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 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.
Cashman
J R
JR
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446.
Park
S B
SB
Yang
Z C
ZC
Wrighton
S A
SA
Jacob
P
P
Benowitz
N L
NL
D002851:Chromatography, High Pressure Liquid; D003497:Cyclic N-Oxides / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000737:chemistry / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D009538:Nicotine / Q000031:analogs & derivatives* / Q000378:metabolism*; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000378:metabolism; D013237:Stereoisomerism
D003497:Cyclic N-Oxides; D007527:Isoenzymes; D009249:NADP; C024270:nicotine 1-N-oxide; D009538:Nicotine; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)