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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent experiments in primates indicate that the phenothiazine drug chlorpromazine hydrochloride inhibits both bile salt-dependent and -independent bile flow in a predictable fashion. Because a significant fraction of bile salt-independent bile flow is postulated to depend upon the activity of a canalicular membrane Na+,K+-ATPase, we have examined the effects chlorpromazine hydrochloride and its metabolites on the ATPase activities of canalicular-enriched rat liver plasma membranes. Chlorpromazine inhibited the activities of both Mg2+- and Na+,K+-ATPases with a linear dose-response relationship between 10 and 100 micronM. The inhibition of Na+,K+-ATPase was pH dependent, showing a maximal inhibition at pH 7.8. Over the pH range 7.0 to 8.2, the inhibition was significantly reduced with the addition of glutathione and was augmented under experimental conditions (ultraviolet irradiation and peroxidase-H2O2) that promote the formation of the chlorpromazine semiquinone free radical. The 7-hydroxychlorpromazine metabolite was as active an inhibitor as the parent drug; however, two sulfoxide metabolites, chlorpromazine sulfoxide and 7-hydroxychlorpromazine sulfoxide, were less effective inhibitors of Na+, K+-ATPase. Our data are consistent with the hypothesis that chlorpromazine cholestasis may be a result of a direct toxic effect on the ATPase activities of hepatic canalicular membranes. Our results further suggest that if chlorpromazine cholestasis occurs through an interaction with canalicular membrane ATPases, the degree of cholestasis may well be influenced by the extent of the conversion of the drug to its more active (free radical) or minimally active (sulfoxide) metabolites and by the local environment (pH and glutathione concentration) of the canalicular membrane.
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PMID:Effects of chlorpromazine hydrochloride and its metabolites on Mg2+- and Na+,K+-ATPase activities of canalicular-enriched rat liver plasma membranes. 14 85

Glycoconjugate distribution on rat gut mucosa has been studied by using peroxidase-labelled lectins (Lotus tetragonolobus, Dolichos biflorus, Arachis hypogaea and Glycine max) after surgical interruption of the common bile duct. Specimens from cholestatic rats were compared with sham-operated (simple laparotomy) and normal controls to determine which of the observed modifications could be due either to the operation itself or to the cholestasis. Most of the modifications occurred in the duodenum. The operation itself modified some binding properties. Lotus tetragonolobus binding extended both in cholestatic and in sham-operated rats, but returned to normal levels earlier in sham-operated than in cholestatic rats. Conversely, cholestasis induced (1) almost total loss of Arachis hypogaea binding in the Golgi zone of superficial duodenal goblet cells; (2) an increase at the 14th postoperative day of Dolichos biflorus binding in the cytoplasmic calyx of goblet cells which then diminished up until the 28th day; and (3) an increase of Glycine max binding in the Golgi zone of goblet cells.
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PMID:Modification of lectin binding in rat gut mucosa during experimental cholestasis. 129 62

Bile duct adenomas are small nodules that are usually found incidentally on the liver surface at abdominal surgery or autopsy. We recently analyzed two such lesions that, in addition to the typical small caliber ducts, contained periductular nests and clusters of uniform round cells, suggestive of endocrine cell proliferation. Follow-up of these patients did not show endocrine tumors elsewhere. The lesions were studied by immunohistochemistry (avidin-biotin-peroxidase technique) and compared with conventional bile duct adenomas (seven cases). The results showed these cells to decorate with several endocrine markers, namely, neuron-specific enolase, chromogranin, synaptophysin, and Leu-7. Endocrine markers were not seen in the cells of conventional bile duct adenomas. Epithelial markers, that is, cytokeratin (CAM 5.2 antibody) and epithelial membrane antigen, were expressed by the cells composing both conventional bile duct adenomas and those with endocrine-like cells, although with less intensity in the endocrine cell clusters. We suggest that some bile duct adenomas contain endocrine cell proliferations that morphologically may resemble a small carcinoid tumor or the so-called pulmonary tumorlet. Neurosecretory granules have previously been identified in some cholangiocarcinomas and in bile duct proliferation associated with cholestasis. The endocrine clusters in biliary adenomas may constitute a diagnostic pitfall and must be separated from metastases of carcinoids or islet cell tumors.
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PMID:Bile duct adenomas with endocrine component. Immunohistochemical study and comparison with conventional bile duct adenomas. 137 Jan 91

The interaction between cell volume and taurocholate excretion into bile was studied in isolated perfused rat liver. Cell swelling due to hypo-osmotic exposure, addition of amino acids or insulin stimulated taurocholate excretion into bile and bile flow, whereas hyperosmotic cell shrinkage inhibited these. These effects were explained by changes in Vmax of taurocholate excretion into bile: Vmax. increased from about 300 to 700 nmol/min per g after cell swelling by 12-15% caused by either hypo-osmotic exposure or addition of amino acids under normo-osmotic conditions. Steady-state taurocholate excretion into bile was not affected when the influent K+ concentration was increased from 6 to 46 mM or decreased to 1 mM with iso-osmoticity being maintained by corresponding changes in the influent Na+ concentration. Replacement of 40 mM-NaCl by 80 mM-sucrose decreased taurocholate excretion into bile by about 70%; subsequent hypo-osmotic exposure by omission of sucrose increased taurocholate excretion to 160%. Only minor, statistically insignificant, effects of aniso-osmotic cell volume changes on the appearance of bolus-injected horseradish peroxidase in bile were observed. Taurocholate (400 microM) exhibited a cholestatic effect during hyperosmotic cell shrinkage, but not during hypo-osmotic cell swelling. Both taurocholate and tauroursodeoxycholate increased liver cell volume. Tauroursodeoxycholate stimulated taurocholate (100 microM) excretion into bile. This stimulatory effect was strongly dependent on the extent of tauroursodeoxycholate-induced cell swelling. During continuous infusion of taurocholate (100 microM) further addition of tauroursodeoxycholate at concentrations of 20, 50 and 100 microM increased cell volume by 10, 8 and 2% respectively, in parallel with a stimulation of taurocholate excretion into bile by 29, 27 and 9% respectively. There was a close relationship between the extent of cell volume changes and taurocholate excretion into bile, regardless of whether cell volume was modified by tauroursodeoxycholate, amino acids or aniso-osmotic exposure. The data suggest that: (i) liver cell volume is one important factor determining bile flow and biliary taurocholate excretion; (ii) swelling-induced stimulation of taurocholate excretion into bile is probably not explained by alterations of the membrane potential; (iii) bile acids modulate liver cell volume; (iv) taurocholate-induced cholestasis may depend on cell volume; (v) stimulation of taurocholate excretion into bile by tauroursodeoxycholate can largely be explained by tauroursodeoxycholate-induced cell swelling.
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PMID:Cell volume and bile acid excretion. 146 69

Many hormones and drugs exert their effects on cells by increasing cytosolic Ca2+ (Cai2+) and activating protein kinase C (PKC). Each of these actions results in cholestasis in the isolated perfused rat liver, but the responsible mechanisms are unclear. We used isolated rat hepatocyte couplets to observe the direct effects of increased Cai2+ and PKC activation on permeability of the hepatocyte tight junction and canalicular volume, two possible determinants of hepatocyte bile secretion. Couplets were stimulated with the Ca2+ agonist vasopressin (10(-8) M) in the absence and presence of the Ca2+ influx antagonist Ni2+ (5 x 10(-3) M) or with the PKC activator phorbol dibutyrate (10(-6) M). Cai2+ was determined by ratio microspectrofluorometry of indo-1, permeability of the couplet tight junctions was assessed by exclusion of horseradish peroxidase from the canalicular space, and changes in canalicular volume over time were measured directly by optical planimetry. Canalicular volume increased by 1.6 +/- 2.5%/min (mean +/- SD) under basal conditions. In response to vasopressin, there was a rapid 15-fold increase in Cai2+, followed first by an increase in paracellular permeability, then by canalicular collapse (15.9 +/- 5.9%/min). Pretreatment with Ni2+ markedly decreased the vasopressin-induced increase in Cai2+ and abolished both the increase in paracellular permeability and the canalicular collapse. Phorbol dibutyrate also increased paracellular permeability but resulted in neither increased Cai2+ nor canalicular collapse. The PKC inhibitor H-7 reversed the effects of both vasopressin and phorbol dibutyrate on tight junction permeability. Bile secretory pressure, measured in isolated perfused rat liver preparations, was acutely increased by vasopressin, but the increase was augmented rather than inhibited by Ni2+.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hormonal regulation of paracellular permeability in isolated rat hepatocyte couplets. 161 38

The morphological and functional alterations of hepatocytes were investigated on autopsy cases of human obstructive jaundice and experimentally common bile duct ligated rats. The livers were morphologically observed by light and electron microscopes, and in order to make clear the mechanism of bile flow, horse radish peroxidase (HRP) was injected in male Wistar rats from the inferior mesenteric vein and administered in retrograde from the common bile duct. In the extrahepatic bile duct obstruction, bile canaliculi were dilated and canalicular microvilli were decreased in number and showed bleb formation, and pericanalicular filamentous structure formed thick network. Injected HRP as a tracer was not presented in the laminar and intercellular space of hepatocytes, and administered HRP in retrograde was presented in the intercellular space through tight junction from bile canaliculi and presented pericanalicular cytoplasmic vesicles. These results suggest that extrahepatic bile duct obstruction induces morphological change in pericanalicular regions and the functional abnormality in the membrane structure of hepatocytes may be persistent cholestasis.
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PMID:[Mechanism of retardation of obstructive jaundice: pathological investigation of alteration in bile flow]. 188 72

In the present paper we provide a basic enzymatic characterization of biliary epithelial cells (BEC) that have been isolated from normal rat liver. When compared with liver parenchymal cells, BEC display the following major features: (a) a very high specific activity of gamma-glutamyltranspeptidase (approx. 200-times higher than the value usually found in hepatocytes); (b) a lack of enzymes that are usually associated with the endoplasmic reticulum in hepatocytes such as cytochrome P-450, aminopyrine demethylase, glucose 6-phosphatase and NADPH cytochrome-c reductase; (c) the presence of enzymes related to the glutathione redox cycle (e.g., GSH-peroxidase, GSSG-reductase and different isozymes of GSH-transferase), but accompanied by a very low content in reduced glutathione. The enzyme pattern of BEC correlates well with histochemical and immunohistochemical studies, as well as with biochemical studies on bile ductular cells isolated from rat liver during cholestasis.
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PMID:Biochemical studies on bile duct epithelial cells isolated from rat liver. 197 79

In an attempt to understand the hepatotoxicity associated with immunosuppressive therapy with cyclosporin A, we investigated the effects of acute cyclosporin A administration on biliary secretion, serum bile acid and bilirubin levels and the histological changes in the hepatic parenchyma in anesthetized male Wistar rats. The animals were divided into three experimental groups that received equal volumes (1 ml, intravenously) of physiological saline (controls), cyclosporin A vehicle (a fat emulsion, Intralipid, mixed with absolute ethanol) or cyclosporin A dissolved in the aforementioned mixture. In another series of assays, horseradish peroxidase was coinjected with cyclosporin A vehicle or with the solution containing cyclosporin A. Only after cyclosporin A administration was an immediate inhibition in bile flow and in the biliary concentrations and secretion of bile acids and bilirubin found. In addition, a delay in the peak time of the appearance of horseradish peroxidase together with a reduction in the biliary excretion rate and in the total amount of horseradish peroxidase excreted were observed during cholestasis. At 40 to 50 min after drug administration, all biliary parameters evaluated had returned to the pretest values. The relationship between bile flow and bile acid secretion showed that cyclosporin A-induced cholestasis is related to a decrease of both the bile acid-dependent and bile acid-independent fractions of bile flow. At the end of the cyclosporin A assays, the serum bile acid, total bilirubin and conjugated bilirubin concentrations were greater than those observed in the controls and Intralipid-treated animals. These effects were dose-dependent. Light microscopy and transmission electron microscopy studies did not reveal architectural hepatic abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of hepatocytary vesicular transport by cyclosporin A in the rat: relationship with cholestasis and hyperbilirubinemia. 237 89

Aggregation and derangement of cytokeratin intermediate filaments are thought to be the key mechanism in the formation of Mallory bodies in alcoholic liver disease (ALD). To study the incidence and patterns of intracellular distribution of aggregated cytokeratin and to determine its utility as a diagnostic marker of ALD, 108 liver biopsy specimens from patients with various liver abnormalities were examined by an avidin--biotin peroxidase complex technique on paraffin section using a monoclonal antibody to cytokeratins (Hybritech). In normal liver (n = 11), only bile duct epithelium was positive. Both bile ducts and hepatocytes were positive in pathologic livers (n = 97). In ALD, 82 per cent of cases (42 of 51) showed cytokeratin positivity versus 15 per cent (seven of 46) in nonalcoholic liver disease (e.g., chronic hepatitis, nonalcoholic cirrhosis, cholestasis, and primary biliary cirrhosis). The highest incidence (100 per cent, 37 of 37) of positivity was obtained in cases with alcoholic hepatitis and cirrhosis compared with only 36 per cent (five of 14) in alcoholic fatty liver. Mallory bodies were found by the immunoperoxidase method in 71 per cent of cases (30 of 42) versus in 40 per cent (17 cases) by hematoxylin--eosin stain. In alcoholic fatty liver and alcoholic hepatitis, centrilobular hepatocytes showed cytokeratin positivity, whereas such reactivity was seen predominantly at the periphery of the regenerative nodules in alcoholic cirrhosis. A rare periportal hepatocyte was positive in the nonalcoholic group. These findings suggest that the differential distribution patterns of aggregated cytokeratin may be helpful in differentiating alcoholic from nonalcoholic liver diseases.
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PMID:Distribution patterns of cytokeratin antigen determinants in alcoholic and nonalcoholic liver diseases. 243 6

The vesicular transport system for biliary secretion of plasma-derived proteins was investigated in rats with chronic bile duct obstruction. Horseradish peroxidase, previously demonstrated to be a suitable tracer for vesicular transport, was employed in these studies. Both the time course of horseradish peroxidase secretion into bile and the morphological events in its uptake, transport, and biliary secretion were found to proceed in a manner essentially identical to that of sham-operated control animals. In addition, fragmentation of hepatocytes leading to sloughing into bile of large pieces of cytoplasm bearing horseradish peroxidase-containing endocytic transport vesicles frequently was observed in the cholestatic animals. These data suggest that the vesicular transport system for the secretion into bile of plasma-derived proteins remains intact and functional during chronic bile duct obstruction and that another mechanism, possibly fragmentation and solubilization of hepatocyte membranes followed by regurgitation of proteins released from endocytic vesicles, may be responsible for the elevation of biliary proteins within plasma seen during cholestasis.
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PMID:Vesicular transport of horseradish peroxidase during chronic bile duct obstruction in the rat. 661 34


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