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2007:
Beyer Richard P; Fry Rebecca C; Lasarev Michael R; McConnachie Lisa A; Meira Lisiane B; Palmer Valerie S; Powell Christine L; Ross Pamela K; Bammler Theo K; Bradford Blair U; Cranson Alex B; Cunningham Michael L; Fannin Rickie D; Higgins Gregory M; Hurban Patrick; Kayton Robert J; Kerr Kathleen F; Kosyk Oksana; Lobenhofer Edward K; Sieber Stella O; Vliet Portia A; Weis Brenda K; Wolfinger Russel; Woods Courtney G; Freedman Jonathan H; Linney Elwood; Kaufmann William K; Kavanagh Terrance J; Paules Richard S; Rusyn Ivan; Samson Leona D; Spencer Peter S; Suk William; Tennant Raymond J; Zarbl Helmut;
Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses.
Toxicological sciences : an official journal of the Society of Toxicology 2007;
99(
1):.
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.
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