基羟基丁基(PHB)-DNA加合物。NNK以可逆和立体选择性的方式代谢为NNAL，并且(S)-NNAL的组织特异性滞留被认为对NNK的致癌性很重要。在本研究中，我们调查了用NNK以及(R)-和(S)-NNAL(饮用水中浓度为10 ppm，处理1 - 20周)长期处理的F344大鼠肝外组织中POB-和PHB-DNA加合物的形成情况。对处理过的大鼠的鼻嗅黏膜、鼻呼吸黏膜、口腔黏膜和胰腺中的POB-和PHB-DNA加合物进行了定量。鼻呼吸黏膜中的加合物形成超过了其他组织。O(2)-[4-(3-吡啶基)-4-氧代丁-1-基]胸苷(O(2)-POB-dThd)或O(2)-[4-(3-吡啶基)-4-羟基丁-1-基]胸苷(O(2)-PHB-dThd)是主要加合物，其次是7-[4-(3-吡啶基)-4-氧代丁-1-基]鸟嘌呤(7-POB-Gua)或7-[4-(3-吡啶基)-4-羟基丁-1-基]鸟嘌呤(7-PHB-Gua)。NNK组和(S)-NNAL组之间的加合物形成有显著相似性，这两组与(R)-NNAL组明显不同。例如，在鼻嗅黏膜中，NNK组和(S)-NNAL组的POB-DNA加合物水平彼此无显著差异，而(R)-NNAL处理产生的POB-DNA加合物量比NNK处理低6 - 33倍。相反，(R)-NNAL处理产生的PHB-DNA加合物水平显著高于NNK或(S)-NNAL处理。在鼻呼吸黏膜、口腔黏膜和胰腺中也观察到类似趋势。这些结果表明，在NNK处理的大鼠的各种组织中(S)-NNAL大量滞留，并支持一种机制，即NNK优先代谢为(S)-NNAL，随后(S)-NNAL在靶组织中滞留并再氧化为NNK，这对NNK的肿瘤发生很重要。
