Iminium metabolite mechanism for nicotine toxicity and addiction: Oxidative stress and electron transfer

The mechanism of nicotine toxicity is not completely delineated. Considerable evidence points to involvement of oxidative stress (OS), reactive oxygen species, lipid peroxidation, DNA damage, and beneficial effect of antioxidants. Previously, a suggestion was advanced for participation of iminium metabolites which might operate, via electron transfer (ET) with redox cycling, to produce radical entities. The conjugated iminium functionality is one of the less well-known ET types. The cationic metabolites arise from several routes, including oxidation of nicotine itself, and protonation of myosmine which originates from nornicotine via demethylation of nicotine. Reduction potentials, which are in the range amenable to ET in vivo, lend credence to the theoretical framework. An alternate metabolic route entails hydrolysis of nicotine iminium to an open-chain ketoamine that, in turn, undergoes nitrosation to form a toxic nitrosamine. Subsequently, the nitrosamine serves as a DNA alkylator which can also generate conjugated iminiums by attack on certain nitrogens of DNA bases. During the past 14 years, the hypothesis has enjoyed substantial support. Increasing evidence points to a role for OS in toxicity by nicotine entailing major body organs, including the lung, cardiovascular system, central nervous system, liver, kidney, testes, ovary, pancreas, and esophagus. The mechanism of addiction is also addressed based on interaction of iminiums with normal electron transport chains or electrical phenomena in the brain. The process might occur with or without participation of reactive oxygen species. Evidence indicates that free radicals are widely involved in cell signaling entailing redox processes in the categories of ion transport, neuromodulation, and transcription. Low levels of radicals appear to participate since high concentrations are associated with toxicity. Various possibilities for future work based on the hypothetical approach are addressed, including some that may have practical utility in relation to health improvement, toxicity, and addiction. Insight should be gained from computational studies on the energetics of electron uptake by metabolic iminiums, and on stability of the resultant delocalized radicals. Additional large-scale investigations of antioxidant effects are needed in order to resolve prior conflicting reports. Other proposals are based on interference with metabolism to iminiums and nitrosamines, and destruction of harmful metabolites. Since the iminium entities are proposed to play crucial, adverse roles, it would be worthwhile to explore them with regard to receptors, physiological activities, possible generation of reactive oxygen species, and effect of antioxidants.