High-throughput respirometric assay identifies predictive toxicophore of mitochondrial injury

Lauren P. Wills, Gyda C. Beeson, Richard E. Trager, Christopher C. Lindsey, Craig C. Beeson, Yuri K. Peterson, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)490-502
Number of pages13
JournalToxicology and Applied Pharmacology
Volume272
Issue number2
DOIs
StatePublished - Oct 15 2013
Externally publishedYes

Keywords

  • ChemBridge
  • LOPAC
  • Mitochondria
  • Renal proximal tubule cells
  • Seahorse Biosciences Extracellular Flux
  • Toxicophore

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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