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High-throughput respirometric assay identifies predictive toxicophore of mitochondrial injury.

Abstract：

:Many environmental chemicals and drugs negatively affect human health through deleterious effects on mitochondrial function. Currently there is no chemical library of mitochondrial toxicants, and no reliable methods for predicting mitochondrial toxicity. We hypothesized that discrete toxicophores defined by distinct chemical entities can identify previously unidentified mitochondrial toxicants. We used a respirometric assay to screen 1760 compounds (5 μM) from the LOPAC and ChemBridge DIVERSet libraries. Thirty-one of the assayed compounds decreased uncoupled respiration, a stress test for mitochondrial dysfunction, prior to a decrease in cell viability and reduced the oxygen consumption rate in isolated mitochondria. The mitochondrial toxicants were grouped by chemical similarity and two clusters containing four compounds each were identified. Cheminformatic analysis of one of the clusters identified previously uncharacterized mitochondrial toxicants from the ChemBridge DIVERSet. This approach will enable the identification of mitochondrial toxicants and advance the prediction of mitochondrial toxicity for both drug discovery and risk assessment.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Wills LP,Beeson GC,Trager RE,Lindsey CC,Beeson CC,Peterson YK,Schnellmann RG

doi

10.1016/j.taap.2013.06.014

subject

Has Abstract

pub_date

2013-10-15 00:00:00

pages

490-502

issue

2

eissn

0041-008X

issn

1096-0333

pii

S0041-008X(13)00287-1

journal_volume

272

pub_type

杂志文章

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