2′-hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes:: Formation of a lung carcinogen precursor
2′-hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes:: Formation of a lung carcinogen precursor
复制标题
DOI：
10.1073/pnas.220207697
复制
发表时间：
2000-11-07
影响因子：
11.1
通讯作者：
Murphy, SE
中科院分区：
文献类型：
--
作者：
Hecht, SS;Hochalter, JB;Murphy, SE
吸烟者或接受尼古丁替代治疗的人以4-氧代-4-（3-吡啶基）丁酸（酮酸）和4-羟基-4-（3-吡啶基）丁酸（羟基酸）的形式排泄约10%的尼古丁剂量。以前，这些酸被认为是由主要尼古丁代谢物可替宁的次级代谢产生的。但我们的数据并不支持这一机制。因此，我们假设尼古丁通过2 '-羟基化代谢，最终产生酮酸和羟基酸作为尿液代谢物。该途径以前在哺乳动物系统中尚未建立，并且由于尼古丁2 '-羟基化的产物而具有潜在意义。4-（methylamino）-1-（3-pyridyl）-1-butanone（aminoketone），可转化为烟草特异性强的肺致癌物。4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮。尼古丁与细胞色素P450 2A 6和辅因子共同孵育时确实产生了氨基酮，经GC-MS鉴定为尼古丁的N-苯甲酰衍生物，其产率为可替宁产率的11%。人肝微粒体与尼古丁一起孵育，通过使用氨基酮作为中间体产生酮酸;可替宁不会形成酮酸。在10份人肝脏样本中，酮酸的形成率为可替宁的5.7%，这些代谢产物的产生相关。这些结果为哺乳动物尼古丁的2 '-羟基化提供了明确的证据，并阐明了人体内源性形成4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮的途径。
Smokers or people undergoing nicotine replacement therapy excrete approximately 10% of the nicotine dose as 4-oxo-4-(3-pyridyl)butanoic acid (keto acid) and 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid). Previously, these acids were thought to arise by secondary metabolism of the major nicotine metabolite cotinine. but our data did not support this mechanism. Therefore, we hypothesized that nicotine is metabolized by 2'-hydroxylation, which would ultimately yield keto acid and hydroxy acid as urinary metabolites. This pathway had not been established previously in mammalian systems and is potentially significant because the product of nicotine 2'-hydroxylation. 4-(methylamino)-1-(3-pyridyl)-1-butanone (aminoketone), can he converted to the potent tobacco-specific lung carcinogen. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Incubation of nicotine with cytochrome P450 2A6 and cofactors did indeed produce aminoketone, which was identified as its N-benzoyl derivative by GC-MS. The rate was 11% of that of cotinine production. Incubation of human liver microsomes with nicotine gave keto acid by using aminoketone as an intermediate; keto acid was not formed from cotinine. In 10 human liver samples, rates of formation of keto acid were 5.7% of those of cotinine and production of these metabolites correlated. These results provide definitive evidence for mammalian 2'-hydroxylation of nicotine and elucidate a pathway by which endogenous formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone could occur in humans.