Enzymatic Oxidation of Nicotine to Nicotine Δ1′(5′) Iminium Ion

Oxidation of nicotine in the presence of rabbit liver 10,000 x g supernatant, NADPH, and cyanide results in the production of 5'-cyanonicotine. NaBD4 reduction of the reaction mixture from a similar incubation of nicotine, NADPH, and supernatant results in the production of deuteronicotine having a single deuterium in the pyrrolidine ring. Oxidation of nicotine to cotinine under 18O2 did not lead to incorporation of 18O in the cotinine produced. These results are explained by the formation of nicotine Δ1'(5') iminium ion as an intermediate in the degradation of nicotine. The formation of the iminium ion is catalyzed by an enzyme system having the properties of a mixed function oxidase. The reaction requires NADPH and O2 and is inhibited by carbon monoxide. It is proposed the nicotine Δ1'(5') iminium ion is formed by loss of water from 5'-hydroxy nicotine. The iminium ion formed from nicotine represents a nicotine analogue with a markedly altered chemical reactivity and must therefore be considered in studies on the physiological action of nicotine.