Linked Life Data

17879390

Source:http://linkedlifedata.com/resource/pubmed/id/17879390

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
20
pubmed:dateCreated
2007-10-3
pubmed:abstractText
Carbamazepine (CBZ)-induced idiosyncratic toxicities are commonly believed to be related to the formation of reactive metabolites. CBZ is metabolized primarily into carbamazepine-10,11-epoxide (CBZE), 2-hydroxycarbamazepine (2-OHCBZ) and 3-hydroxycarbamazepine (3-OHCBZ), in human liver microsomes (HLM). Over the past two decades, the 2,3-arene oxidation has been commonly assumed to be the major bioactivation pathway of CBZ. Recently, CBZE has been also confirmed to be chemically reactive. In order to identify other possible primary and sequential CBZ bioactivation pathways, individual HLM incubations of CBZ, CBZE, 2-OHCBZ and 3-OHCBZ were conducted in the presence of glutathione (GSH). In the CBZ incubation, a variety of GSH adducts were formed via individual or combined pathways of 10,11-epoxidation, arene oxidation and iminoquinone formation. In the CBZE incubation, the only detected GSH adducts were CBZE-SG1 and CBZE-SG2, which represented the two most abundant conjugates observed in the CBZ incubation. In the incubation of either 2-OHCBZ or 3-OHCBZ, a number of sequential GSH adducts were observed. However, none of the 2-OHCBZ-derived GSH adducts were detected in the CBZ incubation. Meanwhile, several GSH adducts were only observed in the CBZ incubation. In conclusion, CBZ can be bioactivated in HLM via 10,11-epoxidation, 2,3-arene oxidation, and several other pathways. In addition, the sequential bioactivation of 3-OHCBZ appeared to play a more important role than that of either CBZE or 2-OHCBZ in the overall bioactivation of CBZ in HLM. The identification of several new bioactivation pathways of CBZ in HLM demonstrates that possible CBZ bioactivation can be more complex than previously thought.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0951-4198
pubmed:author
pubmed:copyrightInfo
Copyright (c) 2007 John Wiley & Sons, Ltd.
pubmed:issnType
Print
pubmed:volume
21
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3317-22
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Identification of primary and sequential bioactivation pathways of carbamazepine in human liver microsomes using liquid chromatography/tandem mass spectrometry.
pubmed:affiliation
Department of Pharmacokinetics, Dynamics & Metabolism, Pfizer Global Research and Development, San Diego, CA 92121, USA. haizhi.bu@pfizer.com
pubmed:publicationType
Journal Article