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 transport processes responsible for bile flow are reviewed. Canalicular bile acid-dependent flow is the result of active transport of bile acids by the hepatocyte into bile canaliculi. Bile acids are taken up by at least two transport systems whose mRNA have been expressed in Xenopus oocytes: (i) a Na(+)-dependent system, named NTCP, and (ii) a Na(+)- independent system, named OATP. Bile acids are then secreted into bile by two other transport systems, an ATP-dependent system and an 'electrogenic' voltage-dependent system. It is not known whether these two systems are mediated by the same protein or by two different proteins. Canalicular bile acid-independent flow is mainly the result of the secretion of glutathione into bile. The canalicular membrane also contains several proteins of the multi drug resistance (MDR) family. MDRI is responsible for biliary secretion of cationic drugs. MDR3 (mdr 2 in mice) plays a major role in the secretion of phospholipids. A third MDR-related protein has been shown recently to be the canalicular carrier of organic anions, such as bilirubin and dyes (the canalicular multiple organic anion transporter, or cMOAT). Biliary epithelial cells secrete a bicarbonate-rich solution, mostly in response to secretin. This secretion depends upon the presence, on the apical membrane of these cells of the CFTR, a chloride channel activated by cAMP and of a chloride/bicarbonate exchanger. Knowledge of these transport systems should allow a better understanding of the mechanisms involved in cholestasis.
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PMID:Review article: new insights into the mechanisms of hepatic transport and bile secretion. 879 13

beta-Estradiol 17beta-D-glucuronide (E(2)17G), an endogenous cholestatic metabolite of estradiol, has been identified as a substrate for both hepatic P-glycoprotein (P-gp) and the multispecific organic anion transporter (MOAT), the liver-specific homologue of the multidrug resistance protein. The aim of the present studies was to determine the role of hepatic P-gp and MOAT in E(2)17G-mediated cholestasis and its biliary excretion using the isolated perfused rat liver. A bolus dose of E(2)17G (2 micromol) alone decreased the bile flow maximally from 1.5 to 0.3 microl/min/g liver. In the presence of an infusion of 1.5 microM daunorubicin or 1.0 microM Taxol, P-gp substrates, E(2)17G cholestasis was blocked such that 2 micromol E(2)17G decreased the bile flow from 1.48 to 1.31 or from 1.70 to 1.31 microl/min/g liver, respectively. In the presence of 1 and 3 microM Taxol, the log dose-response curves for E(2)17G cholestasis were shifted to the right 2-fold and 5-fold, respectively, in a parallel manner. Taxol (10 and 50 microM) inhibited the ATP-dependent transport of 10 microM E(2)17G in canalicular plasma membrane vesicles by 46 and 81%, respectively. Daunorubicin (1.5 microM) also shifted the log dose-response curve for E(2)17G cholestasis to the right about 4-fold. Neither Taxol nor daunorubicin decreased the biliary excretion of E(2)17G. Infusion of cyclosporine (6 microM), an inhibitor of both P-gp and MOAT, significantly blocked both E(2)17G cholestasis and biliary excretion, such that 16 micromol E(2)17G decreased the bile flow only 15-20%. In contrast, bromosulfophthalein, a MOAT substrate, had no effect on either E(2)17G-mediated cholestasis or its biliary excretion. These data indicate that P-gp plays an essential role in E(2)17G-mediated cholestasis and suggest that MOAT functions to deliver high concentrations of E(2)17G to P-gp.
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PMID:MDR1 substrates/modulators protect against beta-estradiol-17beta-D-glucuronide cholestasis in rat liver. 889 55

Various effects of cholestatic drugs, bile acids, and estrogens on the hepatocyte plasma membranes, as well as their changes in the cholestatic diseases are briefly reviewed. Cyclosporin A inhibits bile salt transporter (BST) on the canalicular membrane (CM). Ethynylestradiol reduces canalicular glutathione excretion. Estradiol-17beta-D-glucuronide interacts with MDR1, and taurochenodeoxycholic acid and lithocholate-3-O-glucuronide may interact with vesicular transport system, each of which may relate with the genesis of cholestasis. In Byler disease, biliary chenodeoxycholic acid excretion is defective. Lipopolysaccharide decreases the function of canalicular multispesific organic anion transporter (MOAT) which seems the first step in septic cholestasis. Obstructive jaundice causes reduced activity of both canalicular BST and MOAT. The mechanisms of choleretic action of S-adenosylmethionine and other drugs are also reviewed.
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PMID:[Intrahepatic cholestasis]. 890 38

The mechanisms involved in ethinyl estradiol-induced cholestasis are controversial. Basal bile flow was reduced by ethinyl estradiol administration, with a half time (t1/2) of 12.5 +/- 0.6 h. In contrast, initial taurocholate uptake was not significantly reduced until 3 days to 59% of control and to 13 and 10% of control at 5 and 7 days, respectively. The t1/2 was 4.3 +/- 0.1 days. These physiological changes were correlated with measurement of protein mass and steady-state mRNA for Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase), Na(+)-dependent taurocholate transporter, organic anion transporters, and membrane lipid fluidity. Ethinyl estradiol significantly decreased Na(+)-K(+)-ATPase activity and membrane fluidity. However, neither Na(+)-K(+)-ATPase alpha-subunit nor beta-subunit mass was altered by ethinyl estradiol administration. In contrast, protein content of the Na(+)-dependent taurocholate transporter was significantly reduced to 21% of control (P < 0.001) at 5 days. The Na(+)-dependent taurocholate transporter was identified in sinusoidal membrane fractions as a doublet with a molecular size estimated to be 51 and 56 kDa. Although both bands were reduced with ethinyl estradiol treatment, the 56-kDa band was decreased more rapidly and to a greater extent than the 51-kDa band. The estimated t1/2 of 4.8 +/- 0.6 days for the doublet was similar to that for Na(+)-dependent taurocholate uptake. The organic anion transporter protein mass was similarly reduced with time of ethinyl estradiol administration to 21% of control (P < 0.01) at 5 days. Ethinyl estradiol also rapidly decreased the steady-state mRNA levels of Na(+)-dependent and organic anion transporters to approximately 50% and 15% of control at 5 days, respectively. These studies indicate early generalized abnormalities of the sinusoidal membrane lipid fluidity, Na(+)-K(+)-ATPase activity, and bile acid transport protein content.
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PMID:Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters. 899 49

Impairment of the hepatic transport of bile acids and other organic anions will result in the clinically important syndrome of cholestasis. Cloning of a number of specific hepatic organic anion transporters has enabled studies of their molecular regulation during cholestasis. The best characterized transport system is a 50-51 kDa sodium-dependent taurocholate cotransporting polypeptide (ntcp), which mediates the sodium-dependent uptake of conjugated bile acids at the sinusoidal plasma membrane of hepatocytes. Under physiologic conditions and after depletion of biliary constituents, ntcp remains constitutively expressed throughout the liver acinus. However, both function and expression of ntcp are rapidly down-regulated in rat liver in various models of experimental cholestasis, such as cholestasis induced by common bile duct ligation, estrogen, endotoxin or cytokine treatment. In addition to ntcp, the sinusoidal organic anion transporting polypeptide oatp-1 is also down-regulated at the protein and steady-state mRNA levels in estrogen-cholestasis, but does not affect sodium-independent uptake of taurocholate. The regulation of a recently cloned member of the organic anion transporter family (oatp-2), which is highly expressed in liver, remains to be studied under cholestatic conditions.
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PMID:Molecular regulation of sinusoidal liver bile acid transporters during cholestasis. 962 56

Hepatic dysfunction in sepsis is characterized by hyperbilirubinemia and intrahepatic cholestasis. We hypothesize that sepsis causes decreased hepatic transcription of the bile acid transporter sodium taurocholate cotransporter (Ntcp) and the organic anion transporter multidrug resistance-associated protein (Mrp2) and that interleukin (IL)-6 is important in the down-regulation of Ntcp and Mrp2 expression. Male Sprague-Dawley rats underwent induction of mild, nonlethal sepsis by cecal ligation and single puncture (CLP) or fulminant sepsis by cecal ligation and double puncture (2CLP). Hepatic transcription of Ntcp and Mrp2 rapidly decreased after CLP or 2CLP. Seventy-two hours later, transcription was 60% of baseline in CLP and 14% of baseline in 2CLP. Serum bilirubin was elevated from 24 h onward and cholestasis was observed on fixed liver specimens at 24, 48, and 72 h after 2CLP but not after CLP. Steady-state Ntcp and Mrp2 mRNA was decreased in IL-6-treated cultured hepatocytes and in normal rats given 1 mg/kg intravenous IL-6. We conclude that 1) Ntcp and Mrp2 transcription is down-regulated transiently after CLP and persistently after 2CLP; 2) 2CLP results in hyperbilirubinemia and cholestasis, in part due to persistently decreased transcription of Ntcp and Mrp2; and 3) altered Ntcp and Mrp2 transcription is mediated in part by IL-6.
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PMID:Intraabdominal sepsis down-regulates transcription of sodium taurocholate cotransporter and multidrug resistance-associated protein in rats. 1094 63

Cholestasis in primary biliary cirrhosis results from impairment of bile flow either by reduced transport at the level of the canaliculi or by disturbed bile flow through damaged intrahepatic bile ductules. Whatever its cause, the expression of hepatic transport proteins will be affected. In cholestatic rats: the expression of the multispecific organic anion transporter mrp2 is decreased; the bile salt export pump bsep and the phospholipid transporter mdr2 are less affected; the carrier protein for hepatic uptake of bile salts ntcp is sharply down-regulated; Mrp3, a basolateral ATP-dependent transporter for glucuronides and bile salts, is upregulated. Thus, bile salts that cannot exit the hepatocyte because of the cholestasis are effectively removed across the basolateral membrane. These may be adaptive responses in defence against overloading of hepatocytes with cytotoxic bile salts. These responses show that the expression of hepatic transporter proteins is highly regulated. This occurs by transcriptional and post-transcriptional mechanisms. Primary biliary cirrhosis starts as a disease of the small intrahepatic bile ducts and therefore the experimental evidence for 'cross-talk' between hepatocytes and cholangiocytes is of great interest for this disease and needs to be further investigated. New insights in bile physiology may enable the development of new therapies for cholestatic liver diseases as primary biliary cirrhosis.
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PMID:The pathophysiology of cholestasis with special reference to primary biliary cirrhosis. 1097 15

Down-regulation of multidrug resistance protein 2 (Mrp2), a major canalicular organic anion transporter, has been reported in various cholestatic models and in patients with cholestasis. In the present study, biliary excretion of taurolithocholate-sulfate and temocaprilat, substrates of Mrp2, was studied in bile duct-ligated rats and in cholestatic rats induced by ethinylestradiol (EE). Biliary excretion of temocaprilat was more markedly decreased in bile duct-ligated rats than that of taurolithocholate-sulfate. In contrast, biliary excretion of both compounds were similarly inhibited in EE-treated rat. Such difference of the degree of inhibition may have been caused by the different degree of the inhibition of unknown canalicular transporters other than Mrp2 in bile duct-ligated rats.
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PMID:Biliary excretion of taurolithocholate-sulfate and temocaprilat in cholestatic rats induced by bile duct-ligation and ethinylestradiol. 1227 Jul 42

Physiological cholestasis linked to immature hepatobiliary transport systems for organic anions occurs in rat and human neonates. In utero, the placenta facilitates vectorial transfer of certain fetal-derived solutes to the maternal circulation for elimination. We compared the ontogenesis of organic anion transporters in the placenta and the fetal liver of the rat to assess their relative abundance throughout gestation and to determine whether the placenta compensates for the late maturation of transporters in the developing liver. The mRNA of members of the organic anion transporting polypeptide (Oatp) superfamily, the multidrug resistance protein (Mrp) family, one organic anion transporter (OAT), and the bile acid carriers Na(+)-taurocholate cotransporting polypeptide (Ntcp) and bile salt export pump (Bsep) was quantified by real-time PCR. The most abundant placental transporters were Oatp4a1, whose mRNA increased 10-fold during gestation, and Mrp1. Mrp1 immunolocalized predominantly to epithelial cells of the endoplacental yolk sac, suggesting an excretory role that sequesters fetal-derived solutes in the yolk sac cavity, and faintly to the basal syncytiotrophoblast surface. The mRNA levels of Oatp2b1, Mrp3, and Bsep in the placenta exceeded those in the fetal liver until day 20 of gestation, suggesting that the fetus relies on placental clearance of substrates when expression in the developing liver is low. Mrp3 immunolocalized to the epithelium of the endoplacental yolk sac and less abundantly in the labyrinth zone and endothelium of the maternal arteries. The placental expression of Oatp1a1, Oatp1a4, Oatp1a5, Oatp1b2, Oat, Ntcp, Mrp2, and Mrp6 was low.
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PMID:Temporal expression profiles of organic anion transport proteins in placenta and fetal liver of the rat. 1534 72

To investigate how the liver adapts to chronic obstructive cholestasis, liver samples from infants with early- and late-stage cholestasis were analyzed for changes in the levels of hepatocyte transporters and nuclear receptors. At early-stage cholestasis, most canalicular transporters and sinusoidal uptake transporters were downregulated, including bile salt export pump (BSEP, ABCB11), multidrug resistant protein 3 (MDR3, ABCB4), multidrug-resistant associated protein 2 (MRP2, ABCC2), sodium-dependent taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporter (OATP, SLCO1A2), and nuclear receptor farnesoid X receptor (FXR, NR1H4). At late-stage cholestasis, FXR-BSEP levels returned to normal, MDR3 and MDR1 (ABCB1) were upregulated, and MRP-2 was downregulated. In addition, alternative sinusoidal efflux transporters, organic solute transporter alpha/beta (OSTalpha/beta) and MRP4 were upregulated, and pregnane X receptor (PXR, NR1I2) levels decreased. Cytochrome enzyme P450 7A1 was markedly downregulated at both early and late-stage cholestasis. An analysis of the long-term prognosis of 18 patients revealed lower PXR and constitutive androstane receptor (CAR, NR1I3) levels in the poor prognosis group. In conclusion, at long-term cholestasis, hepatocyte bile efflux was through sinusoidal and canalicular transporters, with FXR-BSEP levels maintained and PXR downregulated. Low PXR and CAR levels were associated with poor prognosis.
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PMID:Expression of hepatocyte transporters and nuclear receptors in children with early and late-stage biliary atresia. 1832 54


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