Abstract
Incubation of S(−)-3H-nicotine with rabbit lung microsomes in the presence of dioxygen and NADPH results in the formation of metabolites that bind covalently to microsomal macromolecules. The addition of cytochrome P-450 monooxygenase inhibitors, α-methylbenzyl aminobenzotriazole and aroclor 1260, inhibited both (S)-nicotine metabolism and covalent binding. The relative rates of oxidation of nicotine Δ1′,5′ iminium ion to cotinine indicates that lung 100,000×g supernatant catalyzed this oxidation approximately 18 times slower than that of liver system based on mg of protein, and increased covalent interactions. Since the activity of lung iminium oxidase appears much lower than the liver, it is tempting to speculate that localized concentrations of nicotine Δ1′,5′ iminium ion in the lung will survive for a longer period of time. These results support that cytochrome P-450 catalyzed oxidation of nicotine leads to the formation of reactive and electrophilic intermediates capable of chemical interactions with biomacromolecules.
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Kim, B.H., Shigenaga, M.K. Metabolism-dependent covalent binding of S(−)-3H-nicotine to lung microsomes in vitro. Arch. Pharm. Res. 16, 89–93 (1993). https://doi.org/10.1007/BF03036852
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DOI: https://doi.org/10.1007/BF03036852