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Chem Res Toxicol. 2011 May 16;24(5):744-51. doi: 10.1021/tx200033v. Epub 2011 Apr 21.

Profiling the reactive metabolites of xenobiotics using metabolomic technologies.

Author information

1
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160, United States.

Abstract

A predominant pathway of xenobiotic-induced toxicity is initiated by bioactivation. Characterizing reactive intermediates will provide information on the structure of reactive species, thereby defining a potential bioactivation mechanism. Because most reactive metabolites are not stable, it is difficult to detect them directly. Reactive metabolites can form adducts with trapping reagents, such as glutathione, which makes the reactive metabolites detectable. However, it is challenging to "fish" these adducts out from a complex biological matrix, especially for adducts generated via uncommon metabolic pathways. In this regard, we developed a novel approach based upon metabolomic technologies to screen trapped reactive metabolites. The bioactivation of pulegone, acetaminophen, and clozapine were reexamined by using this metabolomic approach. In all these cases, a large number of trapped reactive metabolites were readily identified. These data indicate that this metabolomic approach is an efficient tool to profile xenobiotic bioactivation.

PMID:
21469730
PMCID:
PMC3100669
DOI:
10.1021/tx200033v
[Indexed for MEDLINE]
Free PMC Article

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