This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Hirode, M Articles by Urushidani, T Search for Related Content PubMed PubMed Citation Articles by Hirode, M Articles by Urushidani, T Social Bookmarking                         What's this?

Gene expression profiling in rat liver treated with compounds inducing elevation of bilirubin

Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka, Japan; Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, JapanHirode_Mitsuhiro{at}takeda.co.jp

A Horinouchi

Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka, Japan; Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan

T Uehara

Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan

A Ono

Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan; National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan

T Miyagishima

Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan

H Yamada

Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan

T Nagao

Food Safety Commission of Japan, Chiyoda-ku, Tokyo, Japan

Y Ohno

Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan; National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan

T Urushidani

Toxicogenomics Informatics Project, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan; Department of Pathophysiology, Doshisha Women’s College of Liberal Arts, Kyotanabe, Kyoto, Japan

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.

Key Words: bilirubin • liver • principal component analysis • rat • toxicogenomics

Human & Experimental Toxicology, Vol. 28, No. 4, 231-244 (2009)
DOI: 10.1177/0960327109104528


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?