Meta-Analysis of Large-Scale Toxicogenomic Data Finds Neuronal Regeneration Related Protein and Cathepsin D to Be Novel Biomarkers of Drug-Induced Toxicity.
Undesirable toxicity is one of the main reasons for withdrawing drugs from the market or eliminating them as candidates in clinical trials. Although numerous studies have attempted to identify biomarkers capable of predicting pharmacotoxicity, few have attempted to discover robust biomarkers that are coherent across various species and experimental settings. To identify such biomarkers, we conducted meta-analyses of massive gene expression profiles for 6,567 in vivo rat samples and 453 compounds. After applying rigorous feature reduction procedures, our analyses identified 18 genes to be related with toxicity upon comparisons of untreated versus treated and innocuous versus toxic specimens of kidney, liver and heart tissue. We then independently validated these genes in human cell lines. In doing so, we found several of these genes to be coherently regulated in both in vivo rat specimens and in human cell lines. Specifically, mRNA expression of neuronal regeneration-related protein was robustly down-regulated in both liver and kidney cells, while mRNA expression of cathepsin D was commonly up-regulated in liver cells after exposure to toxic concentrations of chemical compounds. Use of these novel toxicity biomarkers may enhance the efficiency of screening for safe lead compounds in early-phase drug development prior to animal testing.
Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Hyosil
H
Kim
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Ju-Hwa
JH
Kim
Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea.
So Youn
SY
Kim
Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea.
Deokyeon
D
Jo
Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea.
Ho Jun
HJ
Park
Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea.
Jihyun
J
Kim
Department of Genome Medicine and Science, School of Medicine, Gachon University, Incheon, Korea.
Sungwon
S
Jung
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Hyun Seok
HS
Kim
Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Korea.
KiYoung
K
Lee
D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D002402:Cathepsin D / Q000032:analysis*; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D009419:Nerve Tissue Proteins / Q000032:analysis*; D015513:Oncogene Proteins / Q000032:analysis*; D043922:Toxicogenetics
D015415:Biomarkers; C428027:NREP protein, human; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D002402:Cathepsin D