title: Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential.
abstract: BACKGROUND
  Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of disorders including cancer, diabetes, and neurodegenerative and cardiovascular diseases. Understanding whether different environmental chemicals and druglike molecules impact mitochondrial function represents an initial step in predicting exposure-related toxicity and defining a possible role for such compounds in the onset of various diseases.
  
  
  OBJECTIVE
  We sought to identify individual chemicals and general structural features associated with changes in mitochondrial membrane potential (MMP).
  
  
  METHODS
  We used a multiplexed [two end points in one screen; MMP and adenosine triphosphate (ATP) content] quantitative high throughput screening (qHTS) approach combined with informatics tools to screen the Tox21 library of 10,000 compounds (~ 8,300 unique chemicals) at 15 concentrations each in triplicate to identify chemicals and structural features that are associated with changes in MMP in HepG2 cells.
  
  
  RESULTS
  Approximately 11% of the compounds (913 unique compounds) decreased MMP after 1 hr of treatment without affecting cell viability (ATP content). In addition, 309 compounds decreased MMP over a concentration range that also produced measurable cytotoxicity [half maximal inhibitory concentration (IC50) in MMP assay/IC50 in viability assay ≤ 3; p < 0.05]. More than 11% of the structural clusters that constitute the Tox21 library (76 of 651 clusters) were significantly enriched for compounds that decreased the MMP.
  
  
  CONCLUSIONS
  Our multiplexed qHTS approach allowed us to generate a robust and reliable data set to evaluate the ability of thousands of drugs and environmental compounds to decrease MMP. The use of structure-based clustering analysis allowed us to identify molecular features that are likely responsible for the observed activity.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, Maryland, USA.
authors.forename: Matias S
authors.initials: MS
authors.lastname: Attene-Ramos
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Sam
authors.initials: S
authors.lastname: Michael
authors.forename: Kristine L
authors.initials: KL
authors.lastname: Witt
authors.forename: Ann
authors.initials: A
authors.lastname: Richard
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tice
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D056945:Hep G2 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D018675:Toxicity Tests
chemical_list: D004785:Environmental Pollutants; D000255:Adenosine Triphosphate