Linked Life Data

18565563

Source:http://linkedlifedata.com/resource/pubmed/id/18565563

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2008-9-10
pubmed:abstractText
Cytochrome P450 (CYP) 2E1 was suggested to be the major enzyme involved in trichloroethylene (TRI) metabolism and TRI-induced hepatotoxicity, although the latter molecular mechanism is not fully understood. The involvement of CYP2E1 in TRI-induced hepatotoxicity and its underlying molecular mechanism were studied by comparing hepatotoxicity in cyp2e1+/+ and cyp2e1-/- mice. The mice were exposed by inhalation to 0 (control), 1000, or 2000 ppm of TRI for 8 h a day, for 7 days, and TRI-hepatotoxicity was assessed by measuring plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histopathology. Urinary metabolites of trichloroethanol and trichloroacetic acid (TCA) were considerably greater in cyp2e1+/+ compared to cyp2e1-/- mice, suggesting that CYP2E1 is the major P450 involved in the formation of these metabolites. Consistent with elevated plasma ALT and AST activities, cyp2e1+/+ mice in the 2000 ppm group showed histopathological inflammation. TRI significantly upregulated PPARalpha, which might function to inhibit NFkappaB p50 and p65 signalling. In addition, TRI-induced NFkappaB p52 mRNA, and significantly positive correlation between NFkappaB p52 mRNA expression and plasma ALT activity levels were observed, suggesting the involvement of p52 in liver inflammation. Taken together, the current study directly demonstrates that CYP2E1 was the major P450 involved in the first step of the TRI metabolism, and the metabolites produced may have two opposing roles: one inducing hepatotoxicity and the other protecting against the toxicity. Intermediate metabolite(s) from TRI to chloral hydrate produced by CYP2E1-mediated oxidation may be involved in the former, and TCA in the latter.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1096-0333
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
231
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
300-7
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Molecular mechanism of trichloroethylene-induced hepatotoxicity mediated by CYP2E1.
pubmed:affiliation
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Japan.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't