Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.5 (5'-nucleotidase)
3,167 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholestatic jaundice is one complication of nonhepatic gram-negative bacterial infection. The endotoxin of Escherichia coli has been reported to cause cholestasis by inhibiting the bile salt-independent fraction (BSIF) of bile in the perfused rat liver. Accordingly, the effects of lipopolysaccharides (LPS) of E. coli and Salmonella enteritidis on the Na+, K+-adenosinetriphosphatase (ATPase) in canalicular-enriched plasma membranes of rate liver were examined. At 20 microgram/ml, both endotoxins inhibited this enzyme by approximately 40%. Maximal inhibition (70%-80%) occurred at concentrations of greater than or equal to 120 microgram/ml. The LPS of neither organism exerted any effect on the activity of Mg++-ATPase or 5'-nucleotidase in the same preparations. Inhibition by the E. coli LPS appeared to be noncompetitive in nature, and the calculated Ki was 45 microgram/ml. Since the Na+, K+-ATPase may be responsible for the elaboration of BSIF, inhibition of this enzyme could be the underlying mechanism for the endotoxin-induced cholestasis.
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PMID:Inhibition of Na+, K+-adenosinetriphosphatase by endotoxin: a possible mechanism for endotoxin-induced cholestasis. 14 99

The hepatotoxicity of CPZ was studied in the isolated perfused rat liver in order to more closely define possible mechanisms of phenothiazine-induced cholestasis. Perfusate concentrations of CPZ were increased from 5 x 10(-6) M to 5 x 10(-4) M until bile secretion was significantly inhibited. Measurements were then made of determinants of bile secretory function, including the magnitude of lobar distribution of perfusate flow, BAIF, and liver plasma membrane enzyme activity, Na+,K+-ATPase, Mg++-ATPase and 5'-nucleotidase. BAIF diminished significantly from control values of 1.76 +/- 0.07 microliter min-1gm-1 of liver to 1.34 +/- 0.15 and 0.80 +/- 0.09 following 2.5 and 5 x 10(-4) M CPZ, respectively. Perfusate flow also diminished from 5.64 +/- 0.44 to 1.24 +/- 0.12 ml min-1 gm-1 of liver 20 min following 5 x 10(-4) M CPZ and was associated with reduced flow to peripheral areas of the hepatic lobes as demonstrated by Tc-HAM. By 30 min, perfusate flow had returned to baseline values. CPZ also transiently diminished the excretion of bile acids in livers receiving a constant infusion of 40 mumol hr-1 sodium taurocholate. Defects in hepatic perfusion could not account entirely for the impairment in BAIF, since comparable mechanical restriction of perfusate flow in controls only diminished BAIF to 1.49 +/- 0.08 microliter min-1gm-1 of liver. CPZ signofocamt;u rediced tje secofoc actovotu pf Mg++-ATPase and 5'-nucleotidase but did not affect Na+,K+-ATPase in liver plasma membrane isolated 20 min after 5 x 10(-4) M CPZ. CPZ also resulted in a profound shift in the recovery of protein in isolated liver plasma membrane fractions from the light (density = 1.16) to heavier (density = 1.18) fractions. These findings, together with previous observations demonstrating alterations in hepatic ultrastructure, indicate that CPZ interacts in a complex manner with hepatocyte plasma and cytoplasmic membrane components and suggest that these drug-membrane interactions independently result in diminished hepatic perfusion, impairment of bile acid excretion, and inhibition of bile acid-independent bile secretion.
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PMID:Effect of chlorpromazine on hepatic perfusion and bile secretory function in the isolated perfused rat liver. 22 76

Liver plasma membranes enriched in bile canaliculi were isolated from rat liver by a modification of the technique of Song et al. (J. Cell Biol. (1969) 41, 124-132) in order to study the possible role of ATPase in bile secretion. Optimum conditions for assaying (Na+ plus K+)-activated ATPase in this membrane fraction were defined using male rats averaging 220 g in weight. (Na+ plus K+)-activated ATPase activity was documented by demonstrating specific cation requirements for Na+ and K+, while the divalent cation, Ca(2+), and the cardiac glycosides, ouabain and scillaren, were inhibitory. (Na+ plus K+)-activated ATPase activity averaged 10.07 plus or minus 2.80 mumol Pi/mg protein per h compared to 50.03 plus or minus 11.41 for Mg(2+)-activated ATPase and 58.66 plus or minus 10.07 for 5'-nucleotidase. Concentrations of ouabain and scillaren which previously inhibited canalicular bile secretion in the isolated perfused rat liver produced complete inhibition of (Na+ plus K+)-activated ATPase without any effect on Mg(2+)-activated ATPase. Both (Na+ plus K+)-activated ATPase and Mg(2+)-activated ATPase demonstrated temperature dependence but differed in temperature optima. Temperature induced changes in specific activity of (Na+ plus K+)-activated ATPase directly paralleled previously demonstrated temperature optima for bile secretion. These studies indicate that (Na+ plus K+)-activated ATPase is present in fractions of rat liver plasma membranes that are highly enriched in bile canaliculi and provide a model for further study of the effects of various physiological and chemical modifiers of bile secretion and cholestasis.
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PMID:Properties of (Na+ plus K+)-activated ATPase in rat liver plasma membranes enriched with bile canaliculi. 23 59

The sera of rats treated with alpha-naphthylisothiocyanate, an agent reported to cause intrahepatic cholestasis, and of rats treated with carbon tetrachloride, are examined for evidence of leakage of bile into blood. The levels of the four bile components assayed, namely IgA, free IgA secretory component, the biliary isoenzyme of 5'-nucleotidase and of direct reacting (conjugated) bilirubin, were all elevated in the sera of rats treated with alpha-naphthylisothiocyanate. No change in any of these components was found in rats treated with carbon tetrachloride, indicating that their appearance in serum is not an inevitable consequence of damage to hepatocytes. As the bile components assayed reach bile by three different routes. their rapid appearance in the sera of rats treated with alpha-naphthylisothiocyanate indicates reflux of bile into blood, presumably as a result of mechanical obstruction of intraheptic bile ducts.
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PMID:Reflux of billiary components into blood in experimental intrahepatic cholestasis induced in rats by treatment with alpha-naphthylisothiocyanate. 43 79

A pattern of results is reported which was found to be common among patients who had intrahepatic cholestasis (IHC) which was rarely found in patients with other hepatic conditions. The pattern was recognized from over 1000 cases suspected of hepatobiliary disease. 29 were diagnosed with IHC, and excluding 4, 25 revealed the following etiological pattern: chlorpromazine (12 patients); pregnancy and oral contraceptive use (8); and other (5). As opposed to patients with acute and chronic hepatic disease, IHC sufferers had relatively normal values for immunoglobulins and antibody titers. A disproportionate elevation of serum bilirubin vis-a-vis serum enzymatic activities separated potential IHC cases into intra- and extrahepatic cholestasis. The following factorial evaluations were useful in distinguishing hepatic disease states: 1) when the sum of the activities of serum alkaline phosphatase, 5'-nucleotidase, aspartate and alanine amiotransferases, and isocitrate dehydrogenase was divided by the serum bilirubin concentration, there was good resolution of the distinction between patients with IHC and those with primary biliary cirrhosis, early and late viral hepatitis, cholelithiasis, and pancreatic and bile duct cancers. 2) Resolution was also achieved when the numerator included alkaline phosphatase, 5'-nucleotidase, and aspartate aminotransferase, but not when alkaline phosphatase alone, or alkaline phosphatase combined with 5'-nucleotidase, was used. The essential lesion in IHC is an excretory defect.
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PMID:Biochemical features of intrahepatic cholestasis. 45 73

Reports on correlations between the activity of so-called "marker enzymes of cholestasis" in serum and the ultrastructural changes of the liver are rare. Therefore studies of ultrastructural changes were carried out in 40 patients with intrahepatic cholestasis. In the patients' serum activity of alkaline phosphatase, bile duct alkaline phosphatase, leucine-aminopeptidase (LAP), and 5'-nucleotidase (5'-Nu) as well as the concentration of bilirubin were determined. The results showed a significant correlation between the morphometry of the bile canaliculi and the serum activity of LAP and 5'-Nu. In patients with elevated LAP, an enlargement of the bile canaliculi could be proved. An increased serum activity of 5'-Nu correlated with a higher incidence of bile canaliculi in the ultrastructural picture. The results suggest an investigation of the ultrastructure of bile canaliculi and the determination of marker enzymes of cholestasis in the serum may both contribute to the assessment of cholestatic liver disease.
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PMID:[Ultrastructural-morphometric analysis of liver biopsies in patients with intrahepatic cholestasis. I. Correlations between morphometry of bile canaliculi and so-called "marker enzymes of cholestasis" (author's transl)]. 80 5

Fifteen patients with cholestatic disorders were treated for 1 to 5 months with phenobarbital. Primary biliary cirrhosis was diagnosed in seven, sclerosing cholangitis in two, intrahepatic biliary hypoplasia in three, and cholestatic hepatitis in three. Except for the patients with cholestatic hepatitis, in whom marked cholestasis was virtually the only abnormality in liver biopsy specimens, serum bilirubin and bile acid concentrations were diminished during therapy, the hepatic clearance of sulfobromophthalein and 131-I-rose bengal was variably enhanced, and there was relief from pruritus. Serum cholesterol concentrations and other measures of hepatic function were not significantly changed during therapy except for serum alkaline phosphatase activity, which rose in twelve patients. Parallel changes occurred in 5'-nucleotidase, suggesting a hepatic origin for the alkaline phosphatase activity. These studies indicate that phenobarbital therapy is associated with improvement in organic anion clearance in some patients with cholestatic disorders and may be beneficial to such patients.
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PMID:Phenobarbital effects in cholestatic liver diseases. 111 64

Serum alkaline phosphatase (AKP), gamma-glutamyl transpeptidase (gamma-GT), 5'-nucleotidase (5'-NT), leucine aminopeptidase (LAP), AKP gamma-GT isoenzymes, and lipoprotein-X (LP-X) were measured in 97 normal pregnant women and 40 patients with intrahepatic cholestasis of pregnancy (ICP). It was found that in ICP the changing patterns in the four hepatobiliary enzymes were different in different gestational weeks of 3 rd trimester. The changes of gamma-GT and 5'NT were more significant, especially the latter. Six bands were found both in serum AKP and gamma-GT isoenzymes. In ICP the rate of occurrence of AKP1 and AKP2 isoenzymes were elevated. Thus, gamma-GT, 5'-NT, AKP and gamma-GT isoenzymes might be more sensitive parameters for monitoring intrahepatic cholestasis of pregnancy.
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PMID:[Changes in hepatobiliary enzymes and its isoenzymes in intrahepatic cholestasis in pregnancy]. 167 17

The reversibility of hepatic fibrosis was investigated in an experimental model of extrahepatic cholestasis in the rat after common bile duct ligation for 2 weeks, followed by bilioduodenal anastomosis for 3 weeks. Bile duct ligation resulted in a transitory marked elevation in the serum concentration of 5'-nucleotidase, alkaline phosphatase, and bilirubin during the first 3 days. Then these levels decreased to threefold, twofold, and 100-fold the normal values, respectively, during the following 4 weeks. Histologic examination of the liver disclosed extensive bile duct proliferation and the formation of periportal fibrosis, with only slight inflammation and necrosis. The distribution of the major components of the hepatic extracellular matrix was analyzed 2 weeks after bile duct ligation, using the indirect immunoperoxidase method. Fibrous septa were found to be strongly stained for collagens I, pro-III, III and IV, fibronectin, and laminin. The most intense staining was found in enlarged periportal areas, collagen IV and laminin being particularly abundant around newly formed bile ducts. These changes paralleled high steady-state levels of alpha 1(I) and alpha 1(IV) collagen and B2 chain laminin mRNAs. Relief of the obstruction for 2 weeks resulted in a shift in the serum concentration of 5'-nucleotidase, alkaline phosphatase, and bilirubin toward normal values. A dramatic resorption of bile duct proliferations and periportal fibrosis were observed. Three weeks after bile duct repermeabilization, immunohistochemical study showed that the pattern of distribution of extracellular matrix components was almost normal, except for collagen IV, which remained abundant in the sinusoids when compared with the normal liver. In parallel, the steady-state B2-chain laminin mRNA level became lower than in cholestatic livers, whereas alpha 1(I) and alpha 1(IV) mRNAs were almost undetectable. These results show that hepatic fibrosis induced by experimental extrahepatic cholestasis in rat disappears in less than 3 weeks after relief of bile duct obstruction, suggesting that an active degradation of matrix protein occurs, except for collagen IV in the sinusoid.
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PMID:Reversibility of hepatic fibrosis in experimentally induced cholestasis in rat. 226 Jun 23

Acid phosphatase, alkaline phosphatase and 5'-nucleotidase activities were analyzed cytophotometrically in cryostat sections of rat liver up to 8 weeks after ligation and transsection of the common bile duct. Ligation resulted in cholestasis and induced alterations in both localization and activity of the enzyme investigated. The cellular distribution but not the activity of acid phosphatase changed in liver parenchyma. In control liver, the final reaction product was localized as discrete granules in the bile canalicular region of hepatocytes. The final reaction product was precipitated more diffusely within the cytoplasm after induction of cholestasis, most probably due to increased fragility of lysosomal membranes. In control liver, alkaline phosphatase activity was low and localized in the bile canalicular plasma membranes only. The total parenchymal activity increased threefold after the induction of cholestasis and is considered to be a compensatory mechanism in order to enhance the excretion of bile salts from hepatocytes. 5'-Nucleotidase was present at the bile canalicular and sinusoidal surfaces of plasma membranes of hepatocytes in control liver; total activity in pericentral areas was significantly higher than in periportal areas. Induction of cholestasis resulted in higher total activity and redistribution of the activity over all three surfaces of the plasma membranes, whereas heterogeneity over the different zones of the acinus disappeared. The appearance of the enzyme at lateral plasma membranes is suggested to be related to the formation of new sites for bile salt transport out of the hepatocytes. With respect to all three enzymes studied, alterations of liver parenchymal cells due to a disturbed bile transport were already established during the first week of cholestasis.
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PMID:Quantitative changes in acid phosphatase, alkaline phosphatase and 5'-nucleotidase activity in rat liver after experimentally induced cholestasis. 238 57


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