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

High-throughput respirometric assay identifies predictive toxicophore of mitochondrial injury.
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高通量呼吸测定法可识别线粒体损伤的预测毒载体。

DOI:
10.1016/j.taap.2013.06.014
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发表时间:
2013
影响因子:
3.8
通讯作者:
Schnellmann,RickG
Schnellmann,RickG
中科院分区:
医学3区
文献类型:
--
作者:
Wills,LaurenP;Beeson,GydaC;Trager,RichardE;Lindsey,ChristopherC;Beeson,CraigC;Peterson,YuriK;Schnellmann,RickG

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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.
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