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Titolo:
Effects of cocaine and its oxidative metabolites on mitochondrial respiration and generation of reactive oxygen species
Autore:
Boess, F; Ndikum-Moffor, FM; Boelsterli, UA; Roberts, SM;
Indirizzi:
Univ Florida, Ctr Environm & Human Toxicol, Gainesville, FL 32611 USA UnivFlorida Gainesville FL USA 32611 Toxicol, Gainesville, FL 32611 USA Swiss Fed Inst Technol, Zurich, Switzerland Swiss Fed Inst Technol Zurich Switzerland Technol, Zurich, Switzerland
Titolo Testata:
BIOCHEMICAL PHARMACOLOGY
fascicolo: 5, volume: 60, anno: 2000,
pagine: 615 - 623
SICI:
0006-2952(20000901)60:5<615:EOCAIO>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
INDUCED HEPATIC-NECROSIS; ELECTRON-TRANSPORT CHAIN; HYDROGEN-PEROXIDE; RAT-LIVER; INDUCED HEPATOTOXICITY; HEPATOCYTE CULTURES; BIOCHEMICAL-CHANGES; RADICAL PRODUCTION; MICE; SUPEROXIDE;
Keywords:
cocaine; reactive oxygen species; mitochondrial respiration; hepatotoxicity; norcocaine; N-hydroxynorcocaine; norcocaine nitroxide;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Roberts, SM Univ Florida, Ctr Environm & Human Toxicol, Box 110885, Gainesville, FL 32611 USA Univ Florida Box 110885 Gainesville FL USA 32611 FL 32611 USA
Citazione:
F. Boess et al., "Effects of cocaine and its oxidative metabolites on mitochondrial respiration and generation of reactive oxygen species", BIOCH PHARM, 60(5), 2000, pp. 615-623

Abstract

Cocaine is capable of producing severe hepatocellular necrosis in laboratory animals and humans. The mechanism of cocaine hepatotoxicity is not well understood, but appears to result from the actions of one or more N oxidative metabolites of cocaine. Mitochondria have been proposed as critical cellular targets for cocaine toxicity, and previous studies have found depressed mitochondrial respiration and increased mitochondrial generation of reactive oxygen species (ROS) in animals treated with cocaine. To examine the potential role of cocaine N-oxidative metabolites in these effects, mitochondrial respiration and ROS generation were examined in isolated mouse mitochondria treated with cocaine and its N-oxidative metabolites-norcocaine, N-hydroxynorcocaine, and norcocaine nitroxide. Cocaine, in concentrations of 0.25 or 0.5 mM, had no effect on state 3 respiration, state 4 respiration, respiratory control ratio (RCR), or ADP/O ratio. Norcocaine (0.5 mM) inhibited state 3 respiration, and N-hydroxynorcocaine (0.5 mM) inhibited both state 3 and state 4 respiration. Norcocaine nitroxide had the greatest effect on mitochondrial respiration; the lower concentration (0.25 mM) completely inhibited both state 3 and state 4 respiration. Preincubation of mitochondria with cocaine or metabolites increased the inhibitory effect of norcocaineand N-hydroxynorcocaine, but not cocaine. Cocaine, norcocaine, and N-hydroxynorcocaine (0.1 mM) had no effect on ROS generation during state 3 respiration, and cocaine and norcocaine decreased ROS generation under state 4 conditions. Norcocaine nitroxide interfered with the fluorescence ROS assay and could not be assessed. The results suggest that the effects of cocaine on mitochondrial respiration are due to its N-oxidative metabolites. Inhibition of mitochondrial respiration by the N-oxidative metabolites of cocaine may be the underlying cause for observed ATP depletion and subsequent cell death. BIOCHEM PHARMACOL 60;5:615-623, 2000. (C) 2000 Elsevier Science Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/20 alle ore 12:13:15