Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.99.3 (diaphorase)
 5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of clofibrate on the fine structure and drug-metabolizing capacity of livers of normolipidemic young adult virgin (YA) and hypercholesterolemic retired breeder (RB) male rats were measured by morphometric and biochemical procedures. The oral administration of clofibrate for 7 days significantly increased liver weight and reduced the cholesterol concentrations in the serum and liver tissue in both groups of animals. The hepatic triglyceride (TG) concentration and the volume of cytoplasmic lipid droplets, presumably TG, as well as the serum TG concentration, increased only in the drug-treated RB rats. Clofibrate treatment resulted in significant increases in the volumes of the hepatocytes and their constituent mitochondria and microbodies and caused a proliferation of the smooth-surfaced endoplasmic reticulum. Although the magnitude of the hypocholesterolemic response was considerably greater in the RB animals, the morphological changes were much more marked in the YA group. However, the surface area of the rough-surfaced endoplasmic reticulum was reduced in the livers of the drug-treated RB rats. NADPH cytochrome c reductase specific activity was significantly increased in both the RB and YA animals, but the concentration of cytochrome P-450 (per mg microsomal protein) increased only in the YA rats. Neither the cytochrome b5 concentration nor the rate of ethylmorphine N-demethylation was significantly affected by clofibrate administration. The results suggest that there is no positive correlation between the hypocholesterolemic response to clofibrate and the degree of subcellular changes in the hepatocytes and that this hypolipidemic drug elicits a minimal effect on the concentrations of the components of the hepatic microsomal drug-metabolizing system.
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PMID:A quantitative analysis of fine structure and drug metabolism in livers of clofibrate-treated young adult and retired breeder rats. 63 78

A study was made of the effect of chronic administration of the hypolipidemic drug clofibrate on the activity and intracellular localization of rat liver aldehyde dehydrogenase. The enzyme was assayed using several aliphatic and aromatic aldehydes. Clofibrate treatment caused a 1.5 to 2.3-fold increase in the liver specific aldehyde dehydrogenase activity. The induced enzyme has a high Km for acetaldehyde and was found to be located in peroxisomes and microsomes. Clofibrate did not alter the enzyme activity in the cytoplasmic fraction. The total peroxisomal aldehyde dehydrogenase activity increased 3 to 4-fold under the action of clofibrate. Disruption of the purified peroxisomes by the hypotonic treatment or in the alkaline conditions resulted in the release of catalase from the broken organelles, while aldehyde dehydrogenase as well as nucleoid-bound urate oxidase and the peroxisomal membrane marker NADH:cytochrome c reductase remained in the peroxisomal 'ghosts'. At the same time, treatment by Triton X-100 led to solubilization of the membrane-bound NADH:cytochrome c reductase and aldehyde dehydrogenase from intact peroxisomes and their 'ghosts'. These results indicate that aldehyde dehydrogenase is located in the peroxisomal membrane. The peroxisomal aldehyde dehydrogenase is active with different aliphatic and aromatic aldehydes, except for formaldehyde and glyceraldehyde. The enzyme Km values lie in the millimolar range for acetaldehyde, propionaldehyde, benzaldehyde and phenylacetaldehyde and in the micromolar range for nonanal. Both NAD and NADP serve as coenzymes for the enzyme. Aldehyde dehydrogenase was inhibited by disulfiram, N-ethylmaleimide and 5,5'-dithiobis(2-nitrobenzoic)acid. According to its basic kinetic properties peroxisomal aldehyde dehydrogenase seems to be similar to a clofibrate-induced microsomal enzyme. The functional role of both enzymes in the liver cells is discussed.
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PMID:Intraparticulate localization and some properties of a clofibrate-induced peroxisomal aldehyde dehydrogenase from rat liver. 399 98

The effect of clofibrate and ethanol in the rat was studied on the following aspects of lipid composition and metabolism: liver delta 5, delta 6 and delta 9 fatty acid desaturases, fatty acid synthetase and fatty acid desaturase microsomal electron transport chain activity and serum cholesterol, triacylglycerols and high (HDL), low (LDL) and very low density lipoprotein (VLDL) levels. Clofibrate administered for 9 days (0.3% W/W) did not modify the relative composition of liver phospholipids and cholesterol, but did diminish triacylglycerol levels increased by ethanol. This effect could be explained by the possible beta-adrenergic blocking properties of clofibrate or by an increased activity of peroxisomal beta-oxidation. Clofibrate also promoted a decrease in serum cholesterol and triacylglycerol levels, delta 6 desaturase activity and a suppression of the electron transport chain as measured by NADH cytochrome b5 reductase and NADH cytochrome c reductase. The drug increased delta 9 desaturase activity and fatty acid synthetase, while no effect could be found in delta 5 desaturase activity. The hypocholesterolenic effect of clofibrate can not be explained through the delta 6 desaturase inhibition, or the fatty acid synthetase enhancement. Ethanol increased the HDL and VLDL and lowered LDL serum concentrations, while clofibrate reversed these results. Considering that clofibrate could have antiatherosclerotic effect in the rat, it is difficult to explain it through these changes in lipoprotein levels, since according to Miller and Miller low HDL levels are predictive of coronary heart disease.
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PMID:Effect of clofibrate on fatty acid desaturation of rats treated with ethanol. 682 Dec 69

1 The effects of the hypolipidaemic agents ICI 53072 and clofibrate on cardiac output and its distribution to the hepatosplanchnic bed were determined by the use of radioactive microspheres in the rat. The effects of these agents on hepatic DNA content were compared with those of phenobarbitone. Also the effects of ICI 53072 on hepatic microsomal enzymes and bile flow were determined together with the effects of phenobarbitone. 2 ICI 53072 and clofibrate both increased liver size and liver blood flow. A daily dose of 25 mg kg-1 ICI 53072 for 5 days increased liver weight by 55% and liver blood flow by 43%, the latter by enhancing the proportion of cardiac output passing to the hepatosplanchnic bed. The increased liver blood flow with clofibrate (480 mg kg-1 daily for 5 days) was the result of greater cardiac output but the change (35%) was half the increase in liver weight. 3 Phenobarbitone (80 mg kg-1 daily for 5 days) produced a fall in DNA content per unit mass of liver but no change in hepatic DNA relative to body weight. ICI 53072 (25 mg kg-1 daily) increased hepatic DNA relative to body weight but by a lesser extent than it increased liver weight as a proportion of body weight; hence DNA content per unit mass of liver decreased. Clofibrate at three dose levels increased hepatic DNA relative to body weight but only one dose significantly decreased DNA content as a proportion of liver weight. 4 Phenobarbitone (80 mg kg-1 daily) increased bile flow whereas ICI 53072 (25 mg kg-1 daily) had no effect. Both treatments increased hepatic cytochrome P450 content and cytochrome c reductase activity. 5 It is concluded that phenobarbitone increases liver size by hepatocyte enlargement rather than cellular proliferation but that the hepatomegaly produced by the hypolipidaemic agents, at least at some doses, is due to a mixture of both processes. 6 It is further concluded that there is no simple relationship between the mechanism of hepatic enlargement resulting from drug treatment and changes in liver blood flow.
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PMID:Comparison of the effects of the hypolipidaemic agents ICI53072 and clofibrate with those of phenobarbitone on liver size, blood flow and DNA content in the rat. 683 62

The effects of three peroxisome proliferators on the mRNA levels for some mitochondrial inner-membrane proteins in rat liver were investigated. Clofibrate, perfluorooctanoic acid, and acetylsalicylic acid all increased the mRNA levels for the mitochondrial-encoded respiratory-chain components cytochrome c oxidase subunit I and NADH dehydrogenase subunit I. Mitochondrial 16S rRNA was also induced by clofibrate. The mRNA levels for the nuclear-encoded mitochondrial inner-membrane proteins adenine nucleotide translocator and cytochrome c1 were selectively induced by the different peroxisome proliferators. Malic enzyme, which is induced by thyroid hormone, was also induced by the three peroxisome proliferators tested. These effects are in some ways similar to those obtained with thyroid hormone.
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PMID:Thyromimetic action of the peroxisome proliferators clofibrate, perfluorooctanoic acid, and acetylsalicylic acid includes changes in mRNA levels for certain genes involved in mitochondrial biogenesis. 855 34