Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Male Swiss-Webster mice were fed diets containing four hypolipidemic agents which are known to induce proliferation of hepatic peroxisomes. Treatment with all four drugs (clofibrate; its structural analogue, nafenopin; and two drugs structurally unrelated to clofibrate, tibric acid and Wy-14,643) produced a marked hepatomegaly in the mice. The extent of the increase in liver weight correlated well with the increases in total hepatic DNA and in the collective volume of hepatocyte peroxisomes. Treatment with these drugs also produced similar increases in the activities of peroxisome-associated enzymes. The most dramatic increases were noted in the activities of the short-chain (8- to 26-fold) and medium-chain (4- to 11-fold) carnitine acyltransferase. Significant increases were also noted in the activities of catalase (twofold to threefold), alpha-glycerophosphate dehydrogenase (twofold to threefold) and the long-chain carnitine acyltransferase (twofold to fourfold). Activity of the latter enzyme, however, is not known to be associated with peroxisome fractions. Concomitant administration of actinomycin D or cycloheximide with a single oral dose of clofibrate diminished the increases in liver weight and carnitine acyltransferase which occurred with clofibrate treatment alone. The finding that the major increase in activity of peroxisome enzymes occurred in those associated with metabolism of acyl CoA groups supports the hypothesis that the hypolipidemic action of the drugs and the proliferation of hepatic peroxisomes are related functions.
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PMID:The hepatic effects of hypolipidemic drugs (clofibrate, nafenopin, tibric acid, and Wy-14,643) on hepatic peroxisomes and peroxisome-associated enzymes. 62 9

The uricosuric drug benzbromarone (3,5-dibromo-4-hydroxyphenyl)-1-(2-ethyl-3-benzofuranyl)methanone, a benzofurane derivative, was studied for its effects on parameters related to hepatic peroxisome proliferation. Groups of male F-344 rats were fed either basal diet, the peroxisome proliferator clofibrate at 5000 ppm as a comparison compound, or benzbromarone at two doses, 1000 and 2000 ppm. Benzbromarone and clofibrate produced hepatomegaly and increases in the activities of catalase, acyl CoA oxidase, malate dehydrogenase, and glycerol-3-phosphate dehydrogenase. Benzbromarone and clofibrate also both induced similar histologic and ultrastructural changes in hepatocytes, including induction of peroxisomes. Therefore, benzbromarone acted as a peroxisome-proliferating agent in rats under these conditions. Benzbromarone differs from other peroxisome proliferators in its chemical structure, uricosuric action, and the morphology of liver peroxisomes that were induced by exposure.
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PMID:Toxicological studies on a benzofurane derivative. II. Demonstration of peroxisome proliferation in rat liver. 226 96

Bis(carboxymethylthio)-1.10 decane (BCMTD), a thiodicarboxylic acid, was shown to be a hypolipidemic peroxisome-proliferating drug as it: (a) decreased the total serum triacylglycerols and cholesterol; (b) induced hepatomegaly; (c) increased the peroxisomal beta-oxidation and catalase activity and the activities of the multiorganelle localized enzymes: palmitoyl-CoA synthetase, palmitoyl-CoA hydrolase, glycerophosphate acyltransferase; (d) decreased the carnitine palmitoyltransferase and urate oxidase activities; and (e) induced the bifunctional eonyl-CoA hydratase in peroxisomes. The present study has confirmed the effect of tiadenol administration on the activities of key enzymes involved in hepatic fatty acid metabolism in male rats. However, the hepatic pleiotropic response was more marked with the dicarboxylic acid than with its alcohol. In a separate dose-response study BCMTD was found to be a more potent inducer of peroxisomal beta-oxidation compared to tiadenol. BCMTD can be activated in vitro to its coenzyme A thioester by a dicarboxyl-CoA synthetase. In control and BCMTD-treated animals, the synthetase activity was found in all cellular fractions except the cytosolic. Whether the acyl-CoA thioesters of peroxisome-proliferating drugs may be mediators of peroxisomal proliferation should be considered.
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PMID:The hypolipidemic peroxisome-proliferating drug, bis(carboxymethylthio)-1.10 decane, a dicarboxylic metabolite of tiadenol, is activated to an acylcoenzyme A thioester. 230 62

The effects of bezafibrate on hepatic peroxisome-associated enzymes of rats, mice, guinea pigs, hamsters, rabbits, dogs and monkeys were examined. Dogs and monkeys were given bezafibrate orally at 30 mg/kg body wt daily for 2 weeks and at 125 mg/kg body wt daily for 13 weeks, respectively, and other species at 100 mg/kg daily for 2 weeks. In male rats, marked changes were observed in the activities of catalase (1.73-fold), D-amino acid oxidase (DAAO; 0.56-fold), fatty acyl-CoA oxidizing system (FAOS; 12.9-fold) and carnitine acetyltransferase (CAT; 35.8-fold); in female rats, the changes were less than in the males. In mice, there were no apparent sex differences in the responses of hepatic peroxisomal enzymes to bezafibrate and the increases in the activities of catalase, FAOS and CAT were 1.76-, 3.75- and 7.94-fold respectively. In guinea pigs, only slight increases in the activities of FAOS (3.00-fold) and CAT (2.83-fold) were observed. In hamsters, the increases in catalase, FAOS and CAT activities, were 1.23-, 2.19- and 2.77-fold respectively. Although rabbits and dogs showed slight increases in CAT activity, no significant response to the drug was observed in monkeys. Hepatomegaly and the increase of hepatic content of peroxisome proliferation-associated polypeptide (PPA-80), which has been recognized as a peroxisomal bifunctional protein in the fatty acid beta-oxidation pathway, were observed only in rats and mice. These results show that there were marked species differences in the effects of bezafibrate on hepatic peroxisomes, and that bezafibrate induced hepatic peroxisome proliferation in rodents, especially rats and mice.
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PMID:Species differences in the effects of bezafibrate, a hypolipidemic agent, on hepatic peroxisome-associated enzymes. 291 22

Rats were treated for 5 to 14 days with perfluoroacetate, perfluorobutyrate and perfluorooctanoate. Alterations in hepatic morphology with special reference to the peroxisomal compartment were investigated by light and electron microscopy following cytochemical staining of catalase activity with the alkaline 3,3'-diaminobenzidine medium. All three compounds induced hepatomegaly and peroxisome proliferation. Perfluorobutyrate and perfluorooctanoate were found to be more active than perfluoroacetate. Perfluorooctanoate-induced peroxisome proliferation was more prevalent in centrilobular than in periportal hepatocytes. Peroxisomes in centrilobular liver cells frequently were of round shape, exhibited diameters of up to 1.5 microns and were predominantly located within smooth endoplasmic reticulum-glycogen areas. In periportal cells, however, clusters of polymorphous peroxisomes ranging from 250 to 1,100 nm in diameter were observed at the periphery of smooth endoplasmic reticulum-glycogen regions. Peroxisome proliferation was accompanied by a change of peroxisomal and mitochondrial enzyme activities, in particular an increase in peroxisomal palmitoyl-CoA oxidation. Significant alterations in the concentration of peroxisomal matrix and membrane polypeptides were also noted. Within the first 2 days, perfluorooctanoate treatment exerted a strong hypolipidemic activity and both compounds perfluorooctanoate and perfluorobutyrate raised the level of hepatic free acid-soluble CoA nearly 10-fold as compared with control livers. The results suggest perfluorinated carboxylic acids to be model substances suitable to correlate biochemical and morphological parameters with the zonal heterogeneity of the peroxisomal compartment in rat liver. Due to the manifold hepatic effects, contact of humans with perfluorinated carboxylic acids or their metabolic precursors may represent a severe health risk.
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PMID:Biochemical effects and zonal heterogeneity of peroxisome proliferation induced by perfluorocarboxylic acids in rat liver. 292 63

A mild variant of Zellweger (cerebro-hepato-renal) syndrome was diagnosed in male and female siblings aged 7 and 2 years. They had mild facial dysmorphia, moderate psychomotor retardation, tapetoretinal degeneration, sensorineural deafness and hepatomegaly. Ultrastructural examination of a liver biopsy in the younger patient revealed the absence of recognizable peroxisomes. In both patients plasma levels of pipecolic acid, phytanic acid, trihydroxycoprostanoic acid and dihydroxycoprostanoic acid were elevated. The very long chain fatty acid C26:0 and the C26:0/C22:0 fatty acid ratio were elevated in plasma, but less than in classical Zellweger syndrome. In cultured fibroblasts, deficient acyl-CoA:dihydroxyacetone phosphate acyltransferase and increased concentrations of C26:0 as well as C26:1 very long chain fatty acids were found within the ranges previously established for patients with classical Zellweger syndrome. Particle-bound catalase was absent in fibroblasts. Despite the relatively mild clinical expression the biochemical abnormalities found in these patients are the result of a general peroxisomal dysfunction similar to the changes in classical Zellweger syndrome.
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PMID:A sibship with a mild variant of Zellweger syndrome. 312 83

The effect of some hypolipidemic agents, which are commercially available and those being developed, on certain biochemical values and on hepatic peroxisomal enzyme activities of rats were examined. Clofibrate (0.25% (w/w) in the diet), p-chlorophenoxy-isobutyryl-glycinamide (CGA) (0.25%), clinofibrate (0.1%), KCD-232 (0.1%) and MLM-160 (0.1%) increased the activities of peroxisomal fatty acyl-CoA oxidizing system, carnitine acetyltransferase, and mitochondrial carnitine palmitoyltransferase. Of peroxisomal enzymes, catalase activity was increased by the above agents, whereas the activities of D-amino acid oxidase and urate oxidase were decreased by clofibrate and CGA, and but were increased by KCD-232 and MLM-160 which are structurally unrelated to clofibrate. No influence on these enzyme activities by AL-369 and probucol treatments were observed. Hepatomegaly was induced by clofibrate, CGA, KCD-232 and MLM-160. Concerning serum lipid levels, clofibrate, CGA, clinofibrate, KCD-232 and MLM-160 decreased both cholesterol and triglyceride levels, whereas probucol decreased only cholesterol level. AL-369 had no influence on serum lipid levels under this condition using normolipemic rat. From these results, it was concluded that differing clofibrate and CGA, clinofibrate, MLM-160 and KCD-232 might not induce peroxisome proliferation in hepatic cells, although these have an influence on the enzyme composition of hepatic peroxisomes.
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PMID:Effects of some hypolipidemic agents on biochemical values and hepatic peroxisomal enzymes in rats: comparison of probucol, CGA, KCD-232, MLM-160, AL-369 and clinofibrate with clofibrate. 362 48

A 2-year-old boy had acute fever, malaise, and somnolence with hepatomegaly, increased blood ammonia content (338 microM), high SGOT, low blood glucose content, and mild acidosis. A liver biopsy showed diffuse accumulation of lipid droplets in swollen hepatocytes, and abnormal urinary metabolites included beta-hydroxy-beta-methyl glutarate (HMG), beta-methylglutaconate, beta-hydroxyisovalerate, and beta-methylglutaric and glutaric acids. In cultured skin fibroblasts and liver, beta-hydroxy-beta-methyl glutaryl CoA lyase activity was about 10% of normal. Therefore, a genetic deficiency of HMGCoA lyase activity can cause a clinical syndrome similar to that of Reye syndrome when the patient is stressed by an acute viral infection.
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PMID:Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome. 615 27

Gemfibrozil is a widely used hypolipidemic drug in humans that causes peroxisome proliferation and hepatocarcinogenesis in rodents. The induction of hepatomegaly and hepatic peroxisome proliferation (measured as peroxisomal acyl CoA oxidase activity), was determined and compared to another peroxisome proliferator, WY-14,643 (0.1% in the diet) in male F344 rats. In a 21-day study, dietary no-observable-effect and lowest-observable-effect levels of gemfibrozil for both hepatomegaly and peroxisome proliferation were 0.002% and 0.005%, respectively. In a 42-day study, dietary concentrations of 0.9-2.0% gemfibrozil induced a similar magnitude of hepatomegaly to WY-14,643 (2.3-fold) but a higher level of peroxisome proliferation (16-18-fold) than the maximum induction for WY-14,643 (13-fold). The plateau in magnitude of gemfibrozil-induced peroxisome proliferation across the 0.9-2.0% dietary concentrations was associated with a plateau in serum concentration of gemfibrozil (approximately 20 micrograms/ml), similar to concentrations reported in human subjects receiving oral gemfibrozil. These results indicate that maximal induction of peroxisome proliferation by gemfibrozil can exceed that of a more potent compound such as WY-14,643, and further suggest that maximal induction of peroxisome proliferation can be limited by steady-state serum concentrations. Moreover, the reported lack of hepatic responses to gemfibrozil in humans is unlikely to be the result of inefficacy or unavailability of this drug, compared to other peroxisome proliferators, in rodents.
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PMID:Gemfibrozil-induced peroxisome proliferation and hepatomegaly in male F344 rats. 749 72

The widely used broad leaf herbicide, dicamba, or Banvel, is similar in structure to xenobiotics which induce hepatic drug metabolism or proliferation of hepatic peroxisomes in rodents. The ability of xenobiotics to effect these hepatic changes often portends their positive outcomes in chronic bioassays. Dicamba's ability to induce hepatomegaly and peroxisome proliferation was studied in male and female Sprague-Dawley rats. Rats were placed on feed containing 0, 0.001, 0.01, 0.1, or 1% dicamba or 0.01% ciprofibrate for 3 weeks. Dicamba had no effect on relative liver weights or feed efficiency in either female or male rats at all doses tested. Dicamba, however, caused a statistically significant increase in peroxisomal beta-oxidation activity in liver homogenates from rats of both sexes fed 1% dicamba. Fatty acyl CoA-oxidase activity was increased in male rats fed 1% dicamba. A protein of M(r) 80 kDa was visible when liver homogenates of female or male rats fed 1% dicamba were subjected to SDS-PAGE. Lauric acid hydroxylase activity and CYP4A-reactive protein were increased in microsomes from male rats fed the highest level of dicamba. Moreover, dicamba was observed to transcriptionally upregulate the peroxisome proliferator-activated receptor (PPAR), a peroxisome proliferator sensitive receptor previously shown to be linked to the transcriptional regulation of a variety of peroxisome-specific enzymes. These studies show that dicamba is a peroxisome proliferator in rats. Although dicamba was not an efficacious inducer of peroxisomal enzymes in these rats, dicamba's ability to transcriptionally activate the PPAR and induce peroxisomal and related enzymes must be considered in the safety evaluation of this herbicide.
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PMID:The herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid) is a peroxisome proliferator in rats. 765 66


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