METABOLISM OF NICOTINE BY HUMAN LIVER-MICROSOMES - STEREOSELECTIVE FORMATION OF TRANS-NICOTINE N'-OXIDE
METABOLISM OF NICOTINE BY HUMAN LIVER-MICROSOMES - STEREOSELECTIVE FORMATION OF TRANS-NICOTINE N'-OXIDE
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DOI：
10.1021/tx00029a008
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发表时间：
1992-09-01
影响因子：
4.1
通讯作者：
BENOWITZ, NL
中科院分区：
文献类型：
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作者：
CASHMAN, JR;PARK, SB;BENOWITZ, NL
人肝微粒体催化（S）-尼古丁的NADPH依赖性氧化。主要产物为5 '-碳原子氧化产物尼古丁DELTA-1'，5 '-亚胺离子，在醛氧化酶存在下可有效转化为γ-内酰胺衍生物可替宁。另一种主要产品是尼古丁N '-氧化物。与描述体外或体内研究的先前报告相反，仅观察到反式尼古丁N-氧化物的形成。未观察到尼古丁脱甲基。尼古丁5-碳原子氧化的生化机制研究强烈暗示了一种主要的细胞色素P-450同工酶（即，P-450 2A 6）作为主要负责DELTA-1 '，5'-亚胺离子的形成。反式尼古丁N '-氧化物的立体选择性形成可能在很大程度上由含黄素的单加氧酶（II型）催化。这些结论是基于对含黄素单加氧酶的替代底物的影响，热灭活研究，免疫印迹研究，和细胞色素P-450的选择性底物。结果表明，（S）-尼古丁反式N '-氧化和DELTA-1'，5 '-亚胺离子形成可能是人肝含黄素单加氧酶II型和细胞色素P-450 2A 6活性的选择性探针，分别用于人体体内表型分析。
Liver microsomes from humans catalyze the NADPH-dependent oxidation of (S)-nicotine. The principal product is the 5'-carbon atom oxidation product, nicotine DELTA-1',5'-iminium ion, which is efficiently converted to the gamma-lactam derivative cotinine in the presence of aldehyde oxidase. Another major product is nicotine N'-oxide. In contrast to previous reports describing in vitro or in vivo studies, formation of only trans-nicotine N-oxide was observed. Demethylation of nicotine was not observed. Studies on the biochemical mechanism of nicotine 5-carbon atom oxidation strongly implicate one major cytochrome P-450 isoenzyme (i.e., P-450 2A6) as largely responsible for DELTA-1',5'-iminium ion formation. Stereoselective formation of trans-nicotine N'-oxide may be catalyzed in large part by the flavin-containing monooxygenase (form II). These conclusions are based on the effects of alternate substrates for the flavin-containing monooxygenase, heat inactivation studies, immunoblot studies, and selective substrates for cytochromes P-450. The results suggest that (S)-nicotine trans N'-oxygenation and DELTA-1',5'-iminium ion formation may be selective probes of human liver flavin-containing monooxygenase form II and cytochrome P-450 2A6 activities, respectively, useful for in vivo phenotyping of humans.