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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many structurally unrelated hypolipidemic agents and certain phthalate-ester plasticizers induce hepatomegaly and proliferation of peroxisomes in liver parenchymal cells of rodents, but there is relatively limited evidence regarding the ability of such compounds to induce peroxisome proliferation in the livers of nonrodent species including man. The present study was designed to determine if DL-040 (4-(((1,3-benzodioxol)-5-yl)methyl)amino-benzoic acid), a newly developed hypolipidemic agent, induces peroxisome proliferation in the liver of adult rhesus monkeys. Feeding of DL-040 (300 mg/kg body wt for 1 week; and 400 mg/kg body wt for 10 weeks) caused a significant increase in peroxisome population as determined by ultrastructural and morphometric analyses. The DL-040-induced peroxisome proliferation was accompanied by increases in the levels of catalase, carnitine acetyltransferase and the peroxisomal fatty acid beta-oxidation system. As expected, DL-040 caused a significant reduction of serum cholesterol and low density lipoprotein content. These data suggest that hepatic peroxisome proliferation is inducible in nonhuman primates at dose levels that exceed therapeutic levels.
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PMID:Induction of fatty acid beta-oxidation and peroxisome proliferation in the liver of rhesus monkeys by DL-040, a new hypolipidemic agent. 384 Mar 74

This study compares changes in the livers of rats treated with di(2-ethylhexyl) phthalate (DEHP) and its straight-chain analogs di(n-hexyl) phthalate (DnHP) and di(n-octyl phthalate (DnOP). Groups of rats were fed diets containing 20,000 ppm of one of these compounds. Subgroups were killed after 3, 10, and 21 days, and the livers were examined by histological, cytological, and biochemical methods. The results show considerable differences between the effects of the branched-chain phthalate ester DEHP and its straight-chain analogs. The major effects on the liver following administration of diets containing DEHP were midzonal and periportal accumulation of small droplets of lipid, hepatomegaly accompanied by an initial burst of mitosis, proliferation of hepatic peroxisomes and of smooth endoplasmic reticulum accompanied by induction of peroxisomal fatty acid oxidation, damage to the peroxisomal membranes as evidenced by increased leakage of catalase to the cytosol, and centrilobular loss of glycogen and falls in glucose-6-phosphatase activity and in low-molecular-weight reducing agents. In contrast, diets containing DnHP or DnOP induced accumulation of large droplets of fat around central veins leading, by 10 days, to mild centrilobular necrosis and a very slight induction of one peroxisomal enzyme and an increase in liver weight, but no significant changes in any other parameters which were affected by DEHP.
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PMID:Comparison of the short-term effects of di(2-ethylhexyl) phthalate, di(n-hexyl) phthalate, and di(n-octyl) phthalate in rats. 396 35

The antilipolytic drug acipimox (5-methylpyrazine-2-carboxylic acid 4-oxide) was given to male rats for 1 week at 500, 1000 and 2000 mg/kg/day and for 2, 6 and 7 months at 20, 100 and 500 mg/kg/day. The peroxisome proliferative effect was evaluated determining the activity of catalase and carnitine acetyltransferase, the rate of cyanide-insensitive palmitoyl CoA oxidation and the electrophoretic profile of liver polypeptides. Hepatic lipid content and distribution were evaluated after 2 and 6 months' treatment. The effect on liver detoxificating function was evaluated by assaying glutathione, cytochrome P-450, glutathione-S-transferase and glutathione-reductase activities after 7 months' treatment. Sub-acute and chronic treatment with a wide range of acipimox doses did not cause hepatomegaly, liver peroxisome proliferation or liver steatosis and did not change some important biochemical variables related to detoxification and biotransformation mechanisms. Acipimox given to rats does not have the negative side-effects of other compounds and seems a safe blood lipid lowering drug.
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PMID:Effect of the antilipolytic compound acipimox on peroxisome marker enzymes, lipid pattern and biotransformation related functions in rat liver. 407 Mar 42

It is well established that the administration to rodents of a variety of structurally diverse chemicals possessing hypotriglyceridemic properties results in hepatomegaly, the induction of hepatic peroxisome (microbody) proliferation, and the development of hepatocellular carcinomas. Studies have led to the hypothesis that persistent proliferation of peroxisomes serves as an endogenous initiator of neoplastic transformation in liver by increasing the intracellular production of H2O2 by the peroxisomal oxidase(s). The objective of the present study was to determine whether hepatic peroxisome proliferation can be induced in cats, chickens, pigeons, and two species of monkeys (rhesus and cynomolgus). The hypolipidemic drug ciprofibrate (2-[4-(2,2-dichloro-cylopropyl)phenoxyl]2-methylpropionic acid) induced peroxisome proliferation in the livers of cats (dose, greater than 40 mg/kg body weight for 4 weeks); chickens (dose greater than 25 mg/kg body weight for 4 weeks); pigeons (300 mg/kg body weight for 3 weeks), rhesus monkeys (50 to 200 mg/kg body weight for 7 weeks) and cynomolgus monkeys (400 mg/kg body weight for 4 weeks). In all five species examined in this study, a marked but variable increase in the activities of peroxisomal catalase, carnitine acetyltransferase, heat-labile enoyl-CoA hydratase, and the fatty acid beta-oxidation system was observed. These results suggest that peroxisome proliferation can be induced in the livers of several species and that it is a dose-dependent but not a species-specific phenomenon.
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PMID:Induction of hepatic peroxisome proliferation in nonrodent species, including primates. 669 13

There is a considerable interest in developing potent and safe hypolipidemic drugs for the prevention and management of coronary heart disease in man. In rodents, many of these hypolipidemic compounds induce hepatomegaly, proliferation of peroxisomes and a polypeptide with an approximate mol. wt. of 80000 in liver cells. In the present study, we have examined 10 hypolipidemic compounds for the induction of peroxisome proliferation associated 80000 mol. wt. polypeptide (polypeptide PPA-80), peroxisomal enzymes and peroxisome proliferation in rat liver, in view of the emerging evidence that hepatic peroxisome proliferators as a class are carcinogenic in rats and mice. All ten compounds, fenofibrate (isopropyl-[4-(p-chlorobenzoyl)2-phenoxy-2-methyl] propionate; LS 2265 (taurine derivative of fenofibrate); bezafibrate (2-(4-(2-[4-chlorobenzamido)ethyl] phenoxy)-methyl propionic acid; gemfibrozil (5-2[2,5-dimethylphenoxy]2-2-dimethylpentanoic acid); methyl clofenapate (methyl-2-[4-(p-chlorophenyl)phenoxy]-2-methyl propionate); DG 5685 (5-[4-phenoxybenzyl]trans-2-(3-pyridyl)1,3-dioxane); DH 6463 (5-[4-phenoxybenzyl] trans-2-(3-pyrimidinyl)-1,3-dioxane); tiadenol(bis[hydroxyethylthio]-7, 10-decane); ciprofibrate (2,-[4-(2,2-dichlorocyclopropyl)-phenoxy]2-methyl propionic acid) and RMI-14,514 ( [5-tetradecycloxy]-2-furancarboxylic acid), produced a marked but variable increase in the activities of peroxisomal enzymes catalase, carnitine acetyltransferase, heat-labile enoyl-CoA hydratase and the fatty acid beta-oxidation system and in the amount of polypeptide PPA-80 as demonstrated by SDS-polyacrylamide gel electrophoresis. The peptide map patterns of polypeptide PPA-80 in liver induced by these compounds were strikingly similar. The ultrastructural studies demonstrate that fenofibrate, ciprofibrate, LS 2265, DG 5685 and DH 6463 can induce proliferation of peroxisomes in liver cells of rats, and further confirm the previous reports of hepatic peroxisome proliferative activity of methyl clofenapate, tiadenol, bezafibrate, gemfibrozil and RMI-14514, as shown morphologically. Whether these structurally unrelated chemicals or their metabolite(s) directly activate the peroxisome specific genes to induce this multi-enzyme system or they exert their action on peroxisomes indirectly by causing fatty acid overload in hepatocytes remains to be elucidated. These chemicals offer a simple and reproducible means of stimulating peroxisomal enzymes in liver and should serve as useful tools, for evaluating the implications of hepatic peroxisome proliferation and in elucidating the mechanism of peroxisome proliferator-induced carcinogenesis.
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PMID:Evaluation of selected hypolipidemic agents for the induction of peroxisomal enzymes and peroxisome proliferation in the rat liver. 684 Jul 92

Hypolipidemic drugs increased 3- to 4-fold the activity of the peroxisomal beta-oxidation system in rat liver, with modest or no effects on catalase activity, liver weight, or peroxisome abundance. This specificity of action was observed in two experimental models: 1) bezafibrate treatment of male rats (25 mg/kg body wt., p.o.) and 2) clofibrate treatment of female rats (5 g/kg chow). Bezafibrate had no effect on the liver content of protein, catalase, or cytochrome oxidase, and little or no effect on mitochondrial beta-oxidation. The results indicate that the hypotriglyceridemic mechanism of action of these drugs involves an induction of the peroxisomal beta-oxidation system, but this mechanism does not obligatorily include gross hepatomegaly or other alterations of peroxisomes that are often caused by hypolipidemic compounds. This dissociation of specific biochemical changes from other effects demonstrates a precise regulation of organelle biogenesis. Peroxisomes synthesized under the influence of bezafibrate or clofibrate have a different enzymatic composition than do normal peroxisomes. These results have several implications. 1) Side effects of clofibrate that are of current clinical concern may be unrelated to its lipid-lowering effects. 2) Measurement of peroxisomal beta-oxidation should be a sensitive and specific tool for screening for new hypotriglyceridemic compounds. 3) Peroxisome proliferation or lack thereof is not central to efficacy. 4) Other new drugs may be discovered that are highly discriminating in elevating specific enzymes of fatty acid catabolism while causing even less or no hepatomegaly and other side effects.-Lazarow, P. B., H. Shio, and M. A. Leroy-Houyet. Specificity in the action of hypolipidemic drugs: increase of peroxisomal beta-oxidation largely dissociated from hepatomegaly and peroxisome proliferation in the rat.
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PMID:Specificity in the action of hypolipidemic drugs: increase of peroxisomal beta-oxidation largely dissociated from hepatomegaly and peroxisome proliferation in the rat. 707 46

A female newborn, the second child of healthy non consanguineous parents, exhibited muscular hypotonia, areflexia, apathy, seizures, hepatomegaly and failure to thrive since birth. The peculiar skull shape was lacking. In the urine pipecolic acid and trihydroxycoprostanoic acid were excreted. At the age of seven weeks she died of bronchopneumonia. Lightmicroscopy revealed malformations and deficiency of myelinisation in the brain, renal cysts and fatty metamorphosis in the enlarged liver, which showed only minimal siderosis. Ultrastructurally no peroxisomes could be found in liver and kidney. No peroxisomes were detected by histochemical demonstration of catalase in frozen liver tissue which was taken immediately after death and stored for three months. Absence of peroxisomes is pathognomonic for the cerebro-hepato-renal syndrome of Zellweger and occurs in the liver irrespective of duration and degree of liver damage. It is best demonstrated by enzymehistochemical electron microscopy. With this method peroxisomes can be visualized even 30 h post mortem. In deep frozen normal liver tissue the activity of catalase remains very stable and enables the identification of peroxisomes even after a 12 months period of storage. In the cerebro-hepato-renal syndrome of Zellweger, frozen liver tissue should be stored for biochemical and diagnostic enzymehistochemical studies.
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PMID:[Morphology and diagnosis of Zellweger syndrome. A contribution to combined cytochemical-finestructural identification of peroxisomes in autopsy material and frozen liver tissue with case report]. 734 41

An eleven month-old boy presented clinically with craniofacial dysmorphia, severe psychomotor retardation, neurological deterioration, no response to visual and acoustic stimuli, failure to thrive, hepatomegaly and adrenal insufficiency. Specific biochemical markers for a peroxisomal deficiency disorder (Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease) revealed pathological results for very long chain fatty acids, phytanic acid, pristanic acid, plasmalogen biosynthesis and catalase, thus confirming the clinical diagnosis. Comparison of clinical and biochemical findings in the patient with the characteristics of the three peroxisomal deficiency disorders showed overlapping with each of these disorders, which corresponds to the current view that these three peroxisomal disorders differ only with respect to onset and severity of the clinical manifestations, but not with regard to the biochemical defects.
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PMID:[Zellweger syndrome, neonatal adrenoleukodystrophy or infantile Refsum's disease in a case with generalized peroxisome defect?]. 768 5

In an effort to identify the effects of the 3-carbon compound pyruvate on free radical production, we measured hepatic total peroxisomal beta-oxidation and catalase activity and the production of lipofuscin-like products in male Sprague-Dawley rats consuming an adequate diet supplemented with pyruvate, vitamin E, or the peroxisome proliferator and free radical enhancer clofibrate for 22 days (n = 5 in each group). Clofibrate feeding induced hepatomegaly, a fivefold increase in total peroxisomal beta-oxidation activity, and a threefold increase in hepatic lipofuscin-like products (P < .05). Pyruvate but not vitamin E inhibited the increase in liver size by 70% (P < .05). Both pyruvate and vitamin E completely inhibited clofibrate-induced increases in lipofuscin-like products (P < .05). Pyruvate but not clofibrate or vitamin E increased plasma concentrations of the nitric oxide metabolites nitrite and nitrate (P < .05). We conclude that with clofibrate-induced peroxisomal proliferation and free radical production, pyruvate will inhibit peroxisomal proliferation and free radical production, inhibit free radical-induced lipid peroxidation, and enhance metabolism of nitric oxide.
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PMID:Pyruvate inhibits clofibrate-induced hepatic peroxisomal proliferation and free radical production in rats. 786 11

Three-week oral administration of 4-(decahydro-6-methyl-3-oxo-cyclopenta(f)quinoline-7-yl)valeric acid (32-1328) in the diet supplemented at concentrations of 0.1% or 0.3% was associated with hepatomegaly and hypotriglyceridemia in male F344 rats. Electron microscopic examination of the liver revealed a remarkable increase of peroxisomes in hepatocytes both in number and size. Biochemically, there were increased activities of peroxisomal marker enzymes including the heat-labile enoyl-CoA hydratase and catalase while the mitochondrial enoyl-CoA hydratase activity was unchanged after feeding of 32-1328. These findings indicate that 32-1328 can exert peroxisome-proliferating activity to rat liver in a manner similar to typical peroxisome proliferators such as clofibrate or di(2-ethylhexyl)phthalate.
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PMID:Peroxisome proliferation of hepatocytes in rats by a microbial degradation product of cholic acid, 4-(decahydro-6-methyl-3-oxocyclopenta(f)quinoline-7-yl)valeric acid. 798 70


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