Ethanol-induced enhancement of cocaine bioactivation and irreversible protein binding: evidence against a role of cytochrome P-450IIE1

Boelsterli, U. A. and Atanasoski, S. and Göldlin, C.. (1991) Ethanol-induced enhancement of cocaine bioactivation and irreversible protein binding: evidence against a role of cytochrome P-450IIE1. Alcoholism : Clinical and Experimental Research , 15 (5). pp. 779-784.

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Official URL: http://edoc.unibas.ch/50258/

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Chronic ethanol consumption potentiates cocaine-induced liver injury in rodents. Since cocaine has to be bioactivated by a cytochrome P-450-dependent N-oxidative pathway to exert its hepatotoxic effects, we studied the role of the ethanol-inducible P-450IIE1 for cocaine metabolism. Male Sprague-Dawley rats were pretreated with either a liquid diet containing ethanol (30% of calories) for 4 weeks or injected with pyrazole (200 mg/kg/day, ip, for 3 days). Both agents induced microsomal p-nitrophenol hydroxylation which is a probe for the catalytic activity of P-450IIE1. However, only ethanol, but not pyrazole, increased both microsomal cocaine N-demethylase activity (by 47%) and the extent of irreversible binding of [3H]-cocaine to microsomal proteins (by 100%), which was taken as a quantitative endpoint for the formation of a reactive metabolite. Cocaine N-demethylation and irreversible protein binding of cocaine were not inhibited by P-450IIE1 isozyme-selective substrates, nor was the rate of cocaine metabolism and binding decreased by functionally active polyclonal anti-rat P-450IIE1 antibodies. Furthermore, pyrazole pretreatment sensitized cultured hepatocytes to the glutathione-dependent cytotoxic effects of nontoxic concentrations of cocaine. These results indicate that (a) cocaine is not a major substrate for the ethanol-inducible P-450IIE1, (b) the enhancing effects of ethanol on cocaine bioactivation may be due to induction of other P-450 isoforms, and (c) induction of P-450IIE1 may potentiate cocaine-induced hepatocellular toxicity in vitro independently of cocaine metabolism, e.g., by P-450IIE1-dependent oxidative stress.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Cellular Neurobiology (Atanasoski)
UniBasel Contributors:Atanasoski, Suzana
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:26 Oct 2017 11:56
Deposited On:26 Oct 2017 11:56

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