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

Chem Res Toxicol. Sep-Oct 1992;5(5):639-46. doi: 10.1021/tx00029a008.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Chromatography, High Pressure Liquid
  • Cyclic N-Oxides / metabolism*
  • Cytochrome P-450 Enzyme System / metabolism
  • Humans
  • Isoenzymes
  • Magnetic Resonance Spectroscopy
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / enzymology*
  • NADP / metabolism
  • Nicotine / analogs & derivatives*
  • Nicotine / metabolism*
  • Oxidation-Reduction
  • Oxygenases / metabolism
  • Stereoisomerism

Substances

  • Cyclic N-Oxides
  • Isoenzymes
  • NADP
  • nicotine 1-N-oxide
  • Nicotine
  • Cytochrome P-450 Enzyme System
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)