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

The effects of rifampicin treatment (10 mg.kg-1.day-1) on pruritus and cholestasis were evaluated in 16 patients with primary biliary cirrhosis and pruritus followed up for 2-24 months. Assessment of pruritus severity, liver tests, aminopyrine breath test, and bile acids was done at 2 weeks and every 3 months after the beginning of the study. Two patients (12.5%) were withdrawn after 2 months of treatment because they had hepatitis caused by rifampicin. Four patients were withdrawn after 4 months because of liver transplantation (3 cases) and the development of leg edema associated with administration of rifampicin. The remaining 10 patients received therapy for 14.4 +/- 0.7 months and did not experience side effects. Pruritus improved in all patients and disappeared in 11 patients (79%) after 3 months of treatment. Moreover, all patients followed up for more than 1 year were free of pruritus. The alkaline phosphatase level decreased significantly, and the aminopyrine breath test results increased significantly after 2 weeks of treatment (P less than 0.001) and did not change thereafter. In the 9 patients treated for 15 months, alkaline phosphatase levels decreased to 63% of the basal levels and aminopyrine breath test results increased to 153% of baseline values. Transaminases, gamma-glutamyltransferase, and total bile salt levels decreased significantly after 2 weeks of treatment but returned to baseline after 3 months. No changes in bilirubin and cholesterol levels were observed. It is concluded that long-term rifampicin treatment is effective for relieving pruritus in primary biliary cirrhosis, but liver enzymes should be monitored to detect drug-induced hepatitis.
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PMID:Effects of long-term rifampicin administration in primary biliary cirrhosis. 158 27

Methyl isobutyl ketone was found to potentiate intrahepatic cholestasis induced by taurolithocholate and the combination of manganese-bilirubin. The aim of this study was to elucidate the mechanism of this potentiation using the lithocholate-induced cholestasis model. Male rats were given methyl isobutyl ketone 7.5 mumol/kg body wt. daily for 3 days. The effect of this treatment on lithocholate-induced cholestasis, bile formation and taurocholic acid transport was examined. The data showed that methyl isobutyl ketone treatment potentiated lithocholate-induced cholestasis and reduced significantly bile salt, phospholipid and cholesterol secretion rates as well as the transport maximum of taurocholic acid. It is suggested that methyl isobutyl ketone potentiates lithocholate-induced cholestasis by reducing the bile salt pool and interfering with the haptic secretion rate of bile salts.
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PMID:Potentiation of lithocholic-acid-induced cholestasis by methyl isobutyl ketone. 160 37

The intravenous administration of dimethylethanolamine in the rat promotes a selective enrichment of liver membranes with polyunsaturated phosphatidylcholines. The effect of dimethylethanolamine pretreatment on cholestasis induced by estradiol 17 beta-D-glucuronide, a potent cholestatic agent, was assessed in this study. Dimethylethanolamine, dissolved in sodium-taurocholate was infused intravenously (0.3 mg/kg/min) for 15 hr. One group of control rats (estradiol 17 beta-D-glucuronide controls) received the bile salt only. An estradiol 17 beta-D-glucuronide bolus was then injected intravenously (10.4 mg/kg) into dimethylethanolamine-pretreated and estradiol 17 beta-D-control rats, and its effect on bile flow and biliary lipid secretion was compared for 3 hr. The estradiol 17 beta-D-glucuronide inhibitory effect on bile flow and biliary lipid secretion was significantly antagonized by dimethylethanolamine pretreatment. The maximum inhibition of bile flow was found 30 min after estradiol 17 beta-D-glucuronide administration, when it decreased from 3.5 +/- 0.4 microliters/min/100 gm (basal) to 0.9 +/- 0.3 microliters/min/100 gm in estradiol 17 beta-D-glucuronide controls, whereas in dimethylethanolamine-pretreated rats this decreased only from 3.2 +/- 0.4 (basal) to 2.3 +/- 0.4 microliters/min/100 gm. Bile flow and the biliary secretion of cholesterol, phosphatidylcholine and bile salts were significantly higher in the dimethylethanolamine-pretreated rats than in estradiol 17 beta-D-glucuronide controls (p less than 0.02) during the cholestatic phase. The inhibitory effect of estradiol 17 beta-D-glucuronide on bile flow was associated with a marked decrease of membrane fluidity (p less than 0.001) assessed by 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy and with a cholesterol enrichment of microsomes, sinusoidal and canalicular liver plasma membranes and inhibition of sinusoidal Na+,K(+)-ATPase activity (p less than 0.05). These membrane alterations persisted 180 min after estradiol 17 beta-D-glucuronide administration despite complete normalization of bile flow. Dimethylethanolamine pretreatment significantly counteracted the reduction of membrane fluidity (p less than 0.001), the cholesterol enrichment and the inhibition of Na+,K(+)-ATPase (p less than 0.05) promoted by estradiol 17 beta-D-glucuronide administration in all membrane subfractions 30 and 180 min after administration. In addition, dimethylethanolamine-pretreated rats had more polyunsaturated fatty acids in membrane phosphatidylcholine with respect to the control groups. Dilatation of canaliculi and loss of microvilli were evident in estradiol 17 beta-D-glucuronide controls 180 min after estradiol 17 beta-D-glucuronide administration.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Improvement of estradiol 17 beta-D-glucuronide cholestasis by intravenous administration of dimethylethanolamine in the rat. 164 61

To examine whether intravenous bilirubin infusion causes cholestasis and impairs liver metabolism, bile secretion and ethanol clearance were measured in 34 anaesthetized pigs before and after intravenous infusion of 0.5 mumol kg-1 min-1 bilirubin for 4.5 hours. Bilirubin infusion increased plasma bilirubin to 556 +/- 76 mumol l-1 and hepatic tissue bilirubin to 3.5 +/- 1.3 mmol kg tissue weight-1. Bilirubin infusion depressed bilirubin secretion and net hepatic uptake of cholate and taurocholate, and caused a 86 +/- 6% reduction of cholate-induced bile secretion. Bilirubin caused formation of large cytoplasmic vacuoles in hepatocytes and dilatation of bile canaliculi. Ethanol clearance and secretin-dependent ductular bile secretion were unaffected by bilirubin. We conclude that intravenous infusion of unconjugated bilirubin causes accumulation of bilirubin in the liver, vacuolization of the hepatocyte cytoplasm and canalicular but not ductular cholestasis. The canalicular cholestasis is not due to impaired hepatic mitochondrial energy metabolism, but may be due to inhibition of a common pathway for lipid, bilirubin and bile salt secretion from hepatocytes.
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PMID:Intravenous bilirubin infusion causes vacuolization of the cytoplasm of hepatocytes and canalicular cholestasis. 181 76

Intraduodenal infusion of hydrophobic bile salts to bile-fistula rats leads within hours to severe hepatocellular necrosis and cholestasis; simultaneous administration of conjugates of ursodeoxycholate, either intraduodenally or intravenously, reduces or prevents liver injury. To evaluate the short-term protective effects of ursodeoxycholate at the cellular level, we incubated primary monolayer cultures of adult rat hepatocytes or freshly isolated washed human erythrocytes for 1 to 240 min with varying defined concentrations of different bile salts in the presence or absence of ursodeoxycholate. Cytolysis was quantified by measuring the release into the medium of cytosolic lactate dehydrogenase (hepatocytes) or hemoglobin (erythrocytes). In both systems, cytolysis increased sigmoidally with increasing bile salt concentration, and the relative toxicity of different bile salts proceeded in the following order: tauroursodeoxycholate was less toxic than taurocholate, which was less toxic than taurodeoxycholate. Taurochenodeoxycholate was more toxic to erythrocytes than taurodeoxycholate; the two were equally toxic to rat hepatocytes. Unconjugated bile salts were more toxic than their conjugates. The addition of tauroursodeoxycholate to taurochenodeoxycholate or taurodeoxycholate led to time-dependent and concentration-dependent reduction or elimination of the toxicity of the more hydrophobic component. Protection was evident within minutes. With respect to hemolysis, at pH 8.5 glyco was less protective than tauroursodeoxycholate, and free ursodeoxycholate was only minimally protective. We conclude that the hepatocytotoxicity of hydrophobic bile salts at millimolar concentrations is markedly reduced in the presence of tauroursodeoxycholate. Conjugates of ursodeoxycholate also prevented disruption of erythrocytes by bile salts, suggesting that protection does not depend on liver-specific pathways of bile salt uptake, compartmentation, transport or metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Conjugates of ursodeoxycholate protect against cytotoxicity of more hydrophobic bile salts: in vitro studies in rat hepatocytes and human erythrocytes. 193 96

The protective effect of ursodeoxycholate conjugates against bile salt hepatotoxicity was studied in chronic bile fistula rats. Taurochenodeoxycholate or taurodeoxycholate, infused intraduodenally at 24 or 16 mumols/100 g rat per hour, respectively, caused cholestasis and severe hepatocellular necrosis within 8 hours. In contrast, tauroursodeoxycholate or taurocholate at 48 mumols/100 g rat per hour were choleretic. Tauroursodeoxycholate was not hepatotoxic, whereas taurocholate produced moderate hepatocellular necrosis. Simultaneous infusion of tauroursodeoxycholate to rats receiving taurochenoxycholate or taurodeoxycholate preserved bile flow and ameliorated hepatic injury in a dose-dependent manner. Tauroursodeoxycholate protected equally by intravenous and intraduodenal routes. Intravenous glycoursodeoxycholate also was protective. The hydrophobicity index of infused bile salts correlated well with their toxicity. Concurrent administration of ursodeoxycholate conjugates did not reduce biliary recovery of intraduodenally infused [24-14C]-taurocholate. Biliary alkaline phosphatase secretion was stimulated by infusion of taurocholate, taurodeoxycholate, or taurochenodeoxycholate; simultaneous infusion of ursodeoxycholate conjugates failed to prevent this increase. We conclude that ursodeoxycholate counteracts hepatoxicity of more hydrophobic bile salts via a direct effect at the level of the liver.
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PMID:Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts. In vivo studies in the rat. 198 22

The uptake and release of radiochromium from adult human vascular endothelial cells in culture was employed to determine the relative toxicity of different bile salts. Endothelial cells after pre-incubation with 51Cr for 18 h were incubated with bile salts for 24 h and percentage chromium release was taken as a measure of toxicity to cells. Lithocholic acid (LC) (potassium salt) was cytotoxic at concentrations greater than 50 microM. However, LC glucuronide, sulfate and the beta-epimer were progressively less toxic with toxicity seen at concentrations of 60, 110 and 180 microM, respectively. The greatest cytotoxic effect was observed with glycolithocholic acid (GLC) (potassium salt) which was toxic at every concentration tested (20-200 microM). Sulfation abolished the toxic effect of GLC. At the concentrations employed for the assay (between 20 and 240 microM) GLC sulfate (disodium salt), taurolithocholic acid sulfate (disodium salt), cholic acid (sodium salt), glycocholic acid (sodium salt), deoxycholic acid (sodium salt) and ursodeoxycholic acid (sodium salt) were not cytotoxic. The 51Cr release cytotoxicity assay was validated with lactate dehydrogenase leakage from endothelial cells with a good correlation (r = 0.87). These data confirm in a human cellular system that LC and its conjugates were the most toxic of the bile salts tested and explains its pathophysiological importance in hepatobiliary disease. It also suggests that biotransformation by either sulfation or beta-epimerisation of bile salts especially of LC, as occurs in patients with intrahepatic or extrahepatic biliary obstruction or severe cholestasis, is hepatoprotective.
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PMID:The effect of bile salts on human vascular endothelial cells. 199 66

The major biological functions of S-adenosyl-L-methionine (SAMe) include methylation of various molecules (transmethylation) and synthesis of cysteine (trans-sulphuration). A stable double salt of SAMe has been found to be effective in intrahepatic cholestasis. The mechanism of its therapeutic effect is not fully understood but presumably involves methylation of phospholipids. Methylation of plasma membrane lipids may affect membrane fluidity and viscosity, which modulate the activities of a number of membrane-associated enzymes, for example, the activity of enzymes involved in Na+/Ca++ exchange (e.g. sarcolemmal vesicles), Na+/K+ adenosine triphosphatase (ATPase) [e.g. hepatocyte plasma membranes], and Na+/H+ exchange (e.g. plasma membranes of colonic cells). Recently, patients with cirrhosis were shown to have an acquired metabolic block in the hepatic conversion of methionine to SAMe. These patients, when administered conventional elemental diets, develop abnormally low plasma concentrations of cysteine and choline, 2 nonessential nutrients present in low concentrations in most elemental diets. These low concentrations probably reflect systemic deficiencies attributable to reduced endogenous syntheses of cysteine and choline caused by limited availability of hepatic SAMe. Such cirrhotic patients are often in negative nitrogen balance and have abnormal hepatic functions, which are corrected by cysteine and choline supplements. Noncirrhotic patients on parenteral elemental diets also become deficient in cysteine and choline. Consequently, these patients may require SAMe as an essential nutrient to normalise their overall hepatic transmethylation and trans-sulphuration activities.
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PMID:Biochemistry and pharmacology of S-adenosyl-L-methionine and rationale for its use in liver disease. 208 85

The prostaglandin system is impaired in cholestasis; bile salts, which are a specific biochemical feature of this condition, have been shown to affect functional properties of cells and tissues, and, in some cases, their action is mediated through an alteration of prostaglandin pathway. Endothelium is a privileged site for the production and the action of arachidonate metabolites-prostacyclin in particular. To determine the effects of bile salts on the properties of vascular endothelium, cultured human endothelial cells were studied. Cholic acid sodium salt was seen to induce a direct injury on endothelial cells, as was demonstrated by a massive dismission of the intracellular radiolabel chromium 51. In the absence of detectable toxic effect, sodium taurocholate caused a significant depression of prostacyclin constitutive production from human endothelial cells. The action of sodium taurocholate was related to its concentration and to the time of exposure, and the alteration of prostacyclin production was found to be reversible. Conversely, the generation of thromboxane A2 was not influenced by this bile salt, which may suggest a specific action of sodium taurocholate on arachidonic acid metabolism. These findings indicate that bile salts may directly alter some functional properties of cultured human endothelial cells and may provide a basis for explaining some generalized manifestations that are observed in pathologic conditions characterized by cholemia.
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PMID:Sodium taurocholate affects prostacyclin constitutive production by cultured human vascular endothelial cells. 211 71

Cyclosporine A is reported to cause cholestasis, but the evidence is confounded by anesthesia and surgery used in acute experiments. To better investigate the effect of cyclosporine on the liver, bile output was directly measured in three cholecystectomized dogs by cannulating the common duct through a chronic duodenal fistula. Control studies were done 1 month after surgery. Cyclosporine in oral doses of 5, 15, and 50 mg.kg-1.d-1 was then given for consecutive 1-week periods. Twice during each study period, bile output was measured for 5 h in fasted, awake animals: 3 h to establish basal conditions, followed by 2 h of taurocholate infusions at 1 and then 2 mumols.kg-1.min-1. Under basal conditions, bile flow rose with each dose of cyclosporine, increasing 63, 127, and 179% above control with cyclosporine 5, 15, and 50 mg.kg-1,d-1, respectively. Bile flow increased similarly during taurocholic acid stimulation. Cyclosporine had no effect on bile salt or bilirubin secretion. In this chronic dog model isolated from other causes of cholestasis, cyclosporine did not induce cholestasis but rather caused a dose-related choleresis without any change in bile salt secretion.
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PMID:The effect of cyclosporine A on bile secretion in dogs. 232 41


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