Linked Life Data

20297803

Source:http://linkedlifedata.com/resource/pubmed/id/20297803

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2010-5-17
pubmed:abstractText
The bioactivation of ticlopidine, a widely used antiplatelet drug, into reactive metabolites and their subsequent covalent binding to cellular macromolecules are thought to be involved in the occurrence of idiosyncratic hepatotoxicity in patients. In the present study, GSH/stable isotope-labeled GSH was used as the trapping agent to investigate the bioactivation pathways of ticlopidine in rat liver microsomes. The samples were analyzed by high-resolution linear ion trap/Orbitrap followed by multiple mass defect filtering (MDF). In total, 17 GSH adducts were detected, and a comprehensive profile for ticlopidine bioactivation has been proposed. The results show that ticlopidine can be directly bioactivated by rat P450s, forming GSH adducts through two major bioactivation pathways, thiophene-S-oxidation and thiophene epoxidation. These adducts were also formed substantially in human liver microsomes. Moreover, ticlopidine can be metabolized via multiple pathways before giving rise to reactive intermediates. The GSH adducts derived from epoxidation of the chlorophenyl moiety of ticlopide and bioactivation of N-dealkylated metabolites are reported here for the first time. The formation of a number of ticlopidine GSH adducts from diversified metabolic pathways mediated by P450s implies a high potential for protein binding and provides a conceivable link between the high reactivity of ticlopidine after bioactivation and the ticlopidine-induced toxicity. Additionally, the current approach has the following advantages as compared to previous high-resolution LC/MS methodologies. First, novel MDF utilized doubly charged ions as filter templates to detect the GSH adducts, mainly doubly charged in the ion source, resulting in broader detection coverage. Second, multiple mass defect filter templates were for the first time applied to reveal different classes of GSH adducts. Finally, a quick check of isotopic doublets and full examination of isotope fingerprints in the accurate mass were introduced to screen out false positives and enhance the identification of low abundant GSH adducts.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1520-5010
pubmed:author
pubmed:issnType
Electronic
pubmed:day
17
pubmed:volume
23
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
909-17
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Investigation of bioactivation of ticlopidine using linear ion trap/orbitrap mass spectrometry and an improved mass defect filtering technique.
pubmed:affiliation
Department of Biotransformation, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, New Jersey 08543, USA.
pubmed:publicationType
Journal Article