Effects of hypolipidaemics cetaben and clofibrate on mitochondrial and peroxisomal enzymes of rat liver

Schön, Hans; Grgurin, Mario; Klune, Gerhard; Prager, Christiane; März, Richard; Legenstein, E; Böck, Peter; Kramar, R.

doi:10.1111/j.2042-7158.1994.tb03759.x

Cited by 15 publications

(4 citation statements)

References 30 publications

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“…The gene expression pattern of isocitrate dehydrogenase was different in the treatment with clofibrate and gemfibrozil. Previous studies have also shown that isocitrate dehydrogenase was activated by clofibrate [6,14], but we have found that the expression of isocitrate dehydrogenase is decreased by gemfibrozil (Table 1). Previous research has identified that cytochrome P450 subfamilies were induced by peroxisome proliferators in liver of male Sprague-Dawley rats [10].…”

Section: Resultsmentioning

confidence: 44%

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

Jung

Park

Hwang

et al. 2004

The Journal of Veterinary Medical Science

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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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Section: Resultsmentioning

confidence: 44%

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

Jung

Park

Hwang

et al. 2004

The Journal of Veterinary Medical Science

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“…Intracellular very-long-chain fatty acid uptake would have been blocked if an inhibition in gene expression of the latter enzyme had occurred [34] and hence would have dramatically inhibited the peroxisomal oxidizing activity. The induction of palmitoyl-CoA oxidase by CLO was established to be a stimulation of peroxisomal functioning [35]. Therefore, the higher activity of palmitoyl-CoA oxidase in EC group vs. CC was probably aimed at the degradation of the abnormally elevated concentration of Mead acid which so far has not been reported to have physiological function.…”

Section: Discussionmentioning

confidence: 91%

Peroxisomal Proliferation in Rat Liver and Essential Fatty Acid Deficiency

Rabetafika

Carreau

Goascogne

2002

J. Clin. Biochem. Nutr.

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SummaryThe effects of essential fatty acid (EFA) deficiency were studied on male Wistar rats membrane lipid composition, enzyme activities and proliferation of liver peroxisome by feeding the animals, during 4 weeks, with fat free diets supplemented or not with a peroxisome proliferator, clofibrate (CLO).In deficient (E) goup, peroxisomal membrane was characterized by higher level of total de nova synthesized unsaturated (n-9 and n-7 series) fatty acids and lower content of EFA (n-6 and n-3 series) and exhibited cholesterol (CHOL) to phospholipids (PLs) ratio diminution compared with that of control (C) group. Co-administration of CLO with the fat-free diet (EC group) enhanced the membrane uptake of n-9 fatty acids. Slight increase of membrane dihydroxyacetone-phosphate acyl-transferase (DHAP-AT) and decrease of palmitoyl-CoA synthetase activities were found in E group which featured normal-shaped peroxisomes.In EC group, enzyme inductions of peroxisomal pamitoyl-CoA oxidase and palmitoyl-CoA synthetase were slightly higher and significantly lower respectively compared with those of C group treated with CLO (CC group) whereas activity of DHAP-AT was stable. Identical marked proliferation of peroxisomes were observed in both groups.It is inferred that, despite the parallel alterations of membrane lipid composition and of enzyme activities of peroxisomes upon 4 weeks of EFA deficient-diet, the biogenesis and proliferation of the organelles were independently processed at a normal level. The possibility of homeostatic regulation and its physiological importance were discussed.

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“…Regardless of iron status, clofibrate treatment caused m-ACO activity to increase by 133%, while clofibrate also enhanced the activity of three rate-limiting enzymes in the TCA cycle, citrate synthase, nicotinamide-linked isocitrate de-hydrogenase, and ␣-ketoglutarate dehydrogenase, by 24, 54, and 153%, respectively (Prager et al, 1993;Schon et al, 1994). In the clofibrate-treated liver, the production of acetyl-CoA is elevated and leads to increased citrate formation via citrate synthase (Ball et al, 1979).…”

Section: Metabolic Adaptations Of M-acomentioning

confidence: 99%

Role of Hypolipidemic Drug Clofibrate in Altering Iron Regulatory Proteins IRP1 and IRP2 Activities and Hepatic Iron Metabolism in Rats Fed a Low-Iron Diet

Huang

Shaw

2002

Toxicology and Applied Pharmacology

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Effects of hypolipidaemics cetaben and clofibrate on mitochondrial and peroxisomal enzymes of rat liver

Cited by 15 publications

References 30 publications

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

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

Peroxisomal Proliferation in Rat Liver and Essential Fatty Acid Deficiency

Role of Hypolipidemic Drug Clofibrate in Altering Iron Regulatory Proteins IRP1 and IRP2 Activities and Hepatic Iron Metabolism in Rats Fed a Low-Iron Diet

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