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Vol. 299, Issue 2, 542-550, November 2001
Departments of Pharmacology (L.A.H., A.L.M., E.M.S., R.F.T.) and
Psychiatry (E.M.S.), Centre for Addiction and Mental Health (E.M.S.,
R.F.T.), University of Toronto, Toronto, Ontario, Canada
The use of ethanol and nicotine is strongly linked; 80 to 95% of heavy
alcohol users are also smokers. In humans, cigarette smoking
significantly enhances CYP2E1 activity, as measured by increased
metabolism of chlorzoxazone in vivo. CYP2E1 metabolizes ethanol and can
generate toxic intermediates. CYP2E1 also bioactivates tobacco smoke
and other procarcinogens and several hepatotoxins. We hypothesized
that, like ethanol, nicotine increases CYP2E1 activity. Rats were
treated once daily with saline, ethanol (0.3, 1.0, and 3.0 g/kg p.o.),
or nicotine bitartrate (0.1, 0.3, and 1.0 mg base/kg s.c.) for 7 days.
After ethanol or nicotine administration, immunostaining for CYP2E1 was
increased in the centrilobular regions of rat liver. Western blot
analyses revealed that hepatic CYP2E1 levels were increased by ethanol
(1.6-2.4-fold) and nicotine (1.3-1.7-fold). In vitro chlorzoxazone
6-hydroxylation analyses demonstrated elevated Vmax values (compared with saline-treated
animals) by using hepatic microsomes from high-dose ethanol (2.27 ± 0.12 versus 1.18 ± 0.23 nmol/mg/min, p < 0.001) or nicotine-treated rats (2.35 ± 0.04 versus 1.32 ± 0.55 nmol/mg/min, p < 0.005), with no change in affinity. The magnitude of enhanced chlorzoxazone metabolism by microsomes from drug-treated animals is consistent with the observed increase in CYP2E1 protein by immunoblot. These data suggest that nicotine may increase CYP2E1-induced toxicity and contribute to cross-tolerance in smokers and people treated with nicotine (e.g., smokers, patients with Alzheimer's disease, ulcerative colitis, neuropsychiatric motor disorders).
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