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Titolo:
Low doses of nicotine and ethanol induce CYP2E1 and chlorzoxazone metabolism in rat liver
Autore:
Howard, LA; Micu, AL; Sellers, EM; Tyndale, RF;
Indirizzi:
Univ Toronto, Dept Pharmacol, Toronto, ON M5S 1A8, Canada Univ Toronto Toronto ON Canada M5S 1A8 macol, Toronto, ON M5S 1A8, Canada Univ Toronto, Dept Psychiat, Toronto, ON, Canada Univ Toronto Toronto ON Canada ronto, Dept Psychiat, Toronto, ON, Canada Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON, Canada Univ Toronto Toronto ON Canada Addict & Mental Hlth, Toronto, ON, Canada
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 2, volume: 299, anno: 2001,
pagine: 542 - 550
SICI:
0022-3565(200111)299:2<542:LDONAE>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
CYTOCHROME P-4502E1; WISTAR RATS; ALCOHOL; MICROSOMES; MAINTENANCE; PERFORMANCE; RECEPTORS; 2E1; INACTIVATION; INTOXICATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
48
Recensione:
Indirizzi per estratti:
Indirizzo: Tyndale, RF Univ Toronto, Dept Pharmacol, 1 Kings Coll Circle, Toronto, ONM5S 1A8, Canada Univ Toronto 1 Kings Coll Circle Toronto ON Canada M5S 1A8ada
Citazione:
L.A. Howard et al., "Low doses of nicotine and ethanol induce CYP2E1 and chlorzoxazone metabolism in rat liver", J PHARM EXP, 299(2), 2001, pp. 542-550

Abstract

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 chlorzoxazonein vivo. CYP2E1 metabolizes ethanol and can generate toxic intermediates. CYP2E1 also bioactivates tobacco smoke and other procarcinogens and severalhepatotoxins. 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 V-max 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 increaseCYP2E1-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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Documento generato il 29/02/20 alle ore 15:04:39