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)

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

Overproduction of the hepatitis B virus (HBV) large envelope polypeptide by transgenic mice containing the entire HBV envelope coding region leads to the formation of extremely long (up to 800 nm), occasionally branching, filamentous 22-nm-diameter hepatitis B surface antigen particles that accumulate within the endoplasmic reticulum of the hepatocyte and are not efficiently secreted. As the endoplasmic reticulum expands to accommodate the increasing cellular filament stores, the hepatocytes become enlarged, hydropic, and eosinophilic and also display the characteristic features of "ground-glass" cells. As filament storage progresses, the ground-glass cells undergo coagulative necrosis and the mice develop an age-dependent lesion, whose severity is related to the intracellular concentration of envelope polypeptide, that is characterized by focal hepatocellular degeneration and necrosis, lobular macrophagic inflammation, and increased serum transaminase activity. Advanced lesions demonstrate hepatocellular hyperplasia evident as lobular architectural disarray and microscopic hepatocellular nodules, many of which no longer contain detectable HBV envelope antigens. These changes may become extreme, producing a massively enlarged liver due to multifocal nodular regenerative hyperplasia. Overproduction of the large HBV envelope polypeptide exerts major structural constraints on HBV particle formation, leading to reduced secretion and progressive intracellular accumulation of hepatitis B surface antigen, which can reach sufficiently high concentrations to be directly cytotoxic to hepatocytes in this transgenic mouse system.
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PMID:Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. 347 14

The short-term effects of citral on the liver have been studied in two strains of rat. Hepatomegaly was accompanied in citral-treated rats by an altered distribution of lipid and glycogen in the liver and peroxisome proliferation occurred in a manner reminiscent of that associated with some hypolipidaemic compounds. Specific biochemical markers supported the morphological changes in the peroxisomes. Cyanide-insensitive palmitoyl CoA oxidation showed, at the maximum, fourfold and threefold inductions in Wistar albino and Long Evans hooded rats, respectively. In addition, induction of cytochrome P-450 levels was greater in the Long Evans than in the Wistar rats, the maximal increases recorded being 81 and 27% respectively. A peroxisome-associated polypeptide of molecular weight 80,000 daltons (PPA-80) was induced, especially in Long Evans rats. No alterations in plasma triglycerides or total cholesterol were detected. The differential induction of the mixed-function oxidase system and the differential proliferation of peroxisomes in these two strains of rat suggest that citral may be metabolized differently in the two strains. The study indicates that peroxisomal and possibly also mitochondrial changes are involved in the action of citral on lipid metabolism.
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PMID:Comparison of the short-term hepatic effects of orally administered citral in Long Evans hooded and Wistar albino rats. 362 39

The hypolipidaemic agents ciprofibrate and Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid) and the phthalate-ester plasticizer di-(2-ethylhexyl)-phthalate (DEHP), like other peroxisome proliferators, produce a significant hepatomegaly and induce the peroxisomal fatty acid beta-oxidation enzyme system together with profound proliferation of peroxisomes in hepatic parenchymal cells. Changes in the profile of liver proteins in rats following induction of peroxisome proliferation by ciprofibrate, Wy-14,643 and DEHP have been analysed by high-resolution two-dimensional gel electrophoresis. The proteins of whole liver homogenates from normal and peroxisome-proliferator-treated rats were separated by two-dimensional gel electrophoresis using isoelectric focusing for acidic proteins and nonequilibrium pH gradient electrophoresis for basic proteins. In the whole liver homogenates, the quantities of six proteins in acidic gels and six proteins in the basic gels increased following induction of peroxisome proliferation. Peroxisome proliferator administration caused a repression of three acidic proteins in the liver homogenates. By the immunoblot method using polyspecific antiserum against soluble peroxisomal proteins and monospecific antiserum against peroxisome proliferation associated Mr 80000 polypeptide (polypeptide PPA-80), the majority of basic proteins induced by these peroxisome proliferators appeared to be peroxisomal proteins. Polypeptide PPA-80 becomes the most abundant protein in the total liver homogenates of peroxisome-proliferator-treated rats. These results indicate that ciprofibrate, DEHP and Wy-14,643 induce marked changes in the profile of specific hepatic proteins and that some of these changes should serve as a baseline to identify a set of gene products that may assist in defining the specific 'peroxisome proliferator domain'.
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PMID:Specific changes in the protein composition of rat liver in response to the peroxisome proliferators ciprofibrate, Wy-14,643 and di-(2-ethylhexyl)phthalate. 400 98

A study was made of the association of actin with different plasma membrane fractions from liver of normal rats and from the enlarged liver of rats bearing a Walker 256 carcinoma where a decrease in the state of polymerisation of cytoplasmic actin has been previously observed. As estimated by the DNAase I inhibition assay, actin constituted approx. 7% and 3%, respectively, of the protein of membrane fractions enriched in lateral or bile-canalicular domains, but only trace amounts were found in the sinusoidal fraction. [3H]Cytochalasin B binding indicated the presence of 20 and 13 pmol of high-affinity binding sites per mg protein in lateral and bile-canalicular fractions, but none in the sinusoidal. Kd for cytochalasin B binding was of the order of 1 nM for lateral and bile-canalicular fractions. Polypeptide profiles obtained by SDS/urea/polyacrylamide gel electrophoresis of non-ionic detergent-insoluble residues differed for all three fractions although some proteins, including actin, occurred as major components of both bile-canalicular and lateral regions. Tumour growth had no effect on the actin content, high-affinity cytochalasin B binding or polypeptide profiles of the three membrane fractions.
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PMID:Plasma membrane associated actin in liver of normal and tumour-bearing rats. 405 15

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

The demonstration of acquired isolated factor X deficiency and of a biclonal homogeneous lambda and kappa light polypeptide chain proteinuria in a patient of 49 years having an obscure hepatomegaly gave clinical evidence for the rate, amyloidosis-associated factor X deficiency, which could be proven by postmortem examination. The mechanisms by which amyloid may affect factor X levels in this case may be preferentially binding to the amyloid fibrils of lambda light chain type.
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PMID:Acquired isolated factor X deficiency associated with systemic amyloidosis. Case report and review of literature. 744 86

X-linked liver glycogenosis (XLG) due to liver phosphorylase kinase (PHK) deficiency is the most frequent liver glycogen storage disease. The affected patients present in early childhood with hepatomegaly and growth retardation. We isolated and determined the structure of human liver alpha subunit of PHK (PHKA2) cDNA. The 3705 base pair open reading frame encodes a polypeptide of 1235 amino acid residues, and the deduced amino acid sequence shows 93 and 68% homology to that of rabbit liver alpha subunit of PHK and human muscle alpha subunit of PHK, respectively. We identified a missense mutation, a valine substitution for glycine at amino acid 193, in the PHKA2 gene of a family with XLG.
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PMID:Isolation of cDNA encoding the human liver phosphorylase kinase alpha subunit (PHKA2) and identification of a missense mutation of the PHKA2 gene in a family with liver phosphorylase kinase deficiency. 754 48

Dehydroepiandrosterone (DHEA) is a newly identified peroxisome proliferator that causes hepatomegaly, peroxisome proliferation, and induction of peroxisome-associated enzymes in rats and mice, and hepatocellular carcinomas in rats. In the present study, we have systematically analyzed sex differences and the effect of castration on DHEA-induced peroxisome proliferation in male and female rats, since no information is available on this subject. DHEA was fed in diet at a concentration of 0.45% for 2 weeks and livers were analyzed for hepatomegaly, peroxisome volume density, peroxisome proliferator associated Mr 80,000 polypeptide (PPA-80), and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (PBE) mRNA. Both intact and castrated rats showed similar response to DHEA characterized by increased peroxisome volume density, PBE mRNA, and PPA-80. Significant difference was observed in the liver weights between castrated and intact animals in both the sexes. Castrated rats that received DHEA had 20%-30% more liver weight than DHEA-administered intact rats. These results clearly indicate that peroxisome proliferative effect of DHEA is not influenced by sex hormones and it is equally potent in both males and females.
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PMID:Dehydroepiandrosterone-induced peroxisome proliferation in the rat: evaluation of sex differences. 793 49

Glucosidase I is an important enzyme in N-linked glycoprotein processing, removing specifically distal alpha-1,2-linked glucose from the Glc3Man9GlcNAc2 precursor after its en bloc transfer from dolichyl diphosphate to a nascent polypeptide chain in the endoplasmic reticulum. We have identified a glucosidase I defect in a neonate with severe generalized hypotonia and dysmorphic features. The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d. The accumulation of the tetrasaccharide Glc(alpha1-2)Glc(alpha1-3)Glc(alpha1-3)Man in the patient's urine indicated a glycosylation disorder. Enzymological studies on liver tissue and cultured skin fibroblasts revealed a severe glucosidase I deficiency. The residual activity was <3% of that of controls. Glucosidase I activities in cultured skin fibroblasts from both parents were found to be 50% of those of controls. Tissues from the patient subjected to SDS-PAGE followed by immunoblotting revealed strongly decreased amounts of glucosidase I protein in the homogenate of the liver, and a less-severe decrease in cultured skin fibroblasts. Molecular studies showed that the patient was a compound heterozygote for two missense mutations in the glucosidase I gene: (1) one allele harbored a G-->C transition at nucleotide (nt) 1587, resulting in the substitution of Arg at position 486 by Thr (R486T), and (2) on the other allele a T-->C transition at nt 2085 resulted in the substitution of Phe at position 652 by Leu (F652L). The mother was heterozygous for the G-->C transition, whereas the father was heterozygous for the T-->C transition. These base changes were not seen in 100 control DNA samples. A causal relationship between the alpha-glucosidase I deficiency and the disease is postulated.
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PMID:A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. 1078 35


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