Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-five patients were treated for retained, recurrent, or primary common duct stones by permanent drainage of the biliary tract with external choledochoduodenostomy. Twenty-one patients had common duct stones which became evident two to fifty years after the initial biliary tract procedure and which may represent stones formed in the common duct. Three recent patients had a clinical history of primary common duct stones, had stones which were soluble in chloroform-methanol solution, and had hepatic bile which was lithogenic as determined by evaluating the molar percentage of cholesterol, phospholipid, and bile salt in bile samples obtained at the time of choledochoduodenostomy. These data suggest that further stone formation is possible and that permanent bypass of the sphincter of Oddi is indicated to prevent recurrent bile duct obstruction. Long-term evaluation of the results of external choledochoduodenostomy indicates that the procedure is safe and effective in the prevention of recurrent biliary tract calculi.
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PMID:Evaluation of the results of external choledochoduodenostomy for retained, recurrent, or primary common duct stones. 10 40

We studied the acute effects of intravenous infusions of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the alert female Rhesus monkey prepared with a total biliary fistula and in a steady bile salt secretory state. In twelve studies (three animals), five doses of radiolabelled chlorpromazine hydrochloride (1-10 mg identical to 2.8-28 mumol/kg) were infused intravenously for 1 h in random order. Cholestasis was induced within minutes in all experiments. The radiolabel appeared rapidly in bile, with similar recoveries in bile and urine and a 90% total cumulative output in 4 days. Both bile flow, bile salt and other biliary lipid outputs were inhibited in a dose related and reversible manner. The apparent bile salt independent bile flow was consistently abolished, and a prompt return to basal values occurred when biliary concentration of the drug and metabolities fell below 1-2 mM. When chlorpromazine hydrochloride was infused at three doses (2.5, 5.0 and 10.0 mg identical to 7-28 mumol/kg) during constant intravenous infusion of 14C sodium taurocholate (300 mumol/h), bile flow, total bile salt output and 14C taurocholate output decreased within minutes. This was accompanied by a progressive rise in the serum 14C taurocholate concentration. After 90 min the taurocholate specific activity in bile increased significantly indicating that bile salt synthesis was inhibited. Secretion of retained bile salts and reversal of inhibition of bile salt synthesis occurred with time: the course of both events was correlated with the dose of the drug. Thus, in monkeys, chlorpromazine hydrochloride induces reversible, dose related cholestasis suppression of the bile salt dependent and independent flow, inhibition of bile salt synthesis and impairment of biliary lipid secretion. We suggest that these effects are due to both bile salt-chlorpromazine interactions and the effect of the latter on canalicular and other membranes.
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PMID:Effects of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the rhesus monkey: a model for chlorpromazine-induced cholestasis. 11 May 98

At [Na+]o = 118 mM the concentrative transfer of cholic and taurocholic acid from the perfusate into the isolated rat liver displays saturation kinetics (taurocholate: V = 299 nmol-min-1-g-1, Km = 61 muM; Cholate: V=327 nmol-min-1-g-1, Km = 436 muM). Perfusion with an isotonic sodium-free medium did not change the feature of a carrier-mediated transport but did markedly reduce V without affecting Km (taurocholate: V = 65 nmol-min-1-g-1, Km = 78 muM; cholate: V = 104 nmol-min-1-g-1, Km = 354 muM). It was experimentally assured that the observed reduction of bile salt uptake was not a consequence of regurgitation of bile salts or due to an excessive intracellular accumulation during cholestasis in the sodium-free state. The rate of taurocholate efflux is very low when compared with the rapid rate of the uptake. A stimulatory action of extracellular sodium on this pathway was also observed. Inhibition of the (Na+ + K+)-ATPase by 1 mM ouabain resulted in a decrease of bile salt uptake. Activation of the enzyme by potassium readmission to a K+-deprived liver enhanced bile salt uptake. The immediate response to alteration of the enzyme activity suggests a close association of a fraction of bile acid active transport with the sodium pump.
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PMID:Investigations on the sodium dependence of bile acid fluxes in the isolated perfused rat liver. 13 26

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

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

The authors report the case of a patient with transient intrahepatic cholestasis following the administration of a soluble gold salt, sodium aurothiopropanol sulfonate. Other manifestations of intolerance to gold salts included exfoliative dermatitis and eosinophilia.
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PMID:Gold salt-induced cholestasis. 15 59

The characteristic low-density lipoprotein of cholestasis (LP-X) earlier described for humans is found with identical properties in dogs and rats after experimental cholestasis. After ligation of the common bile duct, LP-X may be detected in the plasma within the first 20 hours. A period of marked increase in concentration is followed by decreasing plasma concentrations and LP-X becomes undetectable 7-10 days after ligation of the bile duct in rats. High plasma bile salt concentration may alter the structural integrity of LP-X and may in part be responsible for its disappearance after long-lasting and severe biliary obstruction. Plasma decay curves for isolated LP-X injected intravenously into healthy animals revealed a rapid early fall in concentration followed by a gradual decline. The calculated fractional catabolic rate of LP-X was found to be 0.450 +/- 0.069 for dogs and 1.553 +/- 0.096 for rats corresponding to a mean biological half life of 37.7 +/- 6.4 h or 10.7 +/- 0.6 h, respectively. In vitro LP-X degradation occurs in post-heparin plasma, however, it seems to be too early to speculate on the enzyme activity and on the mode of action responsible for this disappearance.
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PMID:On the metabolism of lipoprotein-X (LP-X). 17 81

The flow rate and ionic composition of bile during spontaneous secretion were measured in anaesthetized penguins in which the enterohepatic circulation had been interrupted and with i.v. injection of saline to replace secretory loss. During the first two hours the rate of flow increased, and then remained relatively constant for a further two and a half hours. During this time the concentration of bile salt fell, but the concentrations of other ions showed small fluctuations only. Sodium taurocholate increased the rate of bile flow and the excretion of ions, except that of bicarbonate. Sodium taurolithocholate initially produced cholestasis but later apparently increased bile flow and had an overall choleretic effect. It is suggested that the active excretion of bicarbonate ions by the bile ducts is the predominant regulator of bile secretion in the penguin.
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PMID:Spontaneous and bile salt stimulated bile secretion in the Adelie penguin (Pygoscelis adeliae). 24 60

Alterations of bile salt metabolism have been shown in numerous diseases. Liver damage results in elevated serum bile salt concentrations which may be useful as a sensitive index of hepatocellular disease. Changes in the relative proportions of the individual bile salts in serum occur with cholestasis. Urinary excretion of bile salts, largely in the form of sulphates, increases as a compensatory mechanism. Ileal disease or resection causes bile salt melabsorption. The increase in colonic bile salts produces a watery diarrhoea while the decrease in duodenal levels may cause steatorrhoea. Cholelithiasis may result from alteration in the relative proportions of cholesterol, lecithin and bile salts in bile. The mechanism apparently differs in various conditions predisposing to gallstone formation. A primary alteration of bile salt metabolism has been postulated in several other conditions. Considerable interest centres on the importance of metabolites of bile salts in the pathogenesis of colonic carcinoma. Chenodeoxycholic acid is a successful though costly treatment for selected patients with cholesterol gallstones. Bile salt binding agents, such as cholestyramine, are extremely useful especially in the control of pruritus in patients with cholestasis.
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PMID:Bile salt metabolism. II. Bile salts and disease. 27 37

Bile acid metabolism was studied in rats with cirrhosis induced by carbon tetrachloride (CCl4). Although the typical histologic features of cirrhosis were seen, cholestasis was not present in these animals as evidenced by a normal total serum bilirubin concentration and by a normal hepatic capacity to remove taurocholate infused intravenously. The cirrhotic rats also secreted taurocholate into bile at a normal rate. The total bile salt pool size in the cirrhotic rats was not significantly different from the pool size in normal rats (10.59 +/- 1.19 mumoles per gm. of liver (+/- 1 standard error of the mean) and 10.43 +/- 0.92 mumoles per gm. of liver, respectively). When the bile was drained externally through a chronic bile fistula, the normal rats increased the bile salt synthetic rate approximately 3-fold after 48 hours of drainage. However, the cirrhotic rats failed to significantly increase the synthetic rate for bile salts in response to biliary drainage. The normal rats also had a significant increase in cholic acid synthesis at the maximal synthetic rate, whereas the cirrhotic rats did not. These findings indicate that (when feedback inhibition is removed) CCl4 cirrhotic rats lack the ability to normally increase the activity of 7 alpha-hydroxylase and 12 alpha-hydroxylase, rate-limiting enzymes in the synthesis of bile salts.
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PMID:Bile acid metabolism in the cirrhotic rat. 51 42


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