Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human urine and plasma extracts contain a material that inhibits the enzyme Na+,K(+)-ATPase (the endogenous sodium pump) and produces natriuresis in the bioassay animal. This endogenous sodium pump inhibitor(s), also known as digitalis-like factor, is thought to be involved in sodium and extracellular fluid volume homeostasis. Increased urine and plasma sodium pump inhibiting activity have been reported in patients with cirrhosis and sodium retention. The aim of the study was to assess the renal response to i.v. administration (0.2 ml/min per kg bw for 10 min) of a human urine extract containing sodium pump inhibiting activity (28.5 nmol equivalent ouabain/ml) in eight conscious rats with cirrhosis and ascites and eight control rats. Baseline urinary excretion of Na+,K(+)-ATPase inhibiting activity was significantly higher in cirrhotic rats with ascites than in control rats (235 +/- 40 vs 91 +/- 16; p < 0.01). Human urine extract induced a significant (p < 0.05) increase in glomerular filtration rate in control (3.2 +/- 0.4 to 4.2 +/- 0.5 ml/min) and cirrhotic rats (3.0 +/- 0.3 to 4.0 +/- 0.5 ml/min). In control rats it also increased urinary sodium excretion (1.47 +/- 0.22 to 2.43 +/- 0.5 microEq/min, p < 0.01) and fractional sodium excretion (0.29 +/- 0.01 to 0.43 +/- 0.04%, p < 0.025). In contrast, in cirrhotic rats with ascites neither sodium excretion nor fractional sodium excretion was significantly affected. No changes were observed in plasma aldosterone and atrial natriuretic peptide concentrations in either group. These data suggest that in cirrhosis there is a renal resistance to the natriuretic effect of endogenous sodium pump inhibitor(s).
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PMID:Blunted natriuretic response to human urine extracts with Na+,K(+)-ATPase inhibiting activity in experimental cirrhosis. 807 45

Transmethylation is an important means of altering the biological activity of a wide variety of compounds. In human and experimental CCl4-liver cirrhosis the intrahepatic content of S-adenosyl-L-methionine (SAM), an active methyl donor, and the SAM-transmethylase activity are markedly reduced. Previously, it has been reported that SAM administration preserves hepatocyte plasma membrane Na+/K(+)-ATPase and Ca(2+)-ATPase activities in cirrhotic rats. Therefore, the aim of this work was to study the effect of SAM administration on the membrane lipid composition and the ATPase activity on erythrocytes derived from CCl4-cirrhotic rats. Male Wistar rats were used in these experiments. In group 1, cirrhosis was induced by i.p. administration of CCl4. Animals of group 2 received, in addition to CCl4, three daily doses of SAM (20 mg kg-1, i.m.). Group 3 consisted of cirrhotic animals that, after 8 weeks of CCl4 treatment, received SAM (20 mg kg-1, i.m., three times daily) for 4 weeks without discontinuation of CCl4. Group 4 included animals treated with SAM alone. Seventy-two hours after the end of treatment the rats were anaesthetized, blood was collected by heart puncture and the erythrocyte plasma membranes were isolated. The Na+/K(+)- and (Ca2+ +Mg2+)-ATPase activities and the cholesterol (CH) and phospholipid (PL) contents were determined in the plasma membranes. The Na+/K(+)- and Ca(2+)-ATPase activities were both significantly decreased (twofold) in the CCl4-treated group as compared to controls. Administration of SAM completely prevented this fall in both ATPases. In group 4, the Na+/K(+)-ATPase activity was partially restored but the Ca(2+)-ATPase activity was completely restored.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:S-adenosyl-L-methionine prevents and reverses erythrocyte membrane alterations in cirrhosis. 839 94

The aim of this work was to compare the effects of colchicine and trimethylcolchicinic acid (TMCA) on liver damage induced by bile duct ligation (BDL) for 2 months in male Wistar rats. Colchicine was evaluated at a dose of 10 micrograms rat-1 day-1, p.o. only, because higher doses produced diarrhoea and death. Trimethylcolchicinic acid showed no toxic effects at 10, 50 or 100 micrograms rat-1 day-1, p.o. Biliary obstruction resulted in a 65% mortality, colchicine decreased it to 46% and TMCA (10 micrograms) to 33.3%. Serum markers of liver damage increased by BDL (P < 0.05), colchicine prevented it partially (P < 0.05) and TMCA did it in a dose-dependent manner. Liver peroxidation increased 10 times by BDL and both drugs prevented it. Hepatic glycogen content decreased 80% by BDL, colchicine TMCA (10 micrograms) failed to preserve it and 50 micrograms of TMCA preserved it completely. Hepatocyte and erythrocyte plasma membrane Na+/K(+)- and Ca(2+)-ATPase activities decreased after BDL (P < 0.05) and 100 micrograms of TMCA preserved normal ATPase activities. It is concluded that TMCA is better than colchicine for protecting the liver from BDL-induced cirrhosis and, due to its lower toxicity, can be used at higher and more effective doses without the common side-effects of colchicine, thus making TMCA a suitable compound to be studied in other hepatic lesions and in humans.
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PMID:Comparative study of colchicine and trimethylcolchicinic acid on prolonged bile duct obstruction in the rat. 881 70

Colchicine is one of the most promising drugs for the treatment of cirrhosis. However, due to its toxicity, other drugs are being evaluated and colchicine-like molecules may be good alternatives. The aim of this work was to compare the beneficial effects of colchicine and trimethylcolchicinic acid (a colchicinoid less toxic than colchicine) on CCl4-cirrhosis. The drugs were administered either through CCl4 administration (8 weeks) or after CCl4 intoxication for 4 weeks at a dose of 10 micrograms/rat/day, orally. Liver plasma membranes were isolated for high affinity Ca(2+)-ATPase, gamma-glutamyl transpeptidase and alkaline phosphatase activities. The activities of gamma-glutamyl transpeptidase and alkaline phosphatase were also measured in serum. Liver glycogen content and a marker for lipid peroxidation were determined in liver samples. We found that both compounds preserved and significantly reversed high affinity Ca(2+)-ATPase, gamma-glutamyl transpeptidase and alkaline phosphatase plasma membrane and serum enzyme activities as well as the hepatic glycogen content.
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PMID:Effect of colchicine and trimethylcolchicinic acid on CCl4-induced cirrhosis in the rat. 893 57

Wilson disease is a disorder of copper metabolism characterized by hepatic cirrhosis and neuronal degeneration due to inherited mutations in a gene encoding a putative copper-transporting P-type ATPase. Polyclonal antisera generated against the amino terminus of the Wilson protein detected a specific 165-kDa protein in HepG2 and CaCo cell lysates. Further analysis revealed that this protein is synthesized as a single-chain polypeptide and localized to the trans-Golgi network under steady state conditions. An increase in the copper concentration resulted in the rapid movement of this protein to a cytoplasmic vesicular compartment. This copper-specific cellular redistribution of the Wilson protein is a reversible process that occurs independent of a new protein synthesis. Expression of the wild-type but not mutant Wilson protein in the ccc2Delta strain of Saccharomyces cerevisiae restored copper incorporation into the multicopper oxidase Fet3p, providing direct evidence of copper transport by the Wilson protein. Taken together these data reveal a remarkable evolutionary conservation in the cellular mechanisms of copper metabolism and provide a unique model for the regulation of copper transport into the secretory pathway of eucaryotic cells.
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PMID:Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae. 926 Nov 63

The structural elucidation and mechanism of action of a potential component, LLU-alpha, of what is possibly a multifactorial complex known as "natriuretic hormone" was recently reported [Wechter, W.J. et al. (1996a) Proc. Natl. Acad. Sci. U.S.A. 93: 6002-6007]. "Natriuretic hormone," a long-sought factor, is believed to regulate extracellular fluid volume and consequently be pathomimetic for hypertension, cirrhosis, congestive heart failure and other volume expanded states. The studies reported herein further characterize LLU-alpha. The precursor of the endogenous LLU-alpha was demonstrated to be gamma-tocopherol by radiolabeling studies. The pharmacokinetics of infused rac-LLU-alpha proved to be biphasic (half-lives: 12 min and 6 h). Specificity of the inhibition of the 70 pS potassium channel of the thick ascending limb of the loop of Henle was examined with the natural S-enantiomer being the most potent known inhibitor whereas the analogous alpha-tocopherol metabolite, rac-5-Me-LLU-alpha, showed no inhibition. Rac-LLU-alpha does not inhibit two isozymes of the Na+/K+-ATPase. LLU-alpha is natriuretic acting via inhibition of the 70 pS potassium channel and not Na+/K+-ATPase, the assumed mechanism of action of the "natriuretic hormone." LLU-alpha, a metabolite of a vitamin, if it were found to play a role in the regulation of extracellular fluid volume, would be the second example of a vitamin acting as a precursor for a hormone. Of considerable interest is the fact that this manuscript reports the first biological activity of gamma-tocopherol, a member of the vitamin E complex.
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PMID:Endogenous natriuretic factors 7: biospecificity of a natriuretic gamma-tocopherol metabolite LLU-alpha. 926 27

We have assessed the effect of the oral ingestion of thioacetamide on small intestine structure and function. Thioacetamide-treated rats showed diminished mucosa weight; protein, DNA, and RNA content; and leucine aminopeptidase activity as compared to controls in both jejunum and ileum. In the jejunum, there was a reduction in the activities of alkaline phosphatase, ATPase, glucose-6-phosphatase, and myeloperoxidase, whereas in the ileum, maltase, lactase, and gamma-glutamyltranspeptidase were reduced. In both jejunum and ileum we found enlarged intercellular spaces, dark epithelial enterocytes, and lymphocyte infiltration. Enterocytes showed lobulated nuclei, deranged mitochondria with loss of their cristae, dilated rough endoplasmic reticulum containing dense material, and vesiculation of the smooth endoplasmic reticulum and the Golgi apparatus. Smooth muscle cells of the intestine exhibited ultrastructural alterations. These findings indicate that chronic oral intake of thioacetamide mimics not only hepatic alterations but also small intestine alterations normally associated with human cirrhosis.
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PMID:Hepatotoxic agent thioacetamide induces biochemical and histological alterations in rat small intestine. 928 39

Wilson's disease is an inherited disorder of copper metabolism characterized by hepatic cirrhosis and neuronal degeneration. In this current study, a polyclonal antiserum specific for the Wilson's disease ATPase was used to examine the hepatic expression of this protein. Immunoblot analysis of lysates from human and rat liver detected a single 165-kDa protein, which by immunofluorescence was present only in hepatocytes and localized predominantly to the trans-Golgi network and exclusively in this compartment under low hepatic copper concentrations. Although hepatic copper concentration had no effect on the steady-state levels of the Wilson's disease protein, copper administration in vivo resulted in redistribution of this protein to a cytoplasmic vesicular compartment localized toward the hepatocyte canalicular membrane. The relative abundance of the Wilson's disease protein in the liver was found to be greatest in the fetus before the onset of biliary copper excretion. Taken together, these studies reveal a novel posttranslational mechanism of copper homeostasis in vivo consistent with the proposed function of the Wilson's disease protein in holoceruloplasmin biosynthesis and biliary copper excretion and of relevance to the broad clinical heterogeneity observed in this disease.
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PMID:Hepatocyte-specific localization and copper-dependent trafficking of the Wilson's disease protein in the liver. 1007 40

The Atp7b protein is a copper-transporting ATPase expressed predominantly in the liver and to a lesser extent in most other tissues. Mutations in the ATP7B gene lead to Wilson disease, a copper toxicity disorder characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic and neuro-logical abnormalities. Using homologous recombination to disrupt the normal translation of ATP7B, we have generated a strain of mice that are homozygous mutants (null) for the Wilson disease gene. The ATP7B null mice display a gradual accumulation of hepatic copper that increases to a level 60-fold greater than normal by 5 months of age. An increase in copper concentration was also observed in the kidney, brain, placenta and lactating mammary glands of homo-zygous mutants, although milk from the mutant glands was copper deficient. Morphological abnormalities resembling cirrhosis developed in the majority of the livers from homozygous mutants older than 7 months of age. Progeny of the homozygous mutant females demonstrated neurological abnormalities and growth retardation characteristic of copper deficiency. Copper concentration in the livers of the newborn homozygous null mutants was decreased dramatically. In summary, inactivation of the murine ATP7B gene produces a form of cirrhotic liver disease that resembles Wilson disease in humans and the 'toxic milk' phenotype in the mouse.
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PMID:Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation. 1044 29

Semiquantitative immunoblotting was used to investigate the expression levels of the four major renal aquaporins, the Na-K-2Cl cotransporter of the thick ascending limb, the type 3 Na-H exchanger, and the Na-K-ATPase in kidneys from rats with cirrhosis secondary to common bile duct ligation (CBDL). These rats had significant water retention and hyponatremia. In contrast to models of cirrhosis induced by carbon tetrachloride, aquaporin-2 expression in CBDL-induced cirrhosis was decreased. Thus, these results show that in the setting of extracellular fluid volume expansion, excessive water retention with hyponatremia can occur in the absence of increases in aquaporin-2 abundance. In addition, the expression levels of the two basolateral collecting duct aquaporins (aquaporin-3 and -4) were decreased in CBDL rats relative to sham-operated control rats. Similarly, the Na-K-2Cl cotransporter of the thick ascending limb and the type 3 Na-H exchanger showed decreases in expression. In contrast, the expression levels of aquaporin-1 and the all subunit of the Na-K-ATPase were not decreased. Thus, dysregulation of multiple water channels and ion transporters may play a role in water balance abnormalities associated with CBDL-induced cirrhosis in rats.
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PMID:Renal expression of aquaporins in liver cirrhosis induced by chronic common bile duct ligation in rats. 1047 47


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