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Vol. 282, Issue 3, 1608-1614, 1997
The Addiction Research Foundation and the Department of
Pharmacology, University of Toronto, Toronto, Ontario, Canada (E.S.M.,
R.F.T., E.M.S.), and the Departments of
Medicine and Psychiatry, Nicotine is primarily metabolized to cotinine by cytochromes P450
(CYPs). The degree of variation in the metabolism of nicotine to
cotinine and the relative roles of the polymorphic enzymes CYP2A6 and
CYP2D6 in this metabolism were investigated. The apparent Km and Vmax values
(mean ± S.D.) for cotinine formation in human liver microsomes
(n = 31) were 64.9 ± 32.7 µM and 28.1 ± 28.7 nmol/mg of protein/hr, respectively. A 30-fold difference was seen
among the individual Vmax values, with four
livers showing significantly higher rates of cotinine formation. CYP2D6
is unimportant in nicotine metabolism because quinidine (a CYP2D6
inhibitor) had little effect on inhibition of cotinine formation;
Vmax values for dextromethorphan
(CYP2D6 probe substrate) and nicotine (n = 9) did not
correlate (r = .49, P = .18), and a cDNA CYP2D6
expression system failed to metabolize nicotine to cotinine. CYP2A6
appears to be the major P450 involved in human nicotine metabolism to cotinine. Coumarin, a specific and selective CYP2A6 substrate, competitively inhibited cotinine formation by 85 ± 11%
(mean ± S.D.) in 31 human livers. The Ki
value for this inhibition ranged from 1 to 5 µM, and a CYP2A6
monoclonal antibody inhibited cotinine formation by >75%.
Immunochemically determined CYP2A6 correlated significantly with
nicotine-to-cotinine Vmax values
(r = .90, n = 30, P < .001) and
to inhibition of nicotine metabolism by coumarin (r = .94, n = 30, P < .001). These data indicate that nicotine metabolism is highly variable among individual livers and that
this is due to variable expression of CYP2A6, not CYP2D6.
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
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