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ToxSci Advance Access published online on November 2, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl152
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received October 11, 2006
Accepted October 16, 2006

Systems Toxicology

A Toxicogenomic Approach Revealed Hepatic Gene Expression Changes Mechanistically Linked to Drug-Induced Hemolytic Anemia

Masatomo Rokushima 1 *, Kazuo Omi 1, Akiko Araki 1, Yoshimasa Kyokawa 2, Naoko Furukawa 2, Fumio Itoh 2, Kae Imura 2, Kumiko Takeuchi 2, Manabu Okada 2, Ikuo Kato 2, and Jun Ishizaki 1

1 Discovery Technologies 1, Discovery Research Laboratories, Shionogi & Co., Ltd. 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan
2 Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd. 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan

* To whom correspondence should be addressed.
Masatomo Rokushima, E-mail: masatomo.rokushima{at}shionogi.co.jp


  Abstract

A variety of pharmaceutical compounds causes hemolytic anemia as a significant adverse effect and this toxicity restricts the clinical utility of these drugs. In this study, we applied microarray technology to investigate hepatic gene expression changes associated with drug-induced hemolytic anemia, and to identify potential biomarker genes for this hematotoxicity. We treated female Sprague-Dawley rats with two hemolytic anemia-inducing compounds: phenylhydrazine and phenacetin. Hepatic gene expression profiles were obtained using a whole genome oligonucleotide microarray with pooled RNA samples from individual rats within each dose group, and analyzed in comparison with hepatic histopathology, hematology and blood chemistry data. We identified a small subset of genes that were commonly deregulated in all of the severe hemolytic conditions, some of which were considered to be involved in hepatic events characteristic of hemolytic anemia, such as hemoglobin biosynthesis, heme metabolism and phagocytosis. Among them we selected six up-regulated genes as putative biomarkers, and their expression changes from microarray measurements were confirmed by quantitative real-time PCR using RNAs from individual animals. They were Alas2, beta-glo, Eraf, Hmox1, Lgals3, and Rhced. Expression patterns of all of these genes showed high negative and positive correlation against erythrocyte counts and total bilirubin levels in circulation, respectively, suggesting that these genes may be the potential biomarkers for hemolytic anemia. These findings indicate that drug-induced hemolytic anemia may be detected based on hepatic changes in the expression of a subset of genes that are mechanistically linked to the hematotoxicity.

Keywords: toxicogenomics; microarray; hemolytic anemia; liver; biomarker.
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M. Rokushima, K. Omi, K. Imura, A. Araki, N. Furukawa, F. Itoh, M. Miyazaki, J. Yamamoto, M. Rokushima, M. Okada, et al.
Toxicogenomics of Drug-Induced Hemolytic Anemia by Analyzing Gene Expression Profiles in the Spleen
Toxicol. Sci., November 1, 2007; 100(1): 290 - 302.
[Abstract] [Full Text] [PDF]


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