Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses
Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses
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DOI：
10.1093/toxsci/kfm150
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发表时间：
2007-09-01
影响因子：
3.8
通讯作者：
Zarbl, Helmut
中科院分区：
文献类型：
--
作者：
Beyer, Richard P.;Fry, Rebecca C.;Zarbl, Helmut
基因表达谱分析是一种广泛使用的技术，大多数已发表的微阵列研究的数据都是公开的。这些数据被用于荟萃分析和计算机发现；然而，多个实验室生成的毒物基因组数据的可比性尚未经过严格评估。利用前瞻性多实验室研究的力量，七个中心分别进行了一项共同的毒物基因组学实验，旨在加深对急性毒性剂量的 N-乙酰对氨基苯酚 (APAP) 扰乱肝脏中的分子途径的了解，并揭示 APAP 诱导毒性的可重复基因组特征。非肝毒性 APAP 异构体 N-乙酰基-间氨基苯酚用于鉴定 APAP 特有的基因表达变化。我们的数据表明 c-Myc 是由 APAP 诱导的，并且以 c-Myc 为中心的相互作用组是与肝损伤相关的最重要的蛋白质网络。此外，通过将基因表达与毒性反应的广泛毒理学评估相结合，确定了各中心之间的误差和数据变异性来源以及适应这种变异性的方法。我们表明，基因表达数据的表型锚定对于毒性基因组实验的生物学意义分析是必需的。
Gene expression profiling is a widely used technique with data from the majority of published microarray studies being publicly available. These data are being used for meta-analyses and in silico discovery; however, the comparability of toxicogenomic data generated in multiple laboratories has not been critically evaluated. Using the power of prospective multilaboratory investigations, seven centers individually conducted a common toxicogenomics experiment designed to advance understanding of molecular pathways perturbed in liver by an acute toxic dose of N-acetyl p-aminophenol (APAP) and to uncover reproducible genomic signatures of APAP-induced toxicity. The nonhepatotoxic APAP isomer N-acetyl-m-aminophenol was used to identify gene expression changes unique to APAP Our data show that c-Myc is induced by APAP and that c-Myc-centered interactomes are the most significant networks of proteins associated with liver injury. Furthermore, sources of error and data variability among Centers and methods to accommodate this variability were identified by coupling gene expression with extensive toxicological evaluation of the toxic responses. We show that phenotypic anchoring of gene expression data is required for biologically meaningful analysis of toxicogenomic experiments.