Compound cytotoxicity profiling using quantitative high-throughput screening.
Compound cytotoxicity profiling using quantitative high-throughput screening.
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DOI：
10.1289/ehp.10727
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发表时间：
2008-03
影响因子：
10.4
通讯作者：
Austin CP
中科院分区：
文献类型：
--
作者：
Xia M;Huang R;Witt KL;Southall N;Fostel J;Cho MH;Jadhav A;Smith CS;Inglese J;Portier CJ;Tice RR;Austin CP
化合物对人体产生不良健康影响的倾向通常使用基于动物的试验方法进行评价。这样的方法可能相对昂贵、低通量，并且与被治疗的动物所遭受的疼痛相关。此外，物种生物学的差异可能混淆对人类健康影响的外推。美国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确定一组基于细胞的筛选，以优先考虑化合物进行进一步的毒理学评估。使用定量高通量筛选（qHTS），对先前在一种或多种传统毒理学试验中检测的1，408种化合物的集合进行细胞毒性分析，这些化合物来源于六种常见的外源性毒性靶点（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。进一步测试选定的细胞毒性剂以确定响应动力学。这些化合物的qHTS产生稳健且可重现的结果，其允许跨化合物、跨细胞类型和跨物种比较。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，而另一些化合物则表现出种属或细胞类型特异性细胞毒性。人类和啮齿动物中密切相关的细胞类型和类似细胞类型经常显示出不同的细胞毒性模式。一些化合物诱导类似水平的细胞毒性在动力学研究中表现出明显的时间依赖性，与已知的毒性机制一致。使用qHTS在这个已知化合物的大型库上生成高质量的细胞毒性数据证明了这种方法分析更广泛的测定和化合物的潜力，总的来说，这对于优先考虑化合物进行进一步毒理学评价、鉴定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是有价值的。
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.
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DOI：
10.1073/pnas.81.20.6413
发表时间：
1984-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
HOSHI, H;MCKEEHAN, WL
通讯作者：
MCKEEHAN, WL
影响因子：
4.5
作者：
Knasmüller, S;Mersch-Sundermann, V;Majer, BJ
通讯作者：
Majer, BJ
影响因子：
2.1
作者：
Jellinger, Kurt A.
通讯作者：
Jellinger, Kurt A.
影响因子：
2.2
作者：
CROUCH, SPM;KOZLOWSKI, R;FLETCHER, J
通讯作者：
FLETCHER, J
DOI：
10.1016/j.mrgentox.2005.06.011
发表时间：
2005-11-10
影响因子：
1.9
作者：
Biswas, SJ;Khuda-Bukhsh, AR
通讯作者：
Khuda-Bukhsh, AR