Genomic indicators in the blood predict drug-induced liver injury

被引：37

作者：

Huang, J. ^{[2
,8
]}

Shi, W. ^{[3
]}

Zhang, J. ^{[4
]}

Chou, J. W. ^{[1
]}

Paules, R. S. ^{[5
]}

Gerrish, K. ^{[5
]}

Li, J. ^{[1
]}

Luo, J. ^{[4
]}

Wolfinger, R. D. ^{[6
]}

Bao, W. ^{[6
]}

Chu, T-M ^{[6
]}

Nikolsky, Y. ^{[3
]}

Nikolskaya, T. ^{[3
,11
]}

Dosymbekov, D. ^{[7
]}

Tsyganova, M. O. ^{[7
]}

Shi, L. ^{[8
]}

Fan, X. ^{[2
,8
]}

Corton, J. C. ^{[9
]}

Chen, M. ^{[8
]}

Cheng, Y. ^{[2
]}

Tong, W. ^{[8
]}

Fang, H. ^{[10
]}

Bushel, P. R. ^{[1
]}

机构：

[1] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA

[2] Zhejiang Univ, Coll Pharmaceut Sci, Pharmaceut Informat Inst, Hangzhou 310003, Zhejiang, Peoples R China

[3] GeneGO, St Joseph, MI USA

[4] Syst Analyt, Dept Bioinformat, Waltham, MA USA

[5] NIEHS, Microarray Grp, Res Triangle Pk, NC 27709 USA

[6] SAS, Genom Div, Cary, NC USA

[7] Russian Acad Sci, NI Vavilov Gen Genet Res Inst, Moscow, Russia

[8] US FDA, Ctr Toxicoinformat, Natl Ctr Toxicol Res, Jefferson, AR USA

[9] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA

[10] US FDA, Div Bioinformat, Z Tech Corp, NCTR, Jefferson, AR USA

[11] Russian Acad Sci, Inst Gen Genet, Syst Biol Lab, Moscow V71, Russia

来源：

PHARMACOGENOMICS JOURNAL | 2010年 / 10卷 / 04期

基金：

美国国家科学基金会;

关键词：

prediction; acetaminophen; blood; cross-tissue; liver injury; microarray gene expression; GENE-EXPRESSION PROFILES; SERUM BIOMARKERS; MICROARRAY; MECHANISMS; TOXICITY; HEPATOTOXICITY; NEUTROPHILS; SOFTWARE; PROTEOME; ORGAN;

D O I：

10.1038/tpj.2010.33

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genomic biomarkers for the detection of drug-induced liver injury (DILI) from blood are urgently needed for monitoring drug safety. We used a unique data set as part of the Food and Drug Administration led MicroArray Quality Control Phase-II (MAQC-II) project consisting of gene expression data from the two tissues (blood and liver) to test cross-tissue predictability of genomic indicators to a form of chemically induced liver injury. We then use the genomic indicators from the blood as biomarkers for prediction of acetaminophen-induced liver injury and show that the cross-tissue predictability of a response to the pharmaceutical agent (accuracy as high as 92.1%) is better than, or at least comparable to, that of non-therapeutic compounds. We provide a database of gene expression for the highly informative predictors, which brings biological context to the possible mechanisms involved in DILI. Pathway-based predictors were associated with inflammation, angiogenesis, Toll-like receptor signaling, apoptosis, and mitochondrial damage. The results show for the first time and support the hypothesis that genomic indicators in the blood can serve as potential diagnostic biomarkers predictive of DILI. The Pharmacogenomics Journal (2010) 10, 267-277; doi: 10.1038/tpj.2010.33

引用

页码：267 / 277

页数：11

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