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)

This study was designed to test the hypothesis that increasing the infusion rate of bile salts could overcome drug-induced cholestasis. Cholestasis was induced by administration of 17.5 mumol/L estradiol-17 beta-D-glucuronide during the infusion of taurocholate, tauroursodeoxycholate or dehydrocholate at 20 nmol/min/gm liver. After 30 min, a bolus of 10 mumol of the bile salts was added to the perfusate, and the infusion rate of each bile salt was increased. Taurocholate at a rate of 62 or 125 nmol/min/gm liver, caused a prompt dose-dependent increase of the depressed bile flow and bile salt excretion. A higher rate of taurocholate infusion (180 nmol/min/gm liver) was less effective than either the 62 or 125 rate in increasing bile flow. Infusion of tauroursodeoxycholate at 250 or 390 nmol/min/gm liver also led to a dose-dependent recovery. Further increase of tauroursodeoxycholate infusion rate of 580 nmol/min/gm liver did not provide any additional recovery in bile flow. Dehydrocholate, at rates of 62 or 125 nmol/min/gm liver, gave only a slight enhancement of bile flow. Both taurocholate and tauroursodeoxycholate caused a marked removal of the estradiol-17 beta-D-glucuronide, which had accumulated in the liver. At lower taurocholate infusion rates, the estradiol-17 beta-D-glucuronide was excreted mainly in the bile. At the highest rate, however, biliary excretion of estradiol-17 beta-D-glucuronide declined significantly, and a marked back-efflux of the estrogen into the perfusate was noted. In contrast, tauroursodeoxycholate led to enhanced biliary estradiol-17 beta-D-glucuronide excretion at all increased tauroursodeoxycholate infusion rates and to only a small increase in back-efflux of estradiol-17 beta-D-glucuronide at the two highest tauroursodeoxycholate infusion rates.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Estradiol-17 beta-D-glucuronide (E-17G) cholestasis in perfused rat liver: fate of E-17G and choleretic responses to bile salts. 234 47

The infusion of taurolithocholate (TLC) in vivo or in the isolated perfused liver of the rat causes cholestasis and cellular necrosis. In order to analyze the protective effect of bile salts differing in number and steric position of their hydroxy groups against TLC-induced cholestasis, isolated rat livers were perfused with taurocholate (TC), taurohyocholate (THC), tauroursocholate (TUC), taurodehydrocholate (TDHC), and tauroursodeoxycholate (TUDC) (16 and 32 mumol/l) with or without TLC (8 and 16 mumol/l). Bile flow, bile salt secretion, and the hydroxylation pattern of the bile salts secreted were analyzed. TLC caused complete cholestasis after 15 min of perfusion. All bile salts studied had a protective effect. THC, TC, and TUDC completely abolished the cholestasis induced by TLC while TUC did so only for the first 10 min. TDHC was protective only as long as it was biotransformed into hydroxyoxo bile salts. Coinfusion of bile salts did not influence uptake of TLC (greater than or equal to 93% of dose). Differences were found regarding the amount of TLC biotransformed (% of uptake): TC 50%; THC 32%; TUDC 36%; TUC 20%. Light microscopy revealed cellular necrosis, and dilated canaliculi were found in livers perfused with TLC only or in combination with TUC or TDHC, while the other bile salts prevented these changes. We conclude that bile salts with low micelle-forming capacity have little protective effect against TLC-induced cholestasis. These bile salts induce less biotransformation of TLC than TC, THC, and TUDC. The protective effect is not dependent on the hydrocholeretic effect of the added bile salt and is not due to an uptake inhibition.
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PMID:Taurohyocholate, taurocholate, and tauroursodeoxycholate but not tauroursocholate and taurodehydrocholate counteract effects of taurolithocholate in rat liver. 234 95

Bile flow may be considerably increased in human cirrhosis. The mechanism of this increase has not been established. Two mechanisms have been proposed: a) increased canalicular filtration because of sinusoidal hypertension, or b) secretion by proliferated bile ductules. To distinguish between these two possibilities, we examined the determinants of bile secretion in rats with secondary biliary cirrhosis after bile duct obstruction. Sham-operated animals served as controls. Four weeks after bile duct ligation, all animals had cirrhosis. Bile flow was significantly higher and bile salt secretion significantly lower in cirrhotic animals than in controls. Biliary bicarbonate concentration was significantly higher in cirrhotic animals than in controls. Bile-to-plasma concentration ratio of erythritol was significantly lower in cirrhotic animals than in controls, suggesting a dilution of erythritol by a secretion distal to bile canaliculi. Bile-to-plasma ratio of sucrose was not significantly different in cirrhotics and controls, suggesting that paracellular permeability was not modified. Secretin, at the dose of 3 clinical units/100 g, induced an increase of approximately 75 percent in bile flow, and 70 percent in biliary bicarbonate concentration in cirrhotics. In conclusion, bile flow was increased in biliary cirrhosis in rats. The dilution of erythritol, the increase in biliary bicarbonate concentration and the increased response to secretin strongly suggest that increased choleresis was due, at least in part, to secretion by bile ductules or ducts. These results confirm that secondary biliary cirrhosis is a good experimental model for the study of alterations of bile secretion in cirrhosis.
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PMID:[An increase of choleresis in secondary biliary cirrhosis in rats is caused by bile duct secretion]. 235 Dec 43

Tissue cholestasis is a histologic feature in some patients with alcoholic liver disease, but its significance is unknown. We studied prospectively the clinical, laboratory, and histologic findings of 306 chronic male alcoholics in whom liver tissue was available. Tissue cholestasis permitted identification of two groups: group I, absent or mild cholestasis (239 patients), and group II, moderate to severe cholestasis (67 patients). Statistical evaluation was performed by Student's t test and regression analyses. In patients with tissue cholestasis, 97% had elevated serum cholylglycine levels, while only 61% had significant jaundice (serum bilirubin greater than 5 mg/dl). In patients without tissue cholestasis, 66% had elevated serum cholylglycine and 13.5% jaundice. Highly significant statistical correlations (P less than 0.0001) were found between cholestasis and malnutrition, prothrombin time, AST, alkaline phosphatase, bilirubin, Maddrey's discriminant function, serum cholylglycine level, albumin, and histologic severity score. In group I, 54% survived 60 months versus 22% in group II (P less than 0.0001). Highly significant statistical correlations (P less than 0.0001) were noted between serum cholylglycine levels and the parameters enumerated earlier, but not with survival. We conclude that tissue cholestasis is a highly significant prognostic indicator of outcome in alcoholic hepatitis and is more consistently associated with bile salt retention than jaundice.
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PMID:Prognostic significance of cholestatic alcoholic hepatitis. VA Cooperative Study Group #119. 236 44

Ursodeoxycholate has been advocated for the treatment of cholestatic liver diseases. The coinfusion of tauroursodeoxycholate with taurolithocholate in the perfused rat liver completely prevented the decrease of bile flow and the increase of oxygen uptake found with taurolithocholate only. Bile flow and bile salt secretion were increased with the coinfusion of both bile acids as compared with the infusion of tauroursodeoxycholate only (+4.30 microliters/g liver per 30 min) with 16 and 32 mumol/l tauroursodeoxycholate (+1.55 microliters/g liver per 30 min with 80 and 160 mumol/l). Morphological examination revealed a 50% decrease of the number of necrotic cells in the periportal area. Tauroursodeoxycholate did not inhibit the uptake of taurolithocholate, but increased its transcellular passage and biotransformation. Thus, tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and liver cell toxicity probably by an intracellular mechanism.
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PMID:Tauroursodeoxycholate prevents taurolithocholate-induced cholestasis and toxicity in rat liver. 236 80

Acid phosphatase, alkaline phosphatase and 5'-nucleotidase activities were analyzed cytophotometrically in cryostat sections of rat liver up to 8 weeks after ligation and transsection of the common bile duct. Ligation resulted in cholestasis and induced alterations in both localization and activity of the enzyme investigated. The cellular distribution but not the activity of acid phosphatase changed in liver parenchyma. In control liver, the final reaction product was localized as discrete granules in the bile canalicular region of hepatocytes. The final reaction product was precipitated more diffusely within the cytoplasm after induction of cholestasis, most probably due to increased fragility of lysosomal membranes. In control liver, alkaline phosphatase activity was low and localized in the bile canalicular plasma membranes only. The total parenchymal activity increased threefold after the induction of cholestasis and is considered to be a compensatory mechanism in order to enhance the excretion of bile salts from hepatocytes. 5'-Nucleotidase was present at the bile canalicular and sinusoidal surfaces of plasma membranes of hepatocytes in control liver; total activity in pericentral areas was significantly higher than in periportal areas. Induction of cholestasis resulted in higher total activity and redistribution of the activity over all three surfaces of the plasma membranes, whereas heterogeneity over the different zones of the acinus disappeared. The appearance of the enzyme at lateral plasma membranes is suggested to be related to the formation of new sites for bile salt transport out of the hepatocytes. With respect to all three enzymes studied, alterations of liver parenchymal cells due to a disturbed bile transport were already established during the first week of cholestasis.
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PMID:Quantitative changes in acid phosphatase, alkaline phosphatase and 5'-nucleotidase activity in rat liver after experimentally induced cholestasis. 238 57

A method is described for the rapid determination of urinary bile salt profiles by fast atom bombardment--mass spectrometry (FAB-MS). Urine was passed through a reverse-phase octadecylsilane bonded silica cartridge and the bile salts eluted with methanol. Negative ion FAB spectra could be obtained from the equivalent of 10 microliter of urine loaded onto the target probe with glycerol as matrix. In samples from normal infants and children bile salt peaks were rarely detectable above the background whereas peaks produced by steroid sulphates and glucuronides and bile alcohol glucuronides could usually be identified. In samples from infants and children with cholestasis the major peaks were produced by the taurine and glycine conjugates of di-, tri- and tetrahydroxycholanoic acids (and their monosulphates). In samples from patients with Zellweger syndrome and infantile Refsum's disease, a unique ion at m/z 572 indicated the presence of taurine-conjugated tetrahydroxy-cholestanoic acid(s). The amide linkage to taurine was cleaved by alkaline hydrolysis but not by cholylglycine hydrolase. Capillary gas chromatography--mass spectrometry (GC-MS) of the bile acids liberated by alkaline hydrolysis indicated the presence of at least two nuclear-tetrahydroxylated cholestanoic acids, probably the 6 alpha- and 1 beta-hydroxylated derivatives of 3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholestan-26-oic acid.
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PMID:Rapid diagnosis of Zellweger syndrome and infantile Refsum's disease by fast atom bombardment--mass spectrometry of urine bile salts. 243 77

Evidence of hepatic dysfunction (clinically, chemically, and morphologically) and biliary-tract abnormalities is common in patients receiving TPN. The entity might present as hepatocellular injury (fatty liver, steatonecrosis), intrahepatic cholestasis, acalculous cholecystitis, or cholelithiasis. Infants manifest primarily intrahepatic cholestasis, whereas adults manifest fatty liver early and intrahepatic cholestasis later in the course of therapy. Both groups are at risk for the development of biliary-tract abnormalities. Although most of these changes in the adult are mild and reversible, a small number of patients have recently been reported to develop progressive liver disease. In infants, however, the changes may be more severe, and lead more frequently to progressive liver disease and death. Although this progression to chronic liver disease is worrisome, it is uncertain whether, in patients on long-term therapy, it is due to the TPN or to other conditions or therapies associated with their clinical condition. The pathogenesis of each of these lesions may be multifactorial, including carbohydrate overfeeding, essential-fatty-acid deficiency, amino-acid deficiencies or imbalances, carnitine deficiency, bile-salt toxicity, lipid emulsions, bile-flow reduction, and gallbladder stasis. Therapies in these patients are aimed at alterations in the preceding etiologies (decreased glucose loads, contraction of the gallbladder). Further work is necessary to delineate the exact mechanisms of this entity, especially with regard to the causal relationships of TPN and this entity and to the development of chronic liver disease.
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PMID:Hepatobiliary abnormalities associated with total parenteral nutrition. 250 58

A single i.p. dose of 20 mg/kg of carmustine [1,3-bis-(2-chloroethyl)-1-nitrosourea; BCNU] caused intrahepatic cholestasis in rats within 48 hr of administration. Cholestasis was characterized by a selective reduction of the bile salt independent fraction of bile flow. Increased plasma K+ and decreased plasma Na+ concentrations, consistent with this effect, were observed. Because bile: plasma osmolality and biliary bile salt concentrations were elevated, increased permeability to bile salts and other osmotically active solutes between bile and plasma is unlikely. Bile salt excretion was normal despite the reduced bile flow because biliary bile salt concentration was increased. In contrast, the treated rats were unable to concentrate bromosulfophthalein in bile before, during and after the onset of cholestasis. Because no reduction in hepatic perfusion was observed in vivo in BCNU-treated rats, reduced xenobiotic organic anion excretion may be a selective effect of the drug. The cholestatic effects of BCNU appear to be different from either alpha-naphthylisothiocyanate or estrogenic steroids.
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PMID:Cholestatic effect of carmustine in rats. 254 Mar 12

The effect of therapeutic doses of cyclosporine A (CyA) on bile flow and bile salt output was studied in the rat. Thirty male Sprague-Dawley rats (250 to 380 g) were injected intraperitoneally with CyA (n = 15) or vehicle (n = 15) at the dose of 10 mg.kg-1 for 3 weeks. The effect of CyA on basal and taurocholate-induced bile flow, on basal bile salt output and bile salt output under taurocholate infusion, and the effect of chronic administration of CyA on bile salt-independent bile flow was evaluated. Administration of CyA was associated with a decrease in basal bile flow (5.6 +/- 0.7 vs 6.7 +/- 0.7 microliters.min-1.100 g-1; p less than 0.001) and bile flow under taurocholate infusion (8.0 +/- 0.8 vs 10.9 +/- 1.1 microliters.min-1.100 g-1; p less than 0.001). Basal bile salt output (133.9 +/- 48.2 vs 173.8 +/- 53.6 nmol.min-1.100 g-1; p less than 0.003) and bile salt output under the infusion of taurocholate were significantly lower in cyclosporine-treated rats than in controls (443.3 +/- 48.2 vs 617.2 +/- 172.7 nmol.min-1.100 g-1; p less than 0.001). There was no significant difference in bile salt-independent bile flow between the 2 groups. There was no modification of seric alanine aminotransferase activity or hepatic histology. This study confirms that chronic administration of CyA at therapeutic doses can induce cholestasis. Cholestasis is related mainly to a decrease in bile salt secretion and bile salt-dependent flow.
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PMID:[Effect of chronic administration of cyclosporin A on choleresis in rats]. 259 85


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