Linked Life Data

9772215

Source:http://linkedlifedata.com/resource/pubmed/id/9772215

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1998-11-20
pubmed:abstractText
Acetaminophen (APAP) hepatotoxicity is due to its biotransformation to a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), that is capable of binding to cellular macromolecules. At least two forms of cytochrome P450, CYP2E1 and CYP1A2, have been implicated in this reaction in mice. To test the combined roles of CYP1A2 and CYP2E1 in an intact animal model, a double-null mouse line lacking functional expression of CYP1A2 and CYP2E1 was produced by cross-breeding Cyp1a2-/- mice with Cyp2e1-/- mice. Animals deficient in the expression of both P450s developed normally and exhibited no obvious phenotypic abnormalities. Comparison of the dose-response to APAP (200-1200 mg/kg) indicated that double-null animals were highly resistant to APAP-induced toxicity whereas the wild-type animals were sensitive. Administration of 600 to 800 mg/kg of this drug to male wild-type animals resulted in increased plasma concentrations of liver enzymes (alanine aminotransferase, sorbitol dehydrogenase), lipidosis, hepatic necrosis, and renal tubular necrosis. In contrast, when APAP of equivalent or higher dose was administered to the double-null mice, plasma levels of liver enzymes and liver histopathology were normal. However, administration of 1200 mg of APAP/kg to the double-null mice resulted in infrequent liver lipidosis and mild kidney lesions. Consistent with the protection from hepatotoxicity, the expected depletion of hepatic glutathione (GSH) content was significantly retarded and APAP covalent binding to hepatic cytosolic proteins was not detectable in the double-null mice. Likewise, in vitro activation of APAP by liver microsomes from the double-null mice was approximately one tenth of that in microsomes from wild-type mice. Thus, the protection against APAP toxicity afforded by deletion of both CYP2E1 and CYP1A2 likely reflects greatly diminished production of the toxic electrophile, NAPQI.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0041-008X
pubmed:author
pubmed:copyrightInfo
Copyright 1998 Academic Press.
pubmed:issnType
Print
pubmed:volume
152
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
193-9
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:9772215-Acetaminophen, pubmed-meshheading:9772215-Alanine Transaminase, pubmed-meshheading:9772215-Analgesics, Non-Narcotic, pubmed-meshheading:9772215-Animals, pubmed-meshheading:9772215-Cytochrome P-450 CYP1A2, pubmed-meshheading:9772215-Cytochrome P-450 CYP2E1, pubmed-meshheading:9772215-DNA, pubmed-meshheading:9772215-Dose-Response Relationship, Drug, pubmed-meshheading:9772215-Gene Deletion, pubmed-meshheading:9772215-Genotype, pubmed-meshheading:9772215-Glutathione, pubmed-meshheading:9772215-Kidney Tubules, pubmed-meshheading:9772215-L-Iditol 2-Dehydrogenase, pubmed-meshheading:9772215-Lipidoses, pubmed-meshheading:9772215-Liver, pubmed-meshheading:9772215-Male, pubmed-meshheading:9772215-Mice, pubmed-meshheading:9772215-Mice, Inbred C57BL, pubmed-meshheading:9772215-Mice, Knockout, pubmed-meshheading:9772215-Microsomes, Liver, pubmed-meshheading:9772215-Necrosis, pubmed-meshheading:9772215-Sulfhydryl Compounds, pubmed-meshheading:9772215-Survival Rate
pubmed:year
1998
pubmed:articleTitle
Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice.
pubmed:affiliation
Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't