Low doses of nicotine and ethanol induce CYP2E1 and chlorzoxazone metabolism in rat liver.
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).
Howard
L A
LA
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
Micu
A L
AL
Sellers
E M
EM
Tyndale
R F
RF
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology*; D002753:Chlorzoxazone / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009125:Muscle Relaxants, Central / Q000378:metabolism*; D009538:Nicotine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar
D002492:Central Nervous System Depressants; D009125:Muscle Relaxants, Central; D018722:Nicotinic Agonists; D012333:RNA, Messenger; D000431:Ethanol; D009538:Nicotine; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone