Linked Life Data

18393451

Source:http://linkedlifedata.com/resource/pubmed/id/18393451

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2008-4-21
pubmed:abstractText
Long-term treatment of hypertensive disorders with hydralazine has resulted in some patients developing hepatitis and lupus erythematosus, an autoimmune syndrome. The concentration of hydralazine required to cause 50% cytotoxicity in 2 h (LC(50)) toward isolated rat hepatocytes was found to be 8 mM. Cytotoxicity was delayed by the P450 inhibitor, 1-aminobenzotriazole, suggesting that P450 catalyzed the formation of toxic metabolites from hydralazine. No hydralazine-induced oxidative stress was apparent as there was little effect on hepatocyte lipid peroxidation, protein carbonyl formation, intracellular H(2)O(2), or hepatocyte GSH levels and no effect of butylated hydroxyanisole (BHA) on cytotoxicity. Drug-induced hepatotoxicity in vivo has often been attributed to infiltrating inflammatory cells, for example, neutrophils or resident Kupffer cells whose NADPH oxidase generates H(2)O(2), when activated. The effect of a nontoxic continuous infusion of H(2)O(2) on hydralazine cytotoxicity was investigated. It was found that H(2)O(2) increased hepatocyte susceptibility to hydralazine 4-fold (LC(50), 2 mM). Cytotoxicity was still prevented by the P450 inhibitor but now involved some oxidative stress as shown by increased protein carbonyls, endogenous H(2)O(2), and GSH oxidation. Lipid peroxidation was not increased, and cytotoxicity was not inhibited by BHA. Cytotoxicity, however, was inhibited by 4-hydroxy-2,2,6,6-tetramethylpiperidene-1-oxyl (TEMPOL), a ROS scavenger. Because neutrophils or Kupffer cells release myeloperoxidase on activation, the effect of adding peroxidase to the hepatocytes exposed to H(2)O(2) on hydralazine cytotoxicity was investigated. It was found that peroxidase/H(2)O(2) increased hepatocyte susceptibility to hydralazine 80-fold (LC 50, 0.1 mM). Furthermore, cytotoxicity occurred following extensive oxidative stress that included lipid peroxidation, and cytotoxicity that was now prevented by the antioxidant BHA. These results indicate that three cytotoxic pathways exist for hydralazine: a P450-catalyzed pathway not involving oxidative stress, a P450/H(2)O(2)-catalyzed oxidative stress-mediated cytotoxic pathway not involving lipid peroxidation, and a peroxidase/H(2)O(2)-catalyzed lipid peroxidation-mediated cytotoxic pathway.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0893-228X
pubmed:author
pubmed:issnType
Print
pubmed:volume
21
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
904-10
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Accelerated cytotoxic mechanism screening of hydralazine using an in vitro hepatocyte inflammatory cell peroxidase model.
pubmed:affiliation
Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 3M2 .
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't