Skip Navigation



ToxSci Advance Access published online on June 23, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi235
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
87/1/296    most recent
kfi235v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Minami, K.
Right arrow Articles by Yokoi, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Minami, K.
Right arrow Articles by Yokoi, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received May 27, 2005
Accepted June 2, 2005

Risk Assessment

Relationship between hepatic gene expression profiles and hepatotoxicity in five typical hepatotoxicant-administered rats

Keiichi Minami 1, Toshiro Saito 2, Masatoshi Narahara 2, Hiroyuki Tomita 2, Hirokazu Kato 2, Hisashi Sugiyama 2, Miki Katoh 1, Miki Nakajima 1, and Tsuyoshi Yokoi 1*

1 Division of Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
2 Life science group, Hitachi Ltd., Saitama, Japan

* To whom correspondence should be addressed.
Tsuyoshi Yokoi, E-mail: TYOKOI{at}kenroku.kanazawa-u.ac.jp


  Abstract

In the field of gene expression analysis, DNA microarray technology has a major impact on many different areas including toxicogenomics, such as in predicting the adverse effects of new drug candidates and improving the process of risk assessment and safety evaluation. In this study, we investigated whether there is relationship between the hepatotoxic phenotypes and gene expression profiles of hepatotoxic chemicals measured by DNA microarray analyses. Sprague-Dawley rats (6 weeks old) were administered 5 hepatotoxicants: acetaminophen (APAP), bromobenzene, carbon tetrachloride, dimethylnitrosamine, and thioacetamide. Serum biochemical markers for liver toxicity were measured to estimate the maximal toxic time of each chemical. Hepatic mRNA was isolated and the gene expression profiles were analysed by DNA microarray containing 1,097 drug response genes, such as cytochrome P450s, other phase I and phase II enzymes, nuclear receptors, signal transducers, and transporters. All the chemicals tested generated specific gene expression patterns. APAP was sorted to a different cluster from the other 4 chemicals. From the gene expression profiles and maximal toxic time estimated by serum biochemical markers, we identified 10 up-regulated genes and 10 down-regulated genes as potential markers of hepatotoxicity. By Quality-Threshold (QT) clustering analysis, we identified major up- and down-regulated expression patterns in each group. Interestingly, the average gene expression patterns from the QT clustering were correlated with the mean value profiles from the biochemical markers. Furthermore, this correlation was observed at any extent of hepatotoxicity. In this study, we identified 17 potential toxicity markers and those expression profiles could estimate the maximal toxic time independently of the hepatotoxicity levels. This expression profile analysis could be one of the useful tools for evaluating a potential hepatotoxicant in the drug development process.

Keywords: gene expression profiles; hepatotoxicity; DNA microarray.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 International Journal of ToxicologyHome page
C. Dieterich, D. Iglehart, E. Riccio, J. C. Mirsalis, and H. H. Ng
Microarray Evaluation of the Listeria monocytogenes Infection and Amoxicillin Treatment in Mice
International Journal of Toxicology, May 1, 2008; 27(3): 265 - 272.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
M. R. Fielden, A. Nie, M. McMillian, C. S. Elangbam, B. A. Trela, Y. Yang, R. T. Dunn II, Y. Dragan, R. Fransson-Stehen, M. Bogdanffy, et al.
Interlaboratory Evaluation of Genomic Signatures for Predicting Carcinogenicity in the Rat
Toxicol. Sci., May 1, 2008; 103(1): 28 - 34.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
N. Zidek, J. Hellmann, P.-J. Kramer, and P. G. Hewitt
Acute Hepatotoxicity: A Predictive Model Based on Focused Illumina Microarrays
Toxicol. Sci., September 1, 2007; 99(1): 289 - 302.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.