Linked Life Data

19059302

Source:http://linkedlifedata.com/resource/pubmed/id/19059302

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-2
pubmed:dateCreated
2009-1-13
pubmed:abstractText
Amodiaquine is an antimalarial drug that causes life-threatening agranulocytosis and hepatotoxicity in about 1 in 2000 patients, which is usually associated with an inflammatory response. It was found that the LC(50) (2h) of amodiaquine towards isolated rat hepatocytes was 1mM. The cytotoxic mechanism involved protein carbonylation as well as P450 activation to a reactive metabolite. The cytotoxicity, however, was not reactive oxygen species (ROS)-mediated, as ROS scavengers did not prevent cytotoxicity or protein carbonylation, and it was not accompanied by glutathione (GSH) oxidation or intracellular H(2)O(2) formation. On the other hand, the cytotoxicity could be attributed to a quinoneimine metabolite formation which formed GSH conjugates and GSH-depleted hepatocytes were much more susceptible to amodiaquine. Furthermore, when a non-toxic H(2)O(2) generating system and peroxidase was used to mimic the products formed by inflammatory immune cells, only 15microM amodiaquine was required to cause 50% cell death. In the absence of amodiaquine, hepatocyte viability and glutathione levels were not affected by the H(2)O(2) generating system with or without peroxidase. The toxicity mechanism of amodiaquine in this hepatocyte H(2)O(2)/peroxidase model involved oxidative stress, as cytotoxicity was accompanied by GSH oxidation, decreased mitochondrial membrane potential and protein carbonyl formation which were inhibited by ROS scavengers, 4-hydroxy-2,2,6,6-tetramethylpiperidene-1-oxyl (TEMPOL) or mannitol suggesting a role for a semiquinoneimine radical and ROS in the amodiaquine-H(2)O(2)-mediated cytotoxic mechanism.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0300-483X
pubmed:author
pubmed:issnType
Print
pubmed:day
4
pubmed:volume
256
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
101-9
pubmed:meshHeading
pubmed-meshheading:19059302-Amodiaquine, pubmed-meshheading:19059302-Animals, pubmed-meshheading:19059302-Antimalarials, pubmed-meshheading:19059302-Antioxidants, pubmed-meshheading:19059302-Cell Survival, pubmed-meshheading:19059302-Cyclic N-Oxides, pubmed-meshheading:19059302-Dose-Response Relationship, Drug, pubmed-meshheading:19059302-Enzyme Inhibitors, pubmed-meshheading:19059302-Glutathione, pubmed-meshheading:19059302-Hepatocytes, pubmed-meshheading:19059302-Hydrogen Peroxide, pubmed-meshheading:19059302-Inflammation, pubmed-meshheading:19059302-Male, pubmed-meshheading:19059302-Mannitol, pubmed-meshheading:19059302-Membrane Potentials, pubmed-meshheading:19059302-Mitochondrial Membranes, pubmed-meshheading:19059302-Oxidation-Reduction, pubmed-meshheading:19059302-Oxidative Stress, pubmed-meshheading:19059302-Protein Carbonylation, pubmed-meshheading:19059302-Rats, pubmed-meshheading:19059302-Rats, Sprague-Dawley, pubmed-meshheading:19059302-Spin Labels
pubmed:year
2009
pubmed:articleTitle
Amodiaquine-induced oxidative stress in a hepatocyte inflammation model.
pubmed:affiliation
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't