Nicotine metabolism aldehyde oxidase

Nicotine is extensively metabolized to a nnmber of metabolites (Fig. 3) by the liver. Six primary metabolites of nicotine have been identified. Qnantitatively, the most important metabolite of nicotine in most mammalian species is the lactam derivative, cotinine. In humans, about 70-80% of nicotine is converted to cotinine. This transformation involves two steps. The first is mediated primarily by CYP2A6 to produce nicotine-A -iminium ion, which is in equilibrium with 5 -hydroxynicotine. The second step is catalyzed by a cytoplasmic aldehyde oxidase. Nicotine iminiiim ion has received considerable interest since it is an alkylating agent and, as such, could play a role in the pharmacology of nicotine (Shigenaga etal. 1988). 

A key focus of this chapter has been on the iminium/enamine stage of metabolism (figure 1) as the critical point governing the balance between toxic activation and detoxication pathways. Thus, although AO and MND efficiently intercept the -iminium derived from nicotine, PCP-Im is not a substrate for either enzyme. It seems quite significant that the lack of aldehyde oxidase substrate potential in this case correlates with increased levels of covalent binding of PCP relative to nicotine. 

The hepatotoxic and neurotoxic 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) is metabolized by aldehyde oxidase to its nontoxic MP-2-pyridone metabolite (MPTP lactam). Although S-cotinine is formed primarily from S-nicotine in human smokers by CYP2A6, in vitro studies suggest that aldehyde oxidase contributes to S-nicotine metabolism by oxidizing the intermediate metabolite (S-nicotine A-1, 5 -imminium ion) to S-cotinine. These results suggest that hepatic aldehyde oxidase is a key detoxification enzyme for MPTP and S-nicotine. 

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