Xia Menghang, Huang Ruili, Witt Kristine L, Southall Noel, Fostel Jennifer, Cho Ming-Hsuang, Jadhav Ajit, Smith Cynthia S, Inglese James, Portier Christopher J, Tice Raymond R, Austin Christopher P
NIH Chemical Genomics Center, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-3370, USA.
Environ Health Perspect. 2008 Mar;116(3):284-91. doi: 10.1289/ehp.10727.
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.
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.
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.
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.
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.
通常使用基于动物的测试方法来评估化合物对人类产生不良健康影响的倾向。此类方法可能相对昂贵、通量较低，并且会给受试动物带来痛苦。此外，物种生物学差异可能会混淆对人类健康影响的推断。
国家毒理学计划和美国国立卫生研究院化学基因组学中心正在合作，以确定一系列基于细胞的筛选方法，对化合物进行优先排序以便进一步进行毒理学评估。
使用定量高通量筛选（qHTS）对1408种先前在一种或多种传统毒理学试验中测试过的化合物进行分析，以检测其在源自六种常见外源性毒性靶点（肝脏、血液、肾脏、神经、肺、皮肤）的13种人类和啮齿动物细胞类型中的细胞毒性。对选定的细胞毒性剂进行进一步测试以确定反应动力学。
这些化合物的qHTS产生了可靠且可重复的结果，这使得能够进行跨化合物、跨细胞类型和跨物种的比较。一些化合物在相似浓度下对所有细胞类型都具有细胞毒性，而其他化合物则表现出物种或细胞类型特异性的细胞毒性。人类和啮齿动物中密切相关的细胞类型以及类似的细胞类型常常表现出不同的细胞毒性模式。一些诱导相似细胞毒性水平的化合物在动力学研究中显示出不同的时间依赖性，这与已知的毒性机制一致。
使用qHTS对这个已知化合物大文库生成高质量的细胞毒性数据，证明了该方法在分析更广泛的试验和化合物方面的潜力，总体而言，这对于对化合物进行优先排序以便进一步进行毒理学评估、识别具有特定作用机制的化合物以及潜在地预测体内生物学反应可能具有重要价值。
