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 two isomeric cyanonicotine compounds. The locations of the cyano groups were established by GC--EIMS analyses of the deuterium-labeled products obtained from the specifically deuterium-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 second 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 nitrogen--carbon bond cleavage, implicating the in situ generation of the N-methyleniminium species during the course of metabolic oxidative N-demethylation of nicotine.

Catalytic Mechanism of Cytochrome P450 for 5′-Hydroxylation of Nicotine: Fundamental Reaction Pathways and Stereoselectivity

“…The metabolically generated iminium ion species 2 has been trapped and analyzed as the corresponding diastereomeric 5′-cyano adducts ( 5 ) by the inclusion of cyanide ion in the reaction mixture. 9,10,26,27,32,33 An early study 10 using human liver microsomal preparations assessed the stereochemical course of this transformation using the selectively deuterated trans - and cis -5′-monodeutero disatereomers 3 and 4 , respectively, as substrate (Scheme 1). The deuterium content of the resulting mixture of iminium species 2a and 2b , as assessed by the GC/EIMS analysis of the corresponding cyano adducts 5a and 5b , established that Δ 1′(5′) -iminium ion was formed after the stereoselective loss of the trans -5′-hydrogen.…”