International Journal of Pure and Applied Chemistry (IJPAC)

 

2. Metabolism of nicotine: a molecular modelling analysis

Fazlul Huq

School of Biomedical Sciences, Faculty of Health Sciences, The University of Sydney

E-mail : f.huq@fhs.usyd.edu.au.

 

Abstract:

Over a billion people absorb nicotine into their bodies chronically through cigarette smoking and billions more get exposed to the drug daily through environmental tobacco smoke. Nicotine is an addictive drug. It is a nicotinic cholinergic receptor agonist that exerts a number of physiological effects involving the central and peripheral nervous systems, the cardiovascular system and the endocrine system. The drug undergoes extensive oxidative metabolism in humans with 80-90% being accounted for in terms of urinary metabolites. The primary metabolic pathway in humans and other mammals involves mainly C1’-oxidation catalysed by CYP2A6 to form the highly reactive (S)-nicotine D1’,5’-iminium ion in the first step, which is converted in the second step to (S)-cotinine by the action of cytosolic aldehyde oxidase. Typically, 70-80% of (S)-nicotine is converted to (S)-cotinine before conversion to other metabolites. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that the position of the most negative electric potential and that of HOMO having the highest electron density lie close to C1’, thus providing an explanation as to why C1’-oxidation of nicotine is preferred over N-oxidation. The highly reactive (S)-nicotine D1’,5’-iminium ion is found to have the lowest LUMO-HOMO energy difference in line with its greater kinetic lability.

 

Key words: Nicotine, cotinine, toxicity, molecular modelling

 

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