Gene expression profiling in rat liver treated with compounds inducing elevation of bilirubin.
We have constructed a large-scale transcriptome database of rat liver treated with various drugs. In an effort to identify a biomarker for the diagnosis of elevated total bilirubin (TBIL) and direct bilirubin (DBIL), we extracted 59 probe sets of rat hepatic genes from the data for seven typical drugs, gemfibrozil, phalloidin, colchicine, bendazac, rifampicin, cyclosporine A, and chlorpromazine, which induced this phenotype from 3 to 28 days of repeated administration in the present study. Principal component analysis (PCA) using these probes clearly separated dose- and time-dependent clusters in the treated groups from their controls. Eighteen more drugs in the database, reported to elevate TBIL and DBIL, were estimated by PCA using these probe sets. Of these, 12 drugs, that is methapyrilene, thioacetamide, ticlopidine, ethinyl estradiol, alpha-naphthylisothiocyanate, indomethacin, methyltestosterone, penicillamine, allyl alcohol, aspirin, iproniazid, and isoniazid were also separated from the control clusters, as were the seven typical drugs causing elevation of TBIL and DBIL. The principal component 1 (PC1) value showed high correlation with TBIL and DBIL. In the cases of colchicine, bendazac, chlorpromazine, gemfibrozil, and phalloidin, the possible elevation of TBIL and DBIL could be predicted by expression of these genes 24 h after single administration. We conclude that these identified 59 probe sets could be useful to diagnose the cause of elevation of TBIL and DBIL, and that toxicogenomics would be a promising approach for prediction of this type of toxicity.
Hirode
M
M
Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka, Japan. Hirode_Mitsuhiro@takeda.co.jp
Horinouchi
A
A
Uehara
T
T
Ono
A
A
Miyagishima
T
T
Yamada
H
H
Nagao
T
T
Ohno
Y
Y
Urushidani
T
T
D000818:Animals; D001663:Bilirubin / Q000096:biosynthesis*; D001774:Blood Chemical Analysis; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D020723:Glucuronic Acid / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D004364:Pharmaceutical Preparations / Q000378:metabolism; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D004364:Pharmaceutical Preparations; D020723:Glucuronic Acid; D001663:Bilirubin