| Compound Cytotoxicity Profiling Using Quantitative High-Throughput Screening Menghang Xia,1 Ruili Huang,1 Kristine L. Witt,2 Noel Southall,1 Jennifer Fostel,3 Ming-Hsuang Cho,1 Ajit Jadhav,1 Cynthia S. Smith,2 James Inglese,1 Christopher J. Portier,2 Raymond R. Tice,2 and Christopher P. Austin1 1NIH Chemical Genomics Center, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA; 2National Toxicology Program, and 3National Center for Toxicogenomics, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA Abstract
Background: The propensity of compounds to produce adverse health effects in humans is generally evaluated using animal-based test methods. Such methods can be relatively expensive, low-throughput, and associated with pain suffered by the treated animals. In addition, differences in species biology may confound extrapolation to human health effects. Objective: The National Toxicology Program and the National Institutes of Health Chemical Genomics Center are collaborating to identify a battery of cell-based screens to prioritize compounds for further toxicologic evaluation. Methods: A collection of 1,408 compounds previously tested in one or more traditional toxicologic assays were profiled for cytotoxicity using quantitative high-throughput screening (qHTS) in 13 human and rodent cell types derived from six common targets of xenobiotic toxicity (liver, blood, kidney, nerve, lung, skin) . Selected cytotoxicants were further tested to define response kinetics. Results: qHTS of these compounds produced robust and reproducible results, which allowed cross-compound, cross-cell type, and cross-species comparisons. Some compounds were cytotoxic to all cell types at similar concentrations, whereas others exhibited species- or cell type–specific cytotoxicity. Closely related cell types and analogous cell types in human and rodent frequently showed different patterns of cytotoxicity. Some compounds inducing similar levels of cytotoxicity showed distinct time dependence in kinetic studies, consistent with known mechanisms of toxicity. Conclusions: The generation of high-quality cytotoxicity data on this large library of known compounds using qHTS demonstrates the potential of this methodology to profile a much broader array of assays and compounds, which, in aggregate, may be valuable for prioritizing compounds for further toxicologic evaluation, identifying compounds with particular mechanisms of action, and potentially predicting in vivo biological response. Key words: 1, 536-well, cell viability, NTP 1, 408 compound library, PubChem, qHTS, RT-CES. Environ Health Perspect 116:284–291 (2008) . doi:10.1289/ehp.10727 available via http://dx.doi.org/ [Online 22 November 2007]
Address correspondence to C.P. Austin, Chemical Genomics Center, National Institutes of Health, 9800 Medical Center Dr., MSC 3370, Bethesda, MD 20892-3370 USA. Telephone: (301) 217-5733. Fax: (301) 217-5736. E-mail: austinc@mail.nih.gov We thank A. Yasgar and P. Shinn for the compound management. This research was supported by the Intramural Research Programs of the National Toxicology Program of the NIEHS, and the National Human Genome Research Institute of the NIH, and the NIH Roadmap for Medical Research Molecular Libraries Program The authors declare they have no competing financial interests. Received 31 July 2007 ; accepted 21 November 2007.
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