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 interpretation of the morphological features of alcoholic hepatitis is discussed in terms of a comparison with the results of an ultrastructural and histoenzymological study of the liver biopsies of nine patients. In these patients liver biopsies were performed in the initial stage of the illness and fifteen days after five were re-biopsied, when the clinical and biological signs were improved. The correlations between morphological and biological data were good, especially for the levels of serological and histoenzymological alkaline phosphatase and gamma-glutamyltranspeptidase evaluations. However, when histological appearances had returned to normal, after two weeks of abstinence from alcohol several histological and ultrastructural features of the initial hepatitis persisted. The presence of evolving cirrhosis was a contributing factor to the severity of the changes seen. Morphologically, apart from the changes due to chronic alcoholic intoxication (steatosis, mitochondrial alteration), the hepatitic lesions comprise Mallory's bodies, cytoplasmic oedema and mitochondrial swelling. Cholestasis was invariably present. Histo-enzymologically there was a reduction in ATPase activity suggesting a metabolic failure in the energy producing pathways. In addition, in the periphery of lobules an active cirrhotic process was present, with tubular de-differentiation of hepatocytes and an increase in gamma-glutamyltranspeptidase on the cytoplasmic membrane. Because of the absence of any topographical relationship between hepatitis and cirrhosis, the presence of lymphocytes in the neighbourhood of the ductules suggested an indirect relationship between both processes, perhaps an autoimmune response initiated by Mallory's bodies.
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PMID:[The hepatocyte in acute alcoholic hepatitis. Histoenzymological and ultrastructural analysis (author's transl)]. 3 Oct 27

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

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

Na +, K + -adenosinetriphosphatase (Na +, K + -ATPase) activity was decreased in liver plasma membranes from rats in which cholestasis had been induced by i.v. administration of sodium taurolithocholate (5 mumoles/100 g b. wt). Incubation of liver plasma membranes with taurolithocholate (10--1300 muM) caused significant and dose dependent reductions of Na +, K + -ATPase activity at taurolithocholate concentrations above 100 muM. These findings lend support to the hypothesis that cholestasis induced by monohydroxy bile acids is at least partially the result of an inhibition of hepatic Na +, K + -ATPase activity.
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PMID:Inhibition of hepatic Na +, K + -adenosinetriphosphatase in taurolithocholate-induced cholestasis in the rat. 22 96

The hepatotoxicity of CPZ was studied in the isolated perfused rat liver in order to more closely define possible mechanisms of phenothiazine-induced cholestasis. Perfusate concentrations of CPZ were increased from 5 x 10(-6) M to 5 x 10(-4) M until bile secretion was significantly inhibited. Measurements were then made of determinants of bile secretory function, including the magnitude of lobar distribution of perfusate flow, BAIF, and liver plasma membrane enzyme activity, Na+,K+-ATPase, Mg++-ATPase and 5'-nucleotidase. BAIF diminished significantly from control values of 1.76 +/- 0.07 microliter min-1gm-1 of liver to 1.34 +/- 0.15 and 0.80 +/- 0.09 following 2.5 and 5 x 10(-4) M CPZ, respectively. Perfusate flow also diminished from 5.64 +/- 0.44 to 1.24 +/- 0.12 ml min-1 gm-1 of liver 20 min following 5 x 10(-4) M CPZ and was associated with reduced flow to peripheral areas of the hepatic lobes as demonstrated by Tc-HAM. By 30 min, perfusate flow had returned to baseline values. CPZ also transiently diminished the excretion of bile acids in livers receiving a constant infusion of 40 mumol hr-1 sodium taurocholate. Defects in hepatic perfusion could not account entirely for the impairment in BAIF, since comparable mechanical restriction of perfusate flow in controls only diminished BAIF to 1.49 +/- 0.08 microliter min-1gm-1 of liver. CPZ signofocamt;u rediced tje secofoc actovotu pf Mg++-ATPase and 5'-nucleotidase but did not affect Na+,K+-ATPase in liver plasma membrane isolated 20 min after 5 x 10(-4) M CPZ. CPZ also resulted in a profound shift in the recovery of protein in isolated liver plasma membrane fractions from the light (density = 1.16) to heavier (density = 1.18) fractions. These findings, together with previous observations demonstrating alterations in hepatic ultrastructure, indicate that CPZ interacts in a complex manner with hepatocyte plasma and cytoplasmic membrane components and suggest that these drug-membrane interactions independently result in diminished hepatic perfusion, impairment of bile acid excretion, and inhibition of bile acid-independent bile secretion.
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PMID:Effect of chlorpromazine on hepatic perfusion and bile secretory function in the isolated perfused rat liver. 22 76

Liver plasma membranes enriched in bile canaliculi were isolated from rat liver by a modification of the technique of Song et al. (J. Cell Biol. (1969) 41, 124-132) in order to study the possible role of ATPase in bile secretion. Optimum conditions for assaying (Na+ plus K+)-activated ATPase in this membrane fraction were defined using male rats averaging 220 g in weight. (Na+ plus K+)-activated ATPase activity was documented by demonstrating specific cation requirements for Na+ and K+, while the divalent cation, Ca(2+), and the cardiac glycosides, ouabain and scillaren, were inhibitory. (Na+ plus K+)-activated ATPase activity averaged 10.07 plus or minus 2.80 mumol Pi/mg protein per h compared to 50.03 plus or minus 11.41 for Mg(2+)-activated ATPase and 58.66 plus or minus 10.07 for 5'-nucleotidase. Concentrations of ouabain and scillaren which previously inhibited canalicular bile secretion in the isolated perfused rat liver produced complete inhibition of (Na+ plus K+)-activated ATPase without any effect on Mg(2+)-activated ATPase. Both (Na+ plus K+)-activated ATPase and Mg(2+)-activated ATPase demonstrated temperature dependence but differed in temperature optima. Temperature induced changes in specific activity of (Na+ plus K+)-activated ATPase directly paralleled previously demonstrated temperature optima for bile secretion. These studies indicate that (Na+ plus K+)-activated ATPase is present in fractions of rat liver plasma membranes that are highly enriched in bile canaliculi and provide a model for further study of the effects of various physiological and chemical modifiers of bile secretion and cholestasis.
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PMID:Properties of (Na+ plus K+)-activated ATPase in rat liver plasma membranes enriched with bile canaliculi. 23 59

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

Recent studies have established the clinical efficacy of S-adenosyl-L-methionine (SAMe) in the treatment of cholestasis associated with hepatic diseases, pregnancy and the administration of estrogen-containing oral contraceptives. In 4 clinical trials involving a total of 639 patients with cholestasis due to acute or chronic liver disease, SAMe in an intravenous dose of 800 mg/day or an oral regimen of 1.6 g/day for 2 weeks was superior to placebo in relieving the symptom of pruritus and in restoring serum total bilirubin and serum alkaline phosphatase towards normal. The drug is also effective in intrahepatic cholestasis of pregnancy (ICP), with intravenous administration of 800 mg/day for 2 weeks producing a substantial reduction in pruritus and an improvement in abnormal liver function indices. Moreover, SAMe treatment decreases the incidence of premature labour. SAMe appears to be the first safe and effective approach to the treatment of this syndrome, and also protects against the adverse hepatic effects of small doses of estrogen in patients with a history of ICP by normalising liver biochemistry and the oversaturated biliary lipid composition of the gallbladder bile. In animal models, SAMe reverses the pathological liver changes induced by xenobiotics such as taurolithocholate and alpha-naphthyl-isothiocyanate (ANIT) and the antipsychotic chlorpromazine. Several cooperative mechanisms appear to underlie the anticholestatic action of SAMe, the most important being the restoration of normal hepatocyte membrane fluidity and Na+, K+ ATPase activity, through a reversal of the reduction in phospholipid methylation produced by hepatotoxic agents. In addition, SAMe may act by promoting trans-sulphuration pathway reactions and consequently improving the detoxifying capacity of this metabolic system.
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PMID:Role of S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis. 208 76

Progress has recently been made in the understanding of normal bile secretion mechanisms. The membrane carriers for bile acids have been identified and new insights into intracellular transport mechanisms have been obtained. In particular, characterization of a vesicular pathway involving the Golgi apparatus is well under way. Hypercholeretic bile acids, such as ursodeoxycholic acid, have been discovered. Their choleretic effect is far greater than that of physiological bile acids and they stimulate bicarbonate secretion. Testable hypotheses to explain their hypercholeretic effect have been proposed, in particular the chole-hepatic shunt hypothesis. Several mechanisms capable of inducing cholestasis have been identified: a) inhibition of Na+, K(+)-ATPase; b) increased permeability of the paracellular pathway leading to leakage of bile constituents back into plasma; c) microtubule or microfilament dysfunction; d) increased cytosolic free calcium concentration due to permeabilization of the endoplasmic reticulum calcium stores. It is not yet possible, in a given case, to establish which of these mechanisms is predominant. Several may operate. A better knowledge of the mechanisms involved may lead to improved treatment.
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PMID:Recent concepts in bile formation and cholestasis. 225 45

Bile acids stimulate synthesis of alkaline phosphatase (ALPase) in the liver. We studied how alterations in bile acid type and load affect ATPase activity in hepatic tissue and in the serum. We increased the load of natural bile acids in rats by bile duct obstruction (BDO) or by creating a shunt between the common bile duct and superior vena cava (choledocho-caval shunt or CCS). Concentration of bile acids and ALPase activity in hepatic tissue rose more rapidly in the BDO model than in CCS. ALPase activity on the hepatocellular surface, normally confined to the canaliculus, spread outward to involve basolateral membrane in livers with high total hepatic ALPase activity. When the bile acid pool was reduced by a 12-hour biliary drainage in the CCS model, surface distribution of ALPase reverted to a nearly normal pattern. We substituted the endogenous bile acid pool with an equimolar amount of the single bile acid, taurocholic (TCA), tauroursocholic, taurohyocholic, or tauroursodeoxycholic acid in the CCS. The first two bile acids have a 12 alpha-hydroxyl group, whereas the latter two do not. After 12 hours, hepatic ALPase activity was increased with TCA or tauroursocholic substitution, but not with taurohyocholic or tauroursodeoxycholic. Again, surface distribution of ALPase activity correlated with the tissue ALPase activity. However, the serum activity increased significantly only with TCA, the most detergent of the bile acids. In bile fistula rats only infusion of TCA accelerated biliary secretion of ALPase. The above results suggest that hepatic synthesis and serum activity of ALPase are influenced by two different features of bile acids: the former by structure (the 12 alpha-hydroxyl group) and the latter by a physical property (detergency).
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PMID:Alkaline phosphatase activity in hepatic tissue and serum correlates with amount and type of bile acid load. 229 60


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