Linked Life Data

10869417

Source:http://linkedlifedata.com/resource/pubmed/id/10869417

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2000-7-14
pubmed:abstractText
Diallyl sulfone (DASO(2)) inhibits hepatic CYP2E1. In this investigation, we have tested the hypothesis that an epoxide formed from DASO(2) is responsible for inactivation of hepatic CYP2E1 in mice. An epoxide of DASO(2) (1,2-epoxypropyl-3, 3'-sulfonyl-1'-propene; DASO(3)) was synthesized and conjugated to glutathione (GSH) to produce the conjugates S-(1R,S-[[ 1-hydroxymethyl-2,3'-sulfonyl]-1'-propenyl]ethyl)glutathione (diastereomers) and S-(1-[[2R,S-hydroxypropyl]-3, 3'-sulfonyl]-1'-propenyl)glutathione (diastereomers). Their identities were confirmed by (1)H NMR analysis, and these were used as analytical standards. HPLC analysis revealed a major peak for the GSH conjugates that eluted at 20.5 min. This peak was detected in liver microsomal incubations performed with DASO(2) in the presence of NADPH. A similar peak also was detected in incubations of CYP2E1-expressed lymphoblastoid microsomes, NADPH and DASO(2). The generation of the epoxide-derived GSH conjugates in the microsomal incubations was concentration-dependent, and reached saturation at 0. 75 to 1.0 mM DASO(2). Formation of the conjugates was also time-dependent and peaked at 2.0 h after DASO(2). Levels of DASO(3) formed from DASO(2), as estimated by production of a 4-(p-nitrobenzyl)pyridine derivative, were maximal at 1 mM DASO(2) at 30 min. CYP2E1-dependent p-nitrophenol hydroxylase activity was decreased in microsomes incubated with DASO(2), with alterations that were proportional to the concentration of DASO(2) (0.25-1.0 mM) used. Dose-dependent decreases in hydroxylase activity also were found in microsomes from mice treated in vivo with DASO(2) (25-200 mg/kg). These DASO(2)-induced decreases corresponded with reduced amounts of immunodetectable CYP2E1. Levels of spectrally detectable P450 and heme were both diminished by DASO(2). These results supported the contention that an epoxide formed from DASO(2) mediates the inactivation of hepatic CYP2E1.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
293
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1112-20
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2000
pubmed:articleTitle
Inactivation of hepatic CYP2E1 by an epoxide of diallyl sulfone.
pubmed:affiliation
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't