Linked Life Data

9877205

Source:http://linkedlifedata.com/resource/pubmed/id/9877205

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-2
pubmed:dateCreated
1999-1-26
pubmed:abstractText
Halothane hepatitis occurs because susceptible patients mount immune responses to trifluoroacetylated protein antigens, formed following cytochrome P450-mediated bioactivation of halothane to trifluoroacetyl chloride. In the present study, an in vitro approach has been used to investigate the cytochrome P450 isozyme(s) which catalyze neoantigen formation and to explore the protective role of non-protein thiols (cysteine and reduced glutathione). Significant levels of trifluoroacetyl protein antigens were generated when human liver microsomes, and also microsomes from livers of rats pre-treated with isoniazid, phenobarbital or beta-naphtoflavone, were incubated with halothane plus a nicotinamide adenine dinucleotidephosphate (NADPH) generating system. Immunoblotting studies revealed that the major trifluoroacetyl antigens expressed in vitro exhibited molecular masses of 50-55 kDa and included 60 and 80 kDa neoantigens recognized by antibodies from patients with halothane hepatitis. Much lower concentrations of halothane were required to produce maximal antigen generation in isoniazid-induced rat microsomes, as compared with phenobarbital or isosafrole-induced microsomes (0.5 vs 12.5 microl/ml). In isoniazid-induced microsomes, antigen generation was inhibited > 90% by the nucleophiles cysteine and glutathione and by the CYP2E1-selective inhibitors diallylsulfide and p-nitrophenol, but was unaffected by inhibitors of other P450 isozymes (furafylline, sulfaphenazole or triacetyloleandomycin). Neoantigen formation in six human liver microsomal preparations was inhibited in the presence of diallylsulfide, but not by furafylline, sulfaphenazole or triacetyloleandomycin, and exhibited marked variability which correlated with CYP2E1 levels. These results suggest that the balance between metabolic bioactivation by CYP2E1 and detoxication of reactive metabolites by cellular nucleophiles could be an important metabolic risk factor in halothane hepatitis.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0009-2797
pubmed:author
pubmed:issnType
Print
pubmed:day
6
pubmed:volume
116
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
123-41
pubmed:dateRevised
2010-8-25
pubmed:meshHeading
pubmed-meshheading:9877205-Animals, pubmed-meshheading:9877205-Cysteine, pubmed-meshheading:9877205-Cytochrome P-450 Enzyme System, pubmed-meshheading:9877205-Drug-Induced Liver Injury, pubmed-meshheading:9877205-Enzyme Activation, pubmed-meshheading:9877205-Glutathione, pubmed-meshheading:9877205-Halothane, pubmed-meshheading:9877205-Hepatitis Antigens, pubmed-meshheading:9877205-Individuality, pubmed-meshheading:9877205-Isoenzymes, pubmed-meshheading:9877205-Male, pubmed-meshheading:9877205-Metabolic Detoxication, Drug, pubmed-meshheading:9877205-Microsomes, Liver, pubmed-meshheading:9877205-Peptides, pubmed-meshheading:9877205-Rabbits, pubmed-meshheading:9877205-Rats, pubmed-meshheading:9877205-Rats, Inbred F344, pubmed-meshheading:9877205-Rats, Sprague-Dawley, pubmed-meshheading:9877205-Trichloroacetic Acid
pubmed:year
1998
pubmed:articleTitle
Interindividual variability in P450-dependent generation of neoantigens in halothane hepatitis.
pubmed:affiliation
Department of Molecular Toxicology, Imperial College School of Medicine at St Mary's, London, UK. erieli@ki.se
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't