Compound cytotoxicity profiling using quantitative high-throughput screening.
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.
Xia
Menghang
M
NIH Chemical Genomics Center, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-3370, USA.
Huang
Ruili
R
Witt
Kristine L
KL
Southall
Noel
N
Fostel
Jennifer
J
Cho
Ming-Hsuang
MH
Jadhav
Ajit
A
Smith
Cynthia S
CS
Inglese
James
J
Portier
Christopher J
CJ
Tice
Raymond R
RR
Austin
Christopher P
CP
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D051381:Rats; D015203:Reproducibility of Results; D018675:Toxicity Tests / Q000379:methods*; D015262:Xenobiotics / Q000633:toxicity*
D015262:Xenobiotics