Metabolic oxidation of nicotine to chemically reactive intermediates

Abstract

Studies on the metabolism of nicotine by rabbit liver microsomal fractions in the presence of 0.01 M sodium cyanide have led to the characterization of 2 isomeric cyanonicotine compounds. The locations of the cyano groups were established by GC-EIMS[electron impact mass spectra] analyses of the deuterium [d3]-labeled products obtained from the specifically d3-labeled substrates (S)-nicotine-5'',5''-d2, (R, S)-nicotine-2'',5'',5''d3, and (R,S)-nicotine-N-methyl-d3. One cyano adduct was shown to be 5''-cyanonicotine, a product previously isolated from similar microsomal preparations. The 2nd cyano adduct was shown to be N-(cyanomethyl)nornicotine; this structure assignment was confirmed by synthesis. Formation of N-(cyanomethyl)nornicotine appears to occur, at least in part, without prior NC bond cleavage, implicating the in situ generation of the N-methyleniminium species during the course of metabolic oxidative N-demethylation of nicotine.