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:3.6.3.1 (Mg2+-ATPase)
1,484 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of cytochalasin B-induced intrahepatic cholestasis was examined using electron cytochemical techniques. Since previous studies suggested that the earliest lesions were in hepatic canaliculi, markers were used for three canalicular membrane components, namely ruthenium red for the glycoprotein-rich surface coat, the Mg2+-ATPase reaction as an example of a membrane-bound protein, and uranyl acetate en bloc and ruthenium red staining for the canalicular membrane-associated microfilaments. In rat liver infused in vivo with cytochalasin B, reduction in bile flow correlated with bile canalicular dilation, loss of the ruthenium red-positive surface coat from the canalicular membrane, and loss of demonstrable Mg2+-ATPase activity. In addition, structural alterations in microfilaments with widening of the ectoplasmic zone were noted. In isolated liver cells in vitro, identical changes were found. Bile canaliculi isolated from the in vivo cytochalasin B-infused rat liver lacked their normal investment of microfilaments. Detachment of the filaments from the bile canalicular membrane may be involved in the mechanism of cytochalasin B-induced cholestasis.
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PMID:Bile canalicular membrane pathology in cytochalasin B-induced cholestasis. 14 51

To investigate the mechanisms of erythromycin cholestasis, the effects of erythromycin estolate (EE) on the excretory function of the isolated perfused rat liver and on liver plasma membrane (LM) preparations were studied and compared to those of erythromycin base (EB) and lauryl sulfate (LS), added alone or in combination. EE (at 125 to 200 microM) caused dose-dependent reductions of bile and perfusate flows, bile acid (BA) excretion, and biliary BA concentration. The alterations of the excretory function were only in part due to the decreased perfusate flow. In contrast, both 200 and 300 microM concentrations of EB elicited similar choleretic responses, which were presumably related to the osmotic activity of the drug excreted in the bile. LS did not affect hepatic excretory functions. However, the simultaneous addition of EB and LS resulted in a rate of bile flow lower than that observed with EB alone. EE, but not EB, increased canalicular permeability to [14C]sucrose as measured by bile to plasma (B:P) ratio. Neither drugs altered [14C]erythritol B:P ratio. In LM preparations both Na+,K+- and Mg2+-ATPase activities were inhibited in a dose-dependent manner by EE, but not by EB. The data suggest that EE could affect bile flow by inhibiting cotransport of Na+ and BA and by altering LM permeability and support the view that the effect of erythromycins on the liver may be related to their surface activity.
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PMID:Characterization of the effects of erythromycin estolate and erythromycin base on the excretory function of the isolated rat liver. 299 20

Structural and functional changes in the surface membranes of hepatocytes play a pivotal role in the induction and reversion of some forms of drug-induced cholestasis. To elucidate the mechanism by which S-adenosyl-L-methionine (SAMe) leads to a partial reversion of bile flow impairment caused by ethinyl estradiol (EE), female Sprague-Dawley rats were given oral doses of EE (5 mg per kg per day, for 3 days) with and without simultaneous administration of SAMe (25 mg per kg, 3 times per day, for 3 days). Na+,K+-ATPase activity and membrane microviscosity as measured by fluorescent polarization were assayed in isolated liver plasma membranes (LPMs). SAMe administration to normal and EE-treated rats resulted in a marked increase in Na+,K+-ATPase activity and LPM fluidity. EE alone did not cause any change in the physicochemical properties of the LPMs. Hepatic Mg2+-ATPase and gamma-glutamyl transpeptidase activities were not affected by SAMe alone but increased when SAMe was given together with EE. These data indicate that the interaction of in vivo administered SAMe with hepatocyte plasmalemma and its effect on lipid fluidity and enzymes of the LPMs showed a high specificity and an inverse relationship between Na+,K+-ATPase activity and fluorescence polarization values. Furthermore, modulation of hepatic Na+,K+-ATPase was associated with SAMe-induced protection against bile flow impairment due to EE; however, it was not the causative factor for EE-induced cholestasis under the experimental conditions. These findings suggest that changes in surface membrane structure and function might account in part for the reversal by SAMe of EE-induced impairment of bile secretory function.
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PMID:Modulation by S-adenosyl-L-methionine of hepatic Na+,K+-ATPase, membrane fluidity, and bile flow in rats with ethinyl estradiol-induced cholestasis. 629 6

Disruption of the murine mdr2 (multidrug-resistance) gene, which encodes a phosphatidylcholine flippase, leads to a hepatic disorder because of loss of biliary phospholipid secretion. Among the hereditary human cholestasis, a subtype of progressive familial intrahepatic cholestasis with high gamma-glutamyltranspeptidase (GGT) serum activity shares histological, biochemical, and genetic features with mice lacking mdr2 gene expression (mdr2 -/- mice). No MDR3 (human mdr2 homolog) messenger RNA (mRNA) was detected by Northern blotting in the liver of a patient suffering from this form of PFIC, and the biliary phospholipid level in a second patient was substantially decreased. Thus, the absence of the MDR3 P-glycoprotein may be responsible for this type of PFIC, which, as in the murine model, may be due to a toxic effect of bile acids on the biliary epithelium in absence of biliary phospholipids.
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PMID:Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. 866 48

Ca2+, Mg2+-ATPase is a membrane-bound enzyme localized at the bile canalicular membranes of hepatocytes. Cytoskeleton and tight junctions are important for maintenance of the polar distribution of plasma membrane proteins. In order to understand the mechanisms involved in the redistribution of Ca2+, Mg2+-ATPase due to cholestasis, the relationship between Ca2+, Mg2+-ATPase, microfilaments and tight junctions was examined. Cholestasis was induced in rat liver by common bile duct ligation (CBDL) for 2 weeks. Localization of Ca2+, Mg2+-ATPase activity was studied at the light and electron microscopic level. Double-staining of the enzyme and F-actin was performed using phase-contrast and fluorescence microscopy of 7-nitrobenzene-2-oxa-1,3-diazole phallacidin (NBD-ph), respectively. Immunofluorescence microscopy of ZO-1 was applied for the observation of tight junctions. Furthermore, cytoskeleton and junctional complexes were investigated electron microscopically in saponin-extracted tissues. The results showed that CBDL induced redistribution of Ca2+, Mg2+-ATPase activity from the apical to the entire plasma membrane of hepatocytes, which seemed to occur independently of F-actin. F-actin was present at all membrane domains of hepatocytes in control liver, whereas CBDL increased the amounts of F-actin mainly at the bile canalicular membranes. An inverse distribution pattern of Ca2+, Mg2+-ATPase activity and F-actin was found in epithelial cells of bile ducts in control and cholestatic livers. Marked alterations in microfilaments were observed at the bile canaliculi, which were defined as hypertrophy and atrophy and were in association with changes in tight junctions. Structural impairment of the tight junctions was proven by disordered immunofluorescence of ZO-1. It is concluded that changes in the distribution of Ca2+, Mg2+-ATPase and F-actin due to CBDL are independent of each other. CBDL-induced disorders of microfilaments are related to impairment of structural integrity of tight junctions that is suggested to be responsible for the redistribution of Ca2+, Mg2+-ATPase in hepatocytes.
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PMID:Redistribution of Ca2+, Mg2+-ATPase activity in relation to alterations of the cytoskeleton and tight junctions in hepatocytes of cholestatic rat liver. 892 66

We studied the effect of cyclosporine A on hepatic Ca2+, Mg2+-ATPase and F-actin on bile canalicular and basolateral membranes in rats fed either soyabean lecithin, or triacylglycerol enriched diet, or low fat diet. Ca2+, Mg2+-ATPase histochemical activity was not modified in lecithin-cyclosporine A group, whereas the activity was decreased in the other groups. The triacylglycerol-cyclosporine A group had the lower activity. The histochemical staining of F-actin was quite normal in lecithin-cyclosporine group but decreased in the other cyclosporine A treated groups. The lower staining was observed in the triacylglycerol-cyclosporine group. The alteration of Ca2+, Mg2+-ATPase and F-actin by cyclosporine A, related to cholestasis evidenced by a decrease in bile salt secretion, were prevented by dietary soyabean lecithin and amplified by dietary soyabean triacylglycerol.
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PMID:Modification of Ca2+, Mg2+-ATPase and F-actin distribution in hepatocytes of cyclosporine A treated rats. Effect of soyabean lecithin and triacylglycerol. 987 9

Vectorial sorting of plasma membrane protein-containing vesicles is essential for the establishment and maintenance of cell polarity. In the present study, the involvement of altered vesicle transport in the redistribution of membrane-bound Ca2+, Mg2+-ATPase resulting from cholestasis was investigated in hepatocytes. Cholestasis was induced in rat liver by common bile duct ligation. Ca2+, Mg2+-ATPase activity was demonstrated histochemically at the light and electron microscopical levels. Microtubules, an important factor for transcellular transport of vesicles, were studied in situ by immunofluorescence microscopy and electron microscopy in detergent-extracted preparations. The results showed that microtubules underwent significant changes after common bile duct ligation. The most pronounced alteration was focal accumulation of beta-tubulin in the cytoplasm of hepatocytes after 7 days of common bile duct ligation. At the electron microscopical level, the number of microtubules was increased considerably. In control livers, the activity of Ca2+, Mg2+-ATPase was localized only at the apical plasma membrane of hepatocytes, but it was also present at the basolateral plasma membrane after common bile duct ligation. The number of intracellular vesicles containing Ca2+, Mg2+-ATPase activity was increased strikingly, and some of them were associated with lateral membrane domains in which Ca2+, Mg2+-ATPase activity was found. It is concluded that common bile duct ligation induces the rearrangement of microtubules, which may disturb vectorial transport of Ca2+, Mg2+-ATPase-containing vesicles in hepatocytes, leading to the redistribution of Ca2+, Mg2+-ATPase.
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PMID:The involvement of altered vesicle transport in redistribution of Ca2+, Mg2+-ATPase in cholestatic rat liver. 1010 Jul 33

Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct-ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.
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PMID:Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. 1523 10

In juvenile rats born from mothers with obstructive cholestasis during pregnancy (OCP), transient latent cholestasis together with alterations in the secretion of biliary lipids have been reported. Here we investigated whether the expression of genes involved in this function is already modified at birth and examined the effect of treating pregnant rats with ursodeoxycholic acid (UDCA; i.g., 60 microg/100 g b.w./day). Cholanemia was markedly higher in mothers with OCP, and was further increased by UDCA. In the Control pups, cholanemia increased after birth, whereas in OCP and OCP+UDCA pups, hypercholanemia decreased after birth. Steady-state mRNA levels in neonatal liver were measured by real-time quantitative RT-PCR. The expression of basolateral bile acid transporters was not affected by OCP and was unchanged (Oatp1/1a1 and Oatp4/1b2) or moderately increased (Ntcp and Oatp2/1a4) by UDCA. In both groups, the expression of ABC proteins was either not modified (Bsep, Bcrp and Mrp2) or enhanced (Mrp1 and Mrp3), that of phospholipid flippase Mdr2 was not changed, whereas that of cholesterol transporter Abcg5/Abcg8 was impaired. The expression of the nuclear receptor FXR was not affected by OCP or UDCA, whereas that of SHP and key enzymes in bile acid synthesis (Cyp7a1, Cyp8b1 and Cyp27) was increased in both groups. In conclusion, OCP affects the expression in the neonatal liver of genes involved in hepatobiliary function, which cannot be prevented, at this stage, by treating pregnant rats with UDCA, even though this treatment has been found to partially restore normal lipid secretion later during post-natal development.
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PMID:Effect of maternal cholestasis and treatment with ursodeoxycholic acid on the expression of genes involved in the secretion of biliary lipids by the neonatal rat liver. 1676 92

Alterations in bile secretion at the hepatocellular and cholangiocellular levels may cause cholestasis. Formation of 'toxic bile' may be the consequence of abnormal bile composition and can result in hepatocellular and/or bile duct injury. The canalicular phospholipid flippase (Mdr2/MDR3) normally mediates biliary excretion of phospholipids, which normally form mixed micelles with bile acids and cholesterol to protect the bile duct epithelium from the detergent properties of bile acids. Mdr2 knockout mice are not capable of excreting phospholipids into bile and spontaneously develop bile duct injury with macroscopic and microscopic features closely resembling human sclerosing cholangitis. MDR3 mutations have been linked to a broad spectrum of hepatobiliary disorders in humans ranging from progressive familial intrahepatic cholestasis in neonates to intrahepatic cholestasis of pregnancy, drug-induced cholestasis, intrahepatic cholelithiasis, sclerosing cholangitis and biliary cirrhosis in adults. Other examples for bile injury due to the formation of toxic bile include the cholangiopathy seen in cystic fibrosis, after lithocholate feeding (in mice) and vanishing bile duct syndromes induced by drugs and xenobiotics. Therapeutic strategies for cholangiopathies may target bile composition/toxicity and the affected bile duct epithelium itself, and ideally should also have anti-cholestatic, anti-fibrotic and anti-neoplastic properties. Ursodeoxycholic acid (UDCA) shows some of these properties, but is of limited efficacy in the treatment of human cholangiopathies. By contrast to UDCA, its side chain-shortened homologue norUDCA undergoes cholehepatic shunting leading to a bicarbonate-rich hypercholeresis. Moreover, norUDCA has anti-inflammatory, anti-fibrotic and anti-proliferative effects, and stimulates bile acid detoxification. Upcoming clinical trials will have to demonstrate whether norUDCA or other side chain-modified bile acids are also clinically effective in humans. Finally, drugs for the treatment of cholangiopathies may target bile toxicity via nuclear receptors (FXR, PPARalpha) regulating biliary phospholipid and bile acid excretion.
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PMID:Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases. 1899 69


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