UMLS:C0019209 - FACTA Search

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

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

Young male Sprague-Dawley rats and Syrian hamsters were treated with 25-1000 mg/kg/day di-(2-ethylhexyl) phthalate (DEHP) orally for 14 days. Liver enlargement was observed in both species, the magnitude being greater in the rat than in the hamster. In the rat there was a marked dose-dependent induction of the peroxisomal marker cyanide-insensitive palmitoyl-CoA oxidation and also of carnitine acetyltransferase. Little effect was observed on the mitochondrial markers carnitine palmitoyltransferase and succinate dehydrogenase. Whereas in the rat, increased peroxisomal enzyme activities were observed after treatment with 100 and 250 mg/kg/day DEHP, much less effect was observed in the hamster even after 1000 mg/kg/day DEHP. Parallel morphological investigations demonstrated a greater increase in hepatic peroxisome numbers in the rat than in the hamster. 14C-labeled DEHP was found to be more rapidly hydrolyzed by rat than hamster hepatic and small intestinal mucosal cell preparations and differences were also observed in the absorption and excretion of oral doses of [14C]DEHP. Studies with mono-(2-ethylhexyl) phthalate (MEHP), a primary metabolite of DEHP, and a hypolipidemic drug clofibrate also resulted in a greater increase in hepatic peroxisomal enzymes in the rat compared to the hamster. The results demonstrate that while DEHP, MEHP, and clofibrate induced hepatic peroxisome proliferation in both species, there was a marked species difference in response. Comparative long-term studies in these species may thus help to clarify the role of peroxisome proliferation in the hepatocarcinogenicity of DEHP.
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PMID:Comparative studies on di-(2-ethylhexyl) phthalate-induced hepatic peroxisome proliferation in the rat and hamster. 671 Apr 84

1. The time-course of the effect of clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on lipid plasma levels and palmitoyl-CoA hydrolase and synthetase activities, as well as the correlations with the peroxisomal proliferation phenomenon have been studied in male Sprague-Dawley rats. 2. The administration of the three drugs caused a significant reduction in body weight gain, accompanied with a paradoxical increase in food intake in groups treated with BFB and GFB. 3. Drug treatment produced gross hepatomegaly and increase in peroxisomal beta-oxidation, and these parameters were strongly correlated. The order of potency was BFB > CFB > or = GFB. 4. Both plasma cholesterol (BFB approximately CFB > GFB) and triglyceride (BFB approximately GFB > CFB) levels were reduced in treated animals. There was an inverse correlation between these parameters and peroxisomal beta-oxidation, although the peroxisomal proliferation seemed to explain only a small part of the hypolipidemic effect observed. 5. Cytosolic and microsomal (but not mitochondrial) palmitoyl-CoA hydrolase activities were increased by the three drugs (BFB > CFB > GFB), probably by inducing the hydrolase I isoform, which is insensitive to inhibition by fibrates in vitro. The increased hydrolase activities were directly and strongly correlated with peroxisomal beta-oxidation. 6. Palmitoyl-CoA synthetase activity was also increased by the treatment with fibrates (BFB > CFB > GFB), probably as a consequence of the enhancement of hydrolase activities. 7. Some of the effects of fibrate treatment can be explained, at least in part, in terms of peroxisomal induction and caution should be exercised in the extrapolation of these results to species, such as man,that are insensitive to peroxisomal proliferation.
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PMID:Relationship between plasma lipids and palmitoyl-CoA hydrolase and synthetase activities with peroxisomal proliferation in rats treated with fibrates. 791 11

Male Wistar rats were treated with a low (150 mumol/kg) and a high (750 mumol/kg) dose of either clotrimazole of bifonazole. Bifonazole, but not clotrimazole, exhibited the characteristics of a peroxisome proliferator including hepatomegaly (increase in liver:body weight ratio), up to a 4-fold induction of lauric acid omega-hydroxylase activity and an 8-fold induction of palmitoyl-CoA oxidation by rat liver peroxisomes. This induction of enzyme activities was paralleled by increased protein levels as determined by immunochemical analysis for both liver microsomal cytochrome P4504A1 and the peroxisomal trifunctional protein of the beta-oxidation spiral. In contrast, clotrimazole did not increase protein levels of either cytochrome P4504A or the trifunctional protein. Western blot analyses demonstrated that bifonazole also induced P4502B1/2B2, P4503A and P4501A1, but not P4502E1. Clotrimazole induced a similar spectrum of P450s as determined by Western blotting with the exception that this azole was a marginal P4501A1 inducer under the conditions studied. Taken collectively, our data provides evidence that bifonazole is one of the increasingly recognised, non-carboxylate containing xenobiotics that induce both peroxisome proliferation and the cytochrome P4504A sub-family in rat liver.
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PMID:Bifonazole, but not the structurally-related clotrimazole, induces both peroxisome proliferation and members of the cytochrome P4504A sub-family in rat liver. 857 91

The effects of zileuton, a 5-lipoxygenase inhibitor, on hepatic peroxisomal enzyme activity as well as hepatic drug metabolizing activity in male and female CD-1 mice were assessed after oral administration of the drug (50, 150, or 450 mg/kg/day) for 14 days. The effects were compared to those in mice receiving clofibrate (CLOF;462 mg/kg/day, po) or sodium phenobarbital (PB; 50 mg/kg/day, po). Zileuton pretreatment caused hepatomegaly and elevated liver peroxisomal KCN-insensitive palmitoyl CoA oxidase activity in a dose-dependent manner. However, these changes were marginal (< or = 121% increase), when compared to those elicited by CLOF (approximately 370% increase). In both sexes, zileuton pretreatment also caused a dose-dependent increase in the levels of liver microsomal cytochrome P450 2B and cytochrome P450 4A (CYP4A) proteins, and their associated monoxygenase activity. In the case of CYP4A, the induction of lauric acid 12-hydroxylase activity by zileuton was more pronounced in female (maximal 851% increase) than in male mice (maximal 111% increase). Based on the dose normalized response observed in CD-1 mice, zileuton can be considered a relatively weak inducer of peroxisome enzyme activities (cf.CLOF) and a moderate inducer of cytochromes P450. Moreover, zileuton exhibits characteristics of both a PB- and a CLOF-type hepatic enzyme inducer, especially in the female mice.
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PMID:Hepatic peroxisomal and drug metabolizing activity in CD-1 mice after oral treatment with a novel 5-lipoxygenase inhibitor. 866 44

This report presents new data on mammalian peroxisomes by studying an unusual rodent: the jerboa (Jaculus orientalis). This animal exhibits some unique peroxisomal properties compared to the rat, such as higher cyanide-insensitive palmitoyl-CoA oxidase specific activity, pattern differences in SDS-PAGE peroxisomal proteins as well as in acyl-CoA oxidase immunoblotting. There is also a peculiar response to a peroxisome proliferator, ciprofibrate. With 250 ppm of ciprofibrate in the diet for 2 weeks, we observed a limited liver peroxisome proliferation as well as a palmitoyl-CoA oxidase activity, enzyme content and mRNA increase. However, there was no increase in catalase activity, nor hepatomegaly which are prominent features of peroxisome proliferation in rats treated under the same conditions. The palmitoyl-CoA oxidase activity increase was weak in the kidney and not observed in the heart. Other subcellular organelle marker enzyme activities did not significantly change, especially the mitochondrial D-3-hydroxybutyrate and succinate dehydrogenases, lysosomal acid phosphatase, cytosolic lactate dehydrogenase and the endoplasmic reticulum NADPH-cytochrome c reductase. However, the activity of the liver membrane endoplasmic reticulum linked omega-lauryl hydroxylase (cytochrome P450 IV A1) increases after ciprofibrate treatment. Jerboa also behaves differently compared to the guinea pig after ciprofibrate treatment since the guinea pig has a weak response towards peroxisome proliferators. In conclusion, this first peroxisome study utilizing a different type of rodent as a laboratory animal, reveals that the jerboa shows unique peroxisome properties and responds in a moderate manner to a peroxisome proliferator, ciprofibrate, without leading to any increase in liver mass. This supports the fact that fibrate molecules may have different targets depending upon the species.
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PMID:Properties of peroxisomes from jerboa (Jaculus orientalis). 879 87

Male and female CD rats were administered one of two dose levels of clofibrate, gemfibrozil, or bezafibrate daily by oral gavage for a period of 14 days in order to establish an empirical data base using the Charles River CD rat with a single class of drugs against which the potency of novel proprietary compounds could be compared. Subsequent gross examination of the liver indicated significant and dose-related increases in relative and absolute liver weights in males following clofibrate and gemfibrozil. In females, absolute and relative liver weights were significantly elevated to a similar degree with either dose of gemfibrozil, and absolute liver weights were higher in clofibrate-dosed animals. Bezafibrate had no effect on female liver weights. Clofibrate and gemfibrozil increased hepatic palmitoyl CoA beta-oxidation in both sexes; however, clofibrate had the greater effect in males and gemfibrozil had the least effect in females. Bezafibrate treatment resulted in a very pronounced elevation of palmitoyl CoA beta-oxidation in the males but had no similar effect in the females. Concurrent ELISA analysis for cytochrome CYP4A revealed very good correspondence between beta-oxidation and cytochrome induction for each of the three compounds in males, but other cytochromes were not greatly affected, except CYP1A1 which was elevated in bezafibrate-dosed females. For males, further analysis for markers of cellular proliferation, namely cyclin-dependent kinases (CDK) and proliferating cell nuclear antigen (PCNA), indicated dose-related increases for both with clofibrate, increases at the high dose for gemfibrozil, and, for PCNA, a dose-related increase for bezafibrate. In females, both markers for cell proliferation showed either slight or no increases following any of the three drug treatments. These results demonstrate clear sex-dependent differences in terms of relative potency in the hepatic response of the Sprague-Dawley-derived rat to these peroxisome proliferators. Bezafibrate is most potent and gemfibrozil is least potent in stimulating peroxisome-associated beta-oxidation and cytochrome P450 4A induction in the males. Even though gemfibrozil significantly increased liver weights, beta-oxidation and cytochrome P450 4A in the females increased only after clofibrate treatment, although to a lesser degree than in the males administered the same dose. Similar sex-related differences were observed for cell proliferation. In conclusion, sex-related differences were noted in the potency to stimulate acyl Co-A oxidation, its association with hepatomegaly, and the stimulation of cell proliferation, but CYP4A induction always accompanied any substantial drug-dependent increases in beta-oxidation.
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PMID:Hepatic microsomal enzyme induction, beta-oxidation, and cell proliferation following administration of clofibrate, gemfibrozil, or bezafibrate in the CD rat. 900 43

Four male and three female marmosets in each group were exposed to air only, 1000 ppm of HCFC 225ca or 5000 ppm of HCFC 225cb, for 6 h per day for 28 consecutive days. HCFC 225ca caused a slight reduction in body weight. HCFC 225cb occasionally caused somnolence during exposure and vomiting on the first day of exposure. Clinical chemistry findings included a mild reduction of triglyceride, cholesterol and phospholipid levels and increased GOT level in the HCFC 225ca exposure group. HCFC 225cb also caused a reduction of triglyceride levels in some animals. HCFC 225ca caused a slight increase of hepatic carnitine palmitoyltransferase (CPT) activity while HCFC 225cb slightly increased cyanide-insensitive palmitoyl CoA beta-oxidation (FAOS) activity. In the HCFC 225cb exposure group, an increase in cytochrome P-450 content was also observed. HCFC 225ca caused a fatty change in the hepatic cells. Increased incidence of lipid droplets in the hepatic cells and myelin-like bodies in hepatic cells, Kupffer's cells and hepatic blood vessels were observed electron microscopically in the HCFC 225ca exposure group. A proliferation of smooth endoplasmic reticulum was observed in the HCFC 225cb exposure group. Decreased peroxisome volume density in the HCFC 225ca group, and increased volume density in the HCFC 225cb exposed females were seen. However, organ weight measurement and histopathological examination did not reveal hepatomegaly or hypertrophy with either substance. Although slight changes were noticed in peroxisome volume density and in some of the peroxisomal enzyme activities, the changes related to peroxisome proliferation with HCFC 225ca and 225cb were minimal in marmosets compared to those seen in rats. Histopathological examination and hormonal analysis did not reveal any abnormalities in the pancreas or testes.
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PMID:Four-week repeated inhalation study of HCFC 225ca and HCFC 225cb in the common marmoset. 933 32

The purpose of the workshop "Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?" was to provide a review of the current state of the science on the relationship between peroxisome proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce liver tumors in rats and mice and whether these events occur in humans. A primary goal of the workshop was to determine where consensus might be reached regarding the interpretation of these data relative to the assessment of potential human risks. A core set of biochemical and cellular events has been identified in the rodent strains that are susceptible to the hepatocarcinogenic effects of peroxisome proliferators, including peroxisome proliferation, increases in fatty acyl-CoA oxidase levels, microsomal fatty acid oxidation, excess production of hydrogen peroxide, increases in rates of cell proliferation, and expression and activation of the alpha subtype of the peroxisome proliferator-activated receptor (PPAR-alpha). Such effects have not been identified clinically in liver biopsies from humans exposed to peroxisome proliferators or in in vitro studies with human hepatocytes, although PPAR-alpha is expressed at a very low level in human liver. Consensus was reached regarding the significant intermediary roles of cell proliferation and PPAR-alpha receptor expression and activation in tumor formation. Information considered necessary for characterizing a compound as a peroxisome proliferating hepatocarcinogen include hepatomegaly, enhanced cell proliferation, and an increase in hepatic acyl-CoA oxidase and/or palmitoyl-CoA oxidation levels. Given the lack of genotoxic potential of most peroxisome proliferating agents, and since humans appear likely to be refractive or insensitive to the tumorigenic response, risk assessments based on tumor data may not be appropriate. However, nontumor data on intermediate endpoints would provide appropriate toxicological endpoints to determine a point of departure such as the LED10 or NOAEL which would be the basis for a margin-of-exposure (MOE) risk assessment approach. Pertinent factors to be considered in the MOE evaluation would include the slope of the dose-response curve at the point of departure, the background exposure levels, and variability in the human response. Copyright 1998 Academic Press.
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PMID:Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? 961 23

The purpose of the workshop "Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?" was to provide a review of the current state of the science on the relationship between peroxisome proliferation and hepatocarcinogenesis. There has been much debate regarding the mechanism by which peroxisome proliferators may induce liver tumors in rats and mice and whether these events occur in humans. A primary goal of the workshop was to determine where consensus might be reached regarding the interpretation of these data relative to the assessment of potential human risks. A core set of biochemical and cellular events has been identified in the rodent strains that are susceptible to the hepatocarcinogenic effects of peroxisome proliferators, including peroxisome proliferation, increases in fatty acyl-CoA oxidase levels, microsomal fatty acid oxidation, excess production of hydrogen peroxide, increases in rates of cell proliferation, and expression and activation of the alpha subtype of the peroxisome proliferator-activated receptor (PPAR-alpha). Such effects have not been identified clinically in liver biopsies from humans exposed to peroxisome proliferators or in in vitro studies with human hepatocytes, although PPAR-alpha is expressed at a very low level in human liver. Consensus was reached regarding the significant intermediary roles of cell proliferation and PPAR-alpha receptor expression and activation in tumor formation. Information considered necessary for characterizing a compound as a peroxisome proliferating hepatocarcinogen include hepatomegaly, enhanced cell proliferation, and an increase in hepatic acyl-CoA oxidase and/or palmitoyl-CoA oxidation levels. Given the lack of genotoxic potential of most peroxisome proliferating agents, and since humans appear likely to be refractive or insensitive to the tumorigenic response, risk assessments based on tumor data may not be appropriate. However, nontumor data on intermediate endpoints would provide appropriate toxicological endpoints to determine a point of departure such as the LED10 or NOAEL which would be the basis for a margin-of-exposure (MOE) risk assessment approach. Pertinent factors to be considered in the MOE evaluation would include the slope of the dose-response curve at the point of departure, the background exposure levels, and variability in the human response.
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PMID:Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? 962 96

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