Document Detail


Effects of cocaine and its oxidative metabolites on mitochondrial respiration and generation of reactive oxygen species.
MedLine Citation:
PMID:  10927019     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 norcocaine and 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.
Authors:
F Boess; F M Ndikum-Moffor; U A Boelsterli; S M Roberts
Related Documents :
14568259 - Mangafodipir prevents liver injury induced by acetaminophen in the mouse.
22906019 - Increased platelet activation and thrombosis in transgenic mice expressing constitutive...
8602759 - Mitochondrial defect in huntington's disease caudate nucleus.
23222929 - Thromboelastographic evaluation of blood coagulation in the presence of branded and gen...
15448739 - Nitric oxide and platelet energy metabolism.
22563509 - Severe dengue is associated with consumption of von willebrand factor and its cleaving ...
222789 - The evolution of excitable behaviour in dictyostelium.
1534919 - Thromboxane a2 receptor characterization in human astrocytoma cells and rabbit platelet...
11099659 - The mechanism of apoptosis in human platelets during storage.
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  60     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2000 Sep 
Date Detail:
Created Date:  2000-08-28     Completed Date:  2000-08-28     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  615-23     Citation Subset:  IM    
Affiliation:
Swiss Federal Institute of Technology, Zurich, Switzerland.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Cell Respiration / drug effects
Cocaine / analogs & derivatives*,  metabolism,  pharmacology*
Dopamine Uptake Inhibitors / metabolism,  pharmacology
Mice
Mice, Inbred ICR
Mitochondria / drug effects*,  metabolism
Reactive Oxygen Species / metabolism*
Rhodamines / metabolism
Grant Support
ID/Acronym/Agency:
DA06601/DA/NIDA NIH HHS
Chemical
Reg. No./Substance:
0/Dopamine Uptake Inhibitors; 0/Reactive Oxygen Species; 0/Rhodamines; 109244-58-8/dihydrorhodamine 123; 18717-72-1/norcocaine; 50-36-2/Cocaine; 72182-43-5/8-hydroxynorcocaine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Lipid metabolism as a target for potassium channel effectors.
Next Document:  Role of NADPH:cytochrome P450 reductase in the hypoxic accumulation and metabolism of BRU59-21, a te...