The studies proposed in this application are designed to determine if the tobacco alkaloids (S)-nicotine and (R,S)-N-methylanatabine may contribute to the 28% and 40% decrements, respectively, in MAO-A and MAO-B activity observed in the brains of smokers by PET analysis. Our attention is focused on the potential inhibitor properties of iminium ion metabolites generated by the cytochrome-P450 catalyzed oxidation of these alkaloids since (1) we have preliminary evidence that the delta 1',5' -iminium ion metabolite of (S)-nicotine is an inhibitor of MAO-B, (2) about 70% of (S)-nicotine (and, by inference, structurally related tobacco alkaloids) is metabolized by this pathway and (3) indirect evidence supports the proposal that (S)-nicotine is metabolized by brain enzymes to the iminium ion species.
The specific aims that will be pursued include (1) the characterization of the substrate and inhibitor properties of the compounds of interest with purified MAO-A and MAO-B; (2) an examination of the in vivo MAO-A and MAO-B inhibitor properties of (S)-nicotine and (R,S)-N-methylanatabine in a rodent model; (3) the characterization of the metabolic fate of these compounds using rat and baboon brain mitochondrial and microsomal preparations; and (4) an examination of the potential formation of chemically reactive intermediates of (S)-nicotine and (R,S)-N-methylanatabine in vivo and in brain homogenates by determining the metabolically dependent formation of covalent adducts with liver and brain macromolecules. We submit that these studies should establish or rule out a role for these compounds in the mediation of the loss of MAO-A and MAO-B activity in the brains of smokers.
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