Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses.
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.
Beyer
Richard P
RP
University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, Washington 98195, USA.
Fry
Rebecca C
RC
Lasarev
Michael R
MR
McConnachie
Lisa A
LA
Meira
Lisiane B
LB
Palmer
Valerie S
VS
Powell
Christine L
CL
Ross
Pamela K
PK
Bammler
Theo K
TK
Bradford
Blair U
BU
Cranson
Alex B
AB
Cunningham
Michael L
ML
Fannin
Rickie D
RD
Higgins
Gregory M
GM
Hurban
Patrick
P
Kayton
Robert J
RJ
Kerr
Kathleen F
KF
Kosyk
Oksana
O
Lobenhofer
Edward K
EK
Sieber
Stella O
SO
Vliet
Portia A
PA
Weis
Brenda K
BK
Wolfinger
Russel
R
Woods
Courtney G
CG
Freedman
Jonathan H
JH
Linney
Elwood
E
Kaufmann
William K
WK
Kavanagh
Terrance J
TJ
Paules
Richard S
RS
Rusyn
Ivan
I
Samson
Leona D
LD
Spencer
Peter S
PS
Suk
William
W
Tennant
Raymond J
RJ
Zarbl
Helmut
H
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
D018712:Analgesics, Non-Narcotic; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D000082:Acetaminophen; C524799:Amy1 protein, mouse; D055291:Salivary alpha-Amylases