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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Beyer, RP; Fry, RC; Lasarev, MR; McConnachie, LA; Meira, LB; Palmer, VS; Powell, CL; Ross, PK; Bammler, TK; Bradford, BU; Cranson, AB; Cunningham, ML; Fannin, RD; Higgins, GM; Hurban, P; Kayton, RJ; Kerr, KF; Kosyk, O; Lobenhofer, EK; Sieber, SO; Vliet, PA; Weis, BK; Wolfinger, R; Woods, CG; Freedman, JH; Linney, E; Kaufmann, WK; Kavanagh, TJ; Paules, RS; Rusyn, I; Samson, LD; Spencer, PS; Suk, W; Tennant, RJ; Zarbl, H; Members of the Toxicogenomics Research Consortium,

Published Date

  • September 2007

Published In

Volume / Issue

  • 99 / 1

Start / End Page

  • 326 - 337

PubMed ID

  • 17562736

Pubmed Central ID

  • 17562736

International Standard Serial Number (ISSN)

  • 1096-6080

Digital Object Identifier (DOI)

  • 10.1093/toxsci/kfm150

Language

  • eng

Conference Location

  • United States