A toxicogenomic approach revealed hepatic gene expression changes mechanistically linked to drug-induced hemolytic anemia

被引:11
|
作者
Rokushima, Masatomo
Omi, Kazuo
Araki, Akiko
Kyokawa, Yoshimasa
Furukawa, Naoko
Itoh, Fumio
Imura, Kae
Takeuchi, Kumiko
Okada, Manabu
Kato, Ikuo
Ishizaki, Jun
机构
[1] Shionogi & Co Ltd, Discovery Technol 1, Discovery Res Labs, Fukushima Ku, Osaka 5530002, Japan
[2] Shionogi & Co Ltd, Dev Res Labs, Drug Safety Evaluat, Toyonaka, Osaka 5610825, Japan
关键词
toxicogenomics; microarray; hemolytic anemia; liver; biomarker;
D O I
10.1093/toxsci/kfl152
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
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 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 upregulated 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 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.
引用
收藏
页码:474 / 484
页数:11
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