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)

Hepatocellular Na+,K+-ATPase is an important driving force for bile secretion and has been localized to the basolateral plasma membrane domain. Cholestasis or impaired bile flow is known to modulate the expression, domain specificity, and activity of various transport systems involved in bile secretion. This study examined Na+, K+-ATPase after ethinylestradiol (EE) treatment and after bile duct ligation (BDL), two rat models of cholestasis. It applied quantitative immunoblotting, biochemical and cytochemical determination of enzyme activity, and immunocytochemistry to the same livers. The data showed a good correlation among the results of the different methods. Neither EE nor BDL induced alterations in the subcellular distribution of Na+,K+-ATPase, which was found in the basolateral but not in the canalicular (apical) plasma membrane domain. Protein expression and enzyme activity showed a small (approximately 10%) decrease after EE treatment and a similar increase after BDL. These modest changes could not be detected by immunofluorescence, immuno EM, or cytochemistry. The data, therefore, demonstrate that Na+,K+-ATPase is only slightly affected by EE and BDL. They suggest that other components of the bile secretory apparatus that take effect downstream of the primary basolateral driving force may play a more prominent role in the pathogenesis of cholestasis.
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PMID:Expression, distribution, and activity of Na+,K+-ATPase in normal and cholestatic rat liver. 948 23

MDR1, an ABC transporter that confers multidrug resistance in tumor cells, is constitutively expressed in normal liver canalicular membrane. Human MDR1-expressing multidrug-resistant cells display increased resistance to estradiol-17beta(beta-D-glucuronide) (E217G). MDR1 substrates/modulators inhibit adenosine triphosphate (ATP)-dependent transport of E217G in the rat canalicular membrane and protect against E217G-mediated cholestasis in isolated perfused rat liver. The present studies were designed to determine if E217G is a substrate for MDR1 using a baculovirus expression system and if other estrogen glucuronides interact with MDR1. ATP-dependent transport of E217G (10 micromol/L) was linear for up to 2 minutes and yielded a rate of 45.6 pmol/min/mg protein in membrane vesicles from Sf9 cells infected with MDR1-baculovirus. This transport was saturable (Km = 62 micromol/L) and occurred into an osmotically sensitive space. ATP-dependent transport of E217G (10 micromol/L) was inhibited 63% by 10 micromol/L daunomycin, but not by 100 micromol/L S-(2,4-dinitrophenyl)glutathione (GS-DNP) (a substrate for canalicular multispecific organic anion transporter [cMOAT]). Glucuronide conjugates of the estrogen D-ring (100 micromol/L), estriol-17beta(beta-D-glucuronide) (E317G) and estriol-16(beta-D-glucuronide) (E316G), inhibited MDR1-mediated E217G transport by 58% and 35%, respectively. In contrast, noncholestatic glucuronides, estradiol-3-(beta-D-glucuronide) (E23G) or estradiol-3-sulfate-17beta(beta-D-glucuronide) (E23SO417G), had no effect. E217G neither stimulated MDR1 ATPase activity nor inhibited verapamil-stimulated ATPase activity. Infusion of 1.5 micromol/L doxorubicin or 1 micromol/L taxol protected against cholestasis induced by E316G and E317G in isolated perfused rat liver. These studies identify E217G, and probably E316G and E317G, as endogenous substrates for MDR1.
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PMID:Adenosine triphosphate-dependent transport of estradiol-17beta(beta-D-glucuronide) in membrane vesicles by MDR1 expressed in insect cells. 979 24

Total parenteral nutrition (TPN) causes intrahepatic cholestasis and membrane phospholipid changes. Fatty acid (FA) composition of bile and hepatocyte phospholipid is influenced by dietary FA composition. We hypothesized that altering FA composition of i.v. lipid emulsions modifies 1) severity of TPN-induced cholestasis; 2) hepatocyte membrane composition and function; 3) bile flow and composition. Newborn piglets received either sow's milk, TPN with i.v. soybean oil or TPN with i.v. fish oil (FO). After 3 wk, basal and stimulated bile flow were measured after bolus injections of 20, 50, and 100 micromol/kg of taurocholate (TCA). Bile was analyzed for bile acids, cholesterol, phospholipids, and phospholipid-FA. Sinusoidal and canalicular membrane PL-FA, fluidity, and Na+/K+-ATPase were measured. Although the soybean oil-fed animals developed cholestasis, the FO and milk group had similar liver and serum bilirubin. Basal and stimulated bile flow rates were impaired in the soybean oil but not in the FO group. Hepatocyte membrane FA composition reflected dietary FA. Changes in sinusoidal and canalicular membrane fluidity and sinusoidal Na+/K+-ATPase activity did not explain the effect of FO on TPN-induced cholestasis. Intravenous FO reduces TPN-induced cholestasis by unknown mechanisms.
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PMID:Intravenous fish oil emulsion attenuates total parenteral nutrition-induced cholestasis in newborn piglets. 1002 91

We studied the effect of cyclosporin A (CyA) on liver plasma membrane (LPM) composition, fluidity, and functions and on hepatic glutathione (GS) and oxidative status. We also evaluated the ability of S-adenosylmethionine (SAMe) to antagonize the CyA-induced disturbances in rats. The animals were randomly divided into four groups and treated daily with saline, CyA vehicle, CyA, and SAMe plus CyA, respectively, for 1 week. Bile, blood, and liver samples and LPM vesicles were obtained at the end of the treatments. CyA-induced cholestasis was associated with alterations in LPM composition and fluidity. The contents of total phospholipids, phosphatidylcholine, and proteins were decreased and cholesterol and the cholesterol/phospholipid molar ratio increased. Na(+), K(+)-ATPase activity was decreased, whereas those of 5'-nucleotidase, Mg(2+)-ATPase, and gamma-glutamyltransferase increased. The hepatic contents of proteins and GS and the reduced/oxidized glutathione molar ratio were decreased and hepatic malondialdehyde increased. SAMe cotreatment 1) significantly improved or abolished the CyA-induced changes in LPM fluidity and composition and the changes in the activity of the carrier and enzymes tested, 2) counteracted the hepatic depletion of GS and proteins caused by CyA and normalized the reduced/oxidized glutathione ratio, and, as expected, 3) prevented cholestasis and the inhibitory effect of CyA on hepatobiliary transport of the major bile components. We conclude that CyA-induced cholestasis and hepatotoxicity in the rat is associated with changes in LPM composition and fluidity, liver GS depletion, and oxidative stress. SAMe cotreatment significantly improves or totally protects against these hepatotoxic effects.
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PMID:S-Adenosylmethionine protects against cyclosporin A-induced alterations in rat liver plasma membrane fluidity and functions. 1041 91

We studied the effect of dietary soybean lecithin or triacylglycerol on hepatic Na+,K(+)-ATPase in cyclosporine A-treated rats by means of quantitative immunocytochemistry. Cyclosporine A-treated rats were fed lecithin or a triacylglycerol-enriched diet or a low-fat diet. As a control, one group was only fed the low-fat diet; the three other groups were treated with cyclosporine A solvent and received the low fat, lecithin, or triacylglycerol diet. Bile canalicular staining significantly decreased in all cyclosporine A-treated groups with the higher values in lecithin-fed rats. In basolateral membranes, no decrease was observed in the lecithin-cyclosporine group, in contrast to the other groups. The triacylglycerol-cyclosporine group had lower values in both membrane domains. The alteration of Na+,K(+)-ATPase by cyclosporine A was related to cholestasis evidenced by a decrease in bile salt secretion. These modifications were prevented by dietary soybean lecithin and amplified by dietary soybean triacylglycerol.
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PMID:Effect of dietary lipids on hepatic Na+,K(+)-ATPase in cyclosporine A-treated rats: immunocytochemical analysis of alpha1 subunit by confocal laser scanning microscopy imaging. 1049 47

Uptake of drugs and metabolites from the circulation into the liver is facilitated by transporter proteins in the basolateral membrane of the hepatocyte. Among these proteins are the sodium taurocholate cotransporting protein, various multispecific transporters for organic anions and cations, transporters for glucose, amino acids, and prostaglandins. The canalicular membrane contains a number of ATP-dependent transporters belonging to the families of P-glycoproteins and multidrug resistance-associated proteins. Transport across the canalicular membrane represents the rate-determining step in the secretion of compounds from blood to bile. Mutations of genes encoding these canalicular transporters are associated with liver diseases such as progressive familial intrahepatic cholestasis and Dubin-Johnson syndrome. Wilson's disease appears to be due to a defect of a copper-transporting P-type ATPase. Also, bile ductuli contribute to bile formation. Mutations in the CFTR gene, encoding a chloride channel in bile duct epithelial cells, leads to the hepatic component of cystic fibrosis.
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PMID:Foreword: from classic bile physiology to cloned transporters. 1107 93

Mutations in the FIC1 gene constitute the molecular defect in familial intrahepatic cholestasis I (Fic1 [Byler's disease]) and benign recurrent intrahepatic cholestasis. This report describes the localization of Fic1 in rat liver and intestine, as well as biochemical and transfection studies that support its function as an energy-dependent aminophospholipid translocase. Immunocytochemistry of rat liver and immunoblotting of membrane fractions localized Fic1 to the canalicular, but not basolateral, plasma membrane domain. In the small intestine, Fic1 was localized to the apical membrane of epithelial cells. The distribution of Fic1 in liver plasma membrane fractions from control and taurocholate-treated rats correlated positively with adenosine triphosphate (ATP)-dependent aminophospholipid (phosphatidyl-serine) translocase activity. In canalicular membrane vesicles, translocase activity had an initial velocity of 3.3 nmol phosphatidylserine (PS) translocated per milligram of protein per minute and a K(m) (ATP) = 1.2 mmol/L; was inhibited by vanadate, N-ethylmaleimide, sodium azide, and calcium; and was unidirectional (i.e., from the outer to the inner canalicular plasma membrane leaflet). Transient transfection of CHOK1 cells with FIC1 cDNA resulted in appearance of FIC1 in membrane preparations and energy-dependent PS translocation in cells. These studies indicate that FIC1 is a canalicular P-type ATPase that participates in maintaining the distribution of aminophospholipids between the inner and outer leaflets of the plasma membrane. How this process produces cholestasis is under study.
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PMID:Familial intrahepatic cholestasis 1: studies of localization and function. 1158 74

A total of 18 white Water female rats weighing 180-200 gm were included in the experiment. 9 rats each received 1 ml of Ovral tablets that had been pulverized for suspension in 100 ml of water, and 9 served as controls. The Na+, K+-adenosine triphosphatase (ATP ase) activity of the liver membrane was measured in both groups from the 6th month. The ATPase plasma membrane activity of 8 control rats averages 6.9 micro mol Pi/mg prot/15 minutes. In rats taking Ovral the activity of total APTase averaged 6.3 +or- micro mol P1/mg protein not significantly deviating from the norm. However, in these rats the Na+, K+-ATPase activity averaged 7.7 +or- 3.1 micro mol Pi/mg prot/15 minutes, while in controls the Na+, K+ - ATP ase activity averaged 6.2 +or- 5.2 micro mol Pi/mg prot/165 minutes. The difference between the 2 groups was significant (p M .01), apparently the inhibition of Na+, K+ - ATP ase activity in rats taking Ovral occurred. The mechanism of the clinical pathogenesis of cholestasis in the liver of women taking oral contraceptives is probably attributable to this effect.
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PMID:[The mechanism of intrahepatic cholestasis induced by oral contraceptives]. 1228 68

Previous findings showed that dietary (n-6) polyunsaturated phosphatidylcholines (vegetable lecithin) could efficiently prevent intrahepatic cholestasis induced by cyclosporine A in rats. Mechanistic studies showed that expressions in rat liver of Na(+), K(+)-ATPase, Ca(2+), Mg(2+)-ATPase and F-actin were both decreased by drug administration and both enhanced by (n-6) lecithin enriched diet. There is a possible direct effect of phosphatidylcholines, vectors of polyunsaturated fatty acids provided by the metabolism of the dietary lecithin, on the aforesaid hepatic parameters. Such modulations by drug and diet result in reversed modifications of membrane composition and fluidity. Final outcome is decreased and enhanced bile lipid secretion by cyclosporine and vegetable lecithin enriched diet respectively. Moreover, we advance the hypothesis of a bypass process including a separate and functional actin-independent way for the non micellar and phospholipid-dependent secretion of bile lipids. The relationships between the ATPases, the microfilament components such as F-actin and the different transporters still remain to be clarified. Furthermore, one can speculate on beneficial effects in humans of diets enriched in vegetable lecithins that might prevent cholestasis induced by cyclosporine A.
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PMID:Prevention by dietary (n-6) polyunsaturated phosphatidylcholines of intrahepatic cholestasis induced by cyclosporine A in animals. 1275 33

ATP8B1/FIC1 is a member of the Type IV P-type ATPase family, which function as ATP dependent aminophospholipid translocases (APLT). We identified two familial intrahepatic cholestasis type 1 (FIC1) homologues, ATP8B2 and ATP8B3, with 53% and 45% amino acid identity, respectively. The expression profile for each gene was determined using a 73-tissue human RNA expression array. The subfamily of FIC1-like proteins is expressed in a wide range of tissues. Given that mutations in FIC1 result in liver disease, these proteins may have important roles in other organs in which they are candidates for genetic and acquired diseases.
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PMID:FIC1, a P-type ATPase linked to cholestatic liver disease, has homologues (ATP8B2 and ATP8B3) expressed throughout the body. 1288 Aug 72


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