title: Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses.
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.
authors.affiliation: University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, Washington 98195, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lasarev
authors.forename: Lisa A
authors.initials: LA
authors.lastname: McConnachie
authors.forename: Lisiane B
authors.initials: LB
authors.lastname: Meira
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Palmer
authors.forename: Christine L
authors.initials: CL
authors.lastname: Powell
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Ross
authors.forename: Theo K
authors.initials: TK
authors.lastname: Bammler
authors.forename: Blair U
authors.initials: BU
authors.lastname: Bradford
authors.forename: Alex B
authors.initials: AB
authors.lastname: Cranson
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: Rickie D
authors.initials: RD
authors.lastname: Fannin
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Higgins
authors.forename: Patrick
authors.initials: P
authors.lastname: Hurban
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kayton
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Kerr
authors.forename: Oksana
authors.initials: O
authors.lastname: Kosyk
authors.forename: Edward K
authors.initials: EK
authors.lastname: Lobenhofer
authors.forename: Stella O
authors.initials: SO
authors.lastname: Sieber
authors.forename: Portia A
authors.initials: PA
authors.lastname: Vliet
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Weis
authors.forename: Russel
authors.initials: R
authors.lastname: Wolfinger
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Woods
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Freedman
authors.forename: Elwood
authors.initials: E
authors.lastname: Linney
authors.forename: William K
authors.initials: WK
authors.lastname: Kaufmann
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
authors.forename: Richard S
authors.initials: RS
authors.lastname: Paules
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
authors.forename: Leona D
authors.initials: LD
authors.lastname: Samson
authors.forename: Peter S
authors.initials: PS
authors.lastname: Spencer
authors.forename: William
authors.initials: W
authors.lastname: Suk
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Tennant
authors.forename: Helmut
authors.initials: H
authors.lastname: Zarbl
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D023381:Endpoint Determination; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling / Q000379:methods*; D044404:Genomic Islands; D023281:Genomics / Q000379:methods*; D007536:Isomerism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D015203:Reproducibility of Results; D055291:Salivary alpha-Amylases; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018712:Analgesics, Non-Narcotic; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D000082:Acetaminophen; C524799:Amy1 protein, mouse; D055291:Salivary alpha-Amylases