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)

Glucuronides of lithocholate, chenodeoxycholate and cholate were synthesized enzymatically and characterized by thin layer chromatography, column chromatography and specific enzymatic hydrolysis. Bile salt glucuronides were quantitatively analysed in thr urine of patients with intra- and extra- hepatic cholestasis and were found to be present in 19 out of 20 patients studied. Our patients with intrahepatic cholestasis excreted 8.9 mg non-sulphated and non-glucoronidated bile salts, 18.2 mg sulphated bile salts and 7.2 mg glucuronidated bile salts. The patients with extrahepatic cholestasis excreted 14.7 mg non-sulphated and non-glucuronidated bile salts, 20.7 mg sulphated bile salts and 4.7 mg glucuronidated bile salts. These findings indicate that glucuronidation of bile salts occurs in man and represents a metabolic pathway in patients with cholestasis.
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PMID:Bile salt glucuronides: identification and quantitative analysis in the urine of patients with cholestasis. 125 9

S-adenosyl-L-methionine (SAMe), a molecule naturally present in several body tissues and fluids, is produced, by SAMe synthetase, from ATP and methionine. SAMe has a fundamental role, as methyl group donor, in transmethylation reactions in which the synthesis of membrane phospholipids (especially phosphatidylcholine) is mandatory for the maintenance of membrane fluidity. Another metabolic pathway involving SAMe, transsulphuration, is initiated with the release of -CH3 from the molecule and the formation of S-Adenosyl-homocysteine and then homocysteine and cysteine, a precursor of glutathione the main cellular antioxidant, responsible of detoxification of various compounds and xenobiotics. At last SAMe is implicated in aminopropylation process for the polyamine synthesis. The development of stable double salt of p-toluene sulphonic acid and sulphuric acid of SAMe enables the clinical use of the drug, as a therapeutical agent, for the treatment of a number of liver dysfunctions. In various animal and human models, including controlled trials, it has been demonstrated that SAMe can ameliorate some biochemical parameters and pruritus in cholestasis induced by a range of compounds (i.e. oestrogens, lithocolate, etc) and in intrahepatic cholestasis superimposed to chronic liver disease. Concerning alcohol toxicity, SAMe prevents, in ethanol fed baboons, depletion of glutathione levels, normalizes the mitochondrial enzymes and improves the histological hepatic lesions. In human healthy volunteers it has been recently demonstrated that SAMe, after ethanol ingestion, significantly lowers plasma concentration of ethanol and acetaldehyde as well. Finally, SAMe has been proposed, instead of N-acetylcysteine, as precursor of glutathione, in patients who present late after ingestion of an overdose of paracetamol.
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PMID:[S-adenosyl-L-methionine (SAMe) and its use in hepatology]. 129 37

In order to cast light on the anti-cholestatic and cytoprotective properties of ursodeoxycholic acid (UDCA), intrahepatic transport and secretion of bile salts and biliary phospholipids were investigated by using isolated perfused livers from colchicine-pretreated rats. Administration of taurocholic acid (TCA) after colchicine pretreatment induced marked cholestasis. Tauroursodeoxycholic acid (TUDCA) treatment, in contrast, was associated with maintenance of bile flow, with excretion rates of bile acids and phospholipids similar to those in control animals. Furthermore, TCA-induced cholestasis in colchicine-treated rat livers was clearly decreased by co-administration of TUDCA. Although simultaneous addition of UDCA also showed slight improvement, with or without taurine pre-treatment, biliary bile-salt analysis also showed that cholestasis was markedly remitted as the excretion of taurine-conjugated UDCA was increased. The results suggest that the cytoprotective and anti-cholestatic effects of TUDCA may be linked to action at the intrahepatocyte level, represented by mild detergent effects on organelle lipids and preservation of intracellular transport even under microtubule-dysfunctional conditions. In addition, it was indicated that cytoprotective effects of UDCA may also be exerted after its conjugation with taurine inside hepatocytes.
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PMID:Microtubule-independent choleresis and anti-cholestatic action of tauroursodeoxycholate in colchicine-treated rat liver. 136 Nov 25

The retrospective analysis of 3 clinical observations points out the etiopathogenetic, clinical and therapeutical aspects of the diffuse stenotic cholangitis, which can occur after the surgical treatment of the hepatic hydatid cyst. Although rare (2.9% of hydatid cysts, 13% of those which communicate with the bile ducts), the diffuse stenotic posthydatid cholangitis represents a severe postoperative complication in cases of median cysts, exerting a compression upon the convergence of hepatic ducts and communicating with the biliary tract. Its presence should be clinically suspected if a mechanical icterus with septic angiocholitis, sometimes associated with an external biliary fistula (from the residual cavity), occurs in the postoperative course of these patients, especially if the primary operation has excluded the remanance of an obstacle at the level of the main bile duct. The lesional substrate is comparable with that of the primitive sclerosing cholangitis, from which it differs through its clear relation with the primary treatment of the hepatic hydatid cyst, through the rapid course of stenotic lesions which, although diffuse, may become more marked in certain segments, as well as through the constant suprastenotic dilatation of the bile ducts. In the pathogenesis are involved the caustic action of some scolicide solutions (2 per cent formaldehyde solution, hypertonic salt solution) on the wall of the bile duct and the cystobiliary communication which predisposes to the peroperative occurrence o-a migration syndrome and of angiocholitis. It requires an early surgical reintervention in order to solve the cholestasis and angiocholitis: according to the morphological situation, we have the choice between disobstruction and trans-stenotic calibration drainage, on the one hand, and biliodigestive derivations in the hilum, which are more efficient, on the other. The prognosis is burdened with the vital risk of septic angiocholitis and with the early occurrence of a secondary biliary cirrhosis or of stenotic recurrences. Prophylaxis consists in the performance of a primary surgical treatment, adequate in median and communicating hydatid cysts, avoiding the "blind" intracystic administration of scolicide solutions, which exert a caustic action on the bile ducts.
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PMID:[Sclerosing cholangitis in the evolution of a surgical hepatic hydatid cyst]. 136 83

The mechanisms involved in bile salt-induced choleresis are poorly known. To give an insight in this physiological process, bile salt-associated electrolyte secretion was studied following relief of a short-term (2h) biliary obstruction in the rat, an experimental model that shows an important diminution of bile salt choleretic efficiency. For this purpose, biliary excretion of total bile salts and electrolytes (sodium, chloride and bicarbonate) were studied in such a model during taurocholate infusion at increasing rates. The results showed that bile flow, bile salt output and electrolyte secretion stimulated by taurocholate administration were decreased in the rats that were subjected to biliary obstruction. Besides, the choleretic efficiency of the excreted bile salts, as estimated by the slope of the regression line of bile flow vs. bile salt output, was diminished by 46% (p < 0.005). Multiple regression analysis of bile flow vs. bile salt and electrolyte outputs allowed to detect a selective diminution of the fraction of bile flow related to bile salt-associated electrolyte secretion ("secretory fraction" of the choleretic efficiency of bile salts) (3.2 +/- 0.3 vs. 2.5 +/- 0.2 L/mol, p < 0.05) whereas the "osmotic fraction" of the choleretic efficiency of bile salts was not modified by the treatment (5.0 +/- 0.4 vs. 5.1 +/- 0.3 L/mol, p > 0.05). Since both chloride and bicarbonate biliary concentrations in the volume of bile stimulated by taurocholate were reduced by 53% and 52% respectively, a role of these anions in the generation of bile salt-induced choleresis was suggested. Possible mechanisms involved in such a process and in its early impairment during cholestasis are discussed.
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PMID:Bile salt-associated electrolyte secretion. A study following a short-term biliary obstruction in the rat. 145 Jun 54

In order to study their effects on the bile secretion, cyclosporine and methylprednisolone were injected intravenously into rats at a dose of 10 mg/kg b.w. for 30 min. Methylprednisolone had no effect on bile secretion. Cyclosporine led to transient intrahepatic cholestasis characterized by decreased bile flow as well as a decrease of bile salts and cholesterol in bile. Phospholipid levels were not affected. Liver biopsy showed no particular anomaly. These findings suggest that the observed cholestatic reaction may be due to impairment of the metabolism of cholesterol into bile salts or of the conjugation of bile salts rather than to disturbances in bile secretion. After liver transplantation in humans, cholestasis associated with acute rejection or nonspecific cholestasis cannot be attributed directly to the effect of cyclosporine. Cholestasis can be offset by administering taurocholate at a dose of 10 mumol/min/kg b.w. in order to maintain bile salt and phospholipid levels high enough to ensure proper "vectorization" of cholesterol to bile.
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PMID:Effects of cyclosporine and corticosteroids on bile secretion in the rat. 149 34

Transport processes control not only synthesis and release of LTC4 but also the elimination and excretion of LTC4 and its metabolites. (i) A primary-active ATP-dependent export carrier mediates the release of LTC4 from a leukotriene-generating cell, as exemplified by mastocytoma cells, and as measured in mastocytoma plasma membrane vesicles (2). (ii) Release of cysteinyl leukotrienes into the blood circulation is followed by a rapid elimination with an initial half-life of 38 sec in rats and 4.0 min in man, as measured with the labeled, representative LTC4 catabolite, N-acetyl-LTE4. (iii) 11C-labeled N-acetyl-LTE4 can serve for non-invasive studies on cysteinyl leukotriene elimination and excretion by the liver and kidney in the intact organism using positron emission tomography. An impairment of leukotriene transport from the liver across the canalicular membrane into bile, studied in mutant rats and in extrahepatic cholestasis, leads to a compensatory diversion of cysteinyl leukotriene elimination to the kidney. N-Acetyl-LTE4 labeled with a short-lived positron-emitting isotope provides quantitative insight into the pathways of cysteinyl leukotriene elimination in vivo. (iv) Cysteinyl leukotriene export from the liver into bile is mediated by an ATP-dependent primary-active export carrier. This decisive step in cysteinyl leukotriene elimination has been characterized in hepatocyte canalicular membrane vesicles (3). The leukotriene exporter is deficient in transport mutant rats. The leukotriene carrier is distinct from other ATP-dependent export carriers identified in this membrane domain, such as the ATP-dependent bile salt export carrier (25) and the multidrug export carrier (27).
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PMID:Transport and in vivo elimination of cysteinyl leukotrienes. 149 13

The effect of complete sulfation of conjugated cholic, chenodeoxycholic and deoxycholic acids on bile formation was investigated in rats. The sulfated bile acids were infused intravenously in stepwise increasing doses (1, 2, 3 and 4 mumol/min/100 gm body wt) in rats after 90 min of bile acid pool depletion. The effects of these bile acids on bile flow, bile salt, biliary phospholipid and cholesterol secretion rates were determined. In addition, their choleretic activity and their effect on biliary lipid secretion were calculated. Appropriate controls infused with nonsulfated bile were also performed. The sulfated bile acids increased bile flow with increasing the infusion doses, and the maximum bile flow was significantly higher than nonsulfated bile acids. Although cholestasis was developed during the infusion of nonsulfated bile acids, no cholestatic effect was observed for sulfated bile acids. With the exception of cholic acid, sulfation significantly increased the bile acid secretory rate maximum. The sulfates of chenodeoxycholic and deoxycholic acids were further hydroxylated. The choleretic activities for all the sulfated bile acids were significantly higher than the nonsulfated bile acids. All the sulfated bile acids significantly reduced the biliary lipid secretion, and a significant correlation was found between the choleretic activity and the phospholipid-dependent bile acid secretion. The data also showed that infusion of sulfated taurine-conjugated bile acids produced higher bile flow and bile acid secretion rate and was less effective when biliary lipid secretion rates were reduced compared with glycine conjugates. It is concluded that sulfated conjugated bile acids may have a role in protection during cholestasis either by stimulation of bile flow or by reduction of biliary lipid secretion, thus protecting cell membranes from the detergent properties of high concentrations of nonsulfated bile acids.
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PMID:Effect of complete sulfation of bile acids on bile formation: role of conjugation and number of sulfate groups. 154 24

Male Fischer rats received 0.1 mg/kg (bolus) of elemental aluminum as the sulfate salt via the portal (n = 4) or systemic (n = 4) route of administration. Blood and bile were serially sampled over an 8-h period, postadministration. Aluminum was determined by flameless atomic absorption spectrophotometry. Blood aluminum concentrations declined in a monoexponential fashion, with half-lives of 0.7 h (portal) and 1.08 h (systemic) (p less than 0.05). The corresponding systemic clearances were 48.9 +/- 10.6 and 35.1 +/- 3.64 mL/(h.kg) (p less than 0.05). The systemic availability following portal administration was 0.66, indicating a significant "first-pass" effect. Biliary aluminum recovery (% dose) was negligible following both routes [0.83 +/- 0.062% (portal) versus 1.3 +/- 0.22% (systemic), p less than 0.05]. Bile flow decreased approximately 40% (p less than 0.05) immediately upon injection of aluminum via the portal route only; flow remained suppressed throughout the study. This decrease in bile flow was most likely responsible for the lower biliary recovery with this route. In contrast, liver recovery of aluminum at 8-h postadministration was higher with the portal route (65.4 +/- 4.1 versus 39.4 +/- 2.52%). These results show that reported values for oral "bioavailability" of aluminum, often calculated by the standard AUC ratio method, underestimate the true extent of absorption. One mechanism of aluminum-related jaundice observed clinically may be due to cholestasis.
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PMID:Kinetics of aluminum in rats. III: Effect of route of administration. 154 56

Epomediol (1,3,3-trimethyl-2-oxabicyclo(2.2.2.)octan-6,7-endo,endo-diol) (EPO) is a terpenoid compound shown to reverse 17 alpha-ethinylestradiol (EE)-induced cholestasis in rat. The effect is related to the restoration of normal liver plasma membrane fluidity values. To further characterize the effect of EPO, bile flow and biliary lipid composition were measured in rats treated either with EE or EE associated with EPO. EE significantly reduced the bile flow; this reduction was prevented by concomitant treatment with EPO with an increase in the bile salt secretion rate. EPO alone showed a choleretic effect. The biliary secretion rate of cholesterol was also significantly reduced by EE while being comparable to controls in EE-EPO-treated animals. Phospholipid (PL) biliary excretion was significantly (P less than 0.002) increased by EE either alone or combined with EPO. After EE treatment, the biliary PL composition showed a reduction in phosphatidylcholine (PC) concentration with a parallel increase in lyso-phosphatidylcholine (LPC) when compared to control animals (PC:LPC ratio 5.0 +/- 2.5 vs 26.8 +/- 9.9, mean +/- SD, P less than 0.005). EPO administration to EE-treated rats restored the biliary PC:LPC ratio to control values (27.6 +/- 10.6). EPO alone did not show any appreciable effect as compared to both control and EE-EPO treated animals. As increased concentrations of LPC have been reported to induce an alteration in the function of membrane lipids and membrane-associated proteins, such as regulatory enzymes for bile acid, cholesterol and phospholipid metabolism, these results suggest that the protective effect of EPO in EE-induced cholestasis may be related to the reversal of the alterations in membrane lipid composition and function induced by EE.
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PMID:Effect of ethinylestradiol and epomediol on bile flow and biliary lipid composition in rat. 156 82


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