Gene Expression Analysis of Peroxisome Proliferators- and Phenytoin-Induced Hepatotoxicity Using cDNA Microarray

Abstract

ABSTRACT. The recent DNA microarray technology enables us to understand a large number of gene expression profiling. The technology has potential possibility to comprehend mechanism of multiple genes were related to compounds which have toxicity in biological system. So, the toxicogenomics through this technology may be very powerful for understanding the effect of unknown toxic mechanisms in biological system. We have studied that the effect of compounds related to hepatotoxin in vivo system using DNA microarray and classified chemicals which have been well characterized. We have studied three compounds; 2 peroxisome proliferators: Clofibrate (ethyl-p-chlorophenoxyisobutyrate), gemfibrozil (5-2[2,5-dimethyl-phenoxy]2-2-dimethyl-pentanonic), and an antiepileptic drug: phenytoin (5,5-diphenylhydantoin). Male Sprague-Dawely VAF + albino rats of 5-6 weeks old were treated with each compound for 24 hr and 2 weeks. 4.8 K cDNA microarray in house has been used for gene expression profiling. We found that the clustering of gene expression had similarity like as the toxic phenotype of compounds. KEY WORDS: gene expression, microarray, peroxisome proliferators, phenytoin, toxicogenomics.J. Vet. Med. Sci. 66(11): 1329-1333, 2004 We are gaining information of numerous candidate genes that have been known and unknown their function in biological system through many projects has been done and are processing. Many techniques that are able to analyze many genes and proteins simultaneously in once are used to interpret the information. Microarray technology, one of them, permits the comparison of thousands of genes in different biological systems. Lately, microarray system has been used for the prediction of toxicity through gene expression induced toxicant [15,18] and has shown that compounds with similar toxic mechanisms produce similar changes in gene expression in vivo [5] and in vitro system [2]. As these results, many pharmaceutical companies and research groups are making databases of gene expression related to toxic mechanism induced by compounds that were well characterized. These collected databases of microarray associated with toxicity will shorten the toxicity evaluation steps that are often the rate-limiting step in the discovery and development of new pharmaceuticals.In this study, we have used cDNA microarray methods for analysis of the effect of 3 compounds related to hepatotoxin including 2 peroxisome proliferators: clofibrate (ethyl-p-chlorophenoxyisobutyrate), gemfibrozil (5-2[2, 5-dimethyl-phenoxy] 2-2-dimethyl-pentanonic), and an antiepileptic drug: phenytoin (5, 5-diphenylhydantoin). The peroxisome proliferators have been studied in many toxic study groups because most of peroxisome proliferators have hepatic toxicity. It has been shown that peroxisome proliferator activated receptors play a significant role in regulation of lipid metabolism, hepatic peroxisomal genes expression, insulin sensitivity and glucose homeostasis [8,9]. Also, it was known that phenytoin is an anticonvulsant and cardiac depressan...

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