Metabolism of nicotine by human liver microsomes: stereoselective formation of trans-nicotine N'-oxide

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 oxid...

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Bibliographic Details
Published in:Chemical research in toxicology 1992-09, Vol.5 (5), p.639-646
Main Authors: Cashman, John R, Park, Sang B, Yang, Z. C, Wrighton, Steven A, Jacob, Peyton, Benowitz, Neal L
Format: Article
Language:English
Subjects:
Biological and medical sciences
Chromatography, High Pressure Liquid
Cyclic N-Oxides - metabolism
Cytochrome P-450 Enzyme System - metabolism
Humans
Isoenzymes
Magnetic Resonance Spectroscopy
Medical sciences
Microsomes, Liver - chemistry
Microsomes, Liver - enzymology
NADP - metabolism
Nicotine - analogs & derivatives
Nicotine - metabolism
Oxidation-Reduction
Oxygenases - metabolism
Stereoisomerism
Tobacco, tobacco smoking
Toxicology
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Summary: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.
ISSN:0893-228X
1520-5010
DOI:10.1021/tx00029a008