Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses

Richard P. Beyer, Rebecca C. Fry, Michael R. Lasarev, Lisa A. McConnachie, Lisiane B. Meira, Valerie S. Palmer, Christine L. Powell, Pamela K. Ross, Theo K. Bammler, Blair U. Bradford, Alex B. Cranson, Michael L. Cunningham, Rickie D. Fannin, Gregory M. Higgins, Patrick Hurban, Robert J. Kayton, Kathleen F. Kerr, Oksana Kosyk, Edward K. Lobenhofer, Stella O. SieberPortia A. Vliet, Brenda K. Weis, Russel Wolfinger, Courtney G. Woods, Jonathan H. Freedman, Elwood Linney, William K. Kaufmann, Terrance J. Kavanagh, Richard S. Paules, Ivan Rusyn, Leona D. Samson, Peter S. Spencer, William Suk, Raymond J. Tennant, Helmut Zarbl

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)326-337
Number of pages12
JournalToxicological Sciences
Volume99
Issue number1
DOIs
StatePublished - Sep 1 2007

Keywords

  • Liver injury
  • Phenotypic anchoring
  • Toxicogenomics

ASJC Scopus subject areas

  • Toxicology

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    Beyer, R. P., Fry, R. C., Lasarev, M. R., McConnachie, L. A., Meira, L. B., Palmer, V. S., Powell, C. L., Ross, P. K., Bammler, T. K., Bradford, B. U., Cranson, A. B., Cunningham, M. L., Fannin, R. D., Higgins, G. M., Hurban, P., Kayton, R. J., Kerr, K. F., Kosyk, O., Lobenhofer, E. K., ... Zarbl, H. (2007). Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses. Toxicological Sciences, 99(1), 326-337. https://doi.org/10.1093/toxsci/kfm150