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
<<< |