Multiplicity of Hepatic Excretory Mechanisms for Organic Anions

Alpert, Seymour; Mosher, Michael; Shanske, Alan; Arias, Irwin M.

doi:10.1085/jgp.53.2.238

Cited by 104 publications

(23 citation statements)

References 9 publications

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“…In addition, bile salts, the major organic anions in mammalian bile, appear to be excreted by a pathway different from that involved in biliary excretion of other organic anions such as bilirubin, various dyes, and cholecystographic agents (5,6). Theoretically, bile secretory failure (cholestasis) can result from several mechanisms involving these pathways of bile secretion.…”

Section: Introductionmentioning

confidence: 99%

Alteration of Bile Canalicular Enzymes in Cholestasis. A POSSIBLE CAUSE OF BILE SECRETORY FAILURE

Simon¹,

Arias²

1973

J. Clin. Invest.

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A B S T R A C T Bile secretory failure (cholestasis) may result from several possible mechanisms involved in bile secretion. We have examined the possibility that abnormalities in enzyme content, composition, and turnover of liver plasma membrane constituents are altered in cholestasis.Severe and mild cholestasis were produced by 5 days of bile duct ligation and ethinyl estradiol administration, respectively. Bile duct ligation but not ethinyl estradiol treatments was associated with elevations of the serum bilirubin level and 5'-nucleotidase activity. However, basal bile flow and bilirubin transport maximum (T.) were significantly reduced after ethinyl estradiol treatment. Liver plasma membrane fractions rich in canalicular membranes were prepared from groups of rats in each of three categories: normal, after bile duct ligation, or ethinyl estradiol administration, and their respective controls. Electron microscopy and enzyme marker studies demonstrated plasma membrane fractions free of significant contamination.Plasma membrane fractions prepared from mild as well as severe cholestasis had increased alkaline phosphatase activity, and reduced 5'-nucleotidase and Mg'+-ATPase activities. Co'+-CMPase activity was unchanged. Kinetic analysis of 5'-nucleotidase and Mg'+-ATPase activities in plasma membrane fractions demonstrated reduced Vrna (but unaltered Ki). Reducted Vmax was unrelated to addition in vitro of di-or trihydroxy bile salts or ethinyl estradiol and, therefore, suggests that reduced activities in cholestasis are due to decreased enzyme content. Cholestasis was not associated with changes in the synthesis or degradation rate of pulse-labeled plasma

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Section: Introductionmentioning

confidence: 99%

Alteration of Bile Canalicular Enzymes in Cholestasis. A POSSIBLE CAUSE OF BILE SECRETORY FAILURE

Simon¹,

Arias²

1973

J. Clin. Invest.

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“…Subcellular fractionation experiments on liver biopsies demonstrate that lysosomes accumulate melanin [94]. A similar black hepatic pigmentation has been observed in Corriedale sheep [88,95]. Injection of [ 3 H]epinephrine or its metabolite [ 3 H]metanephrine glucuronide, compounds which are normally excreted into bile, results in lysosomal accumulation of radioactivity [87].…”

Section: Dubin-johnson Syndromementioning

confidence: 72%

“…Both Corriedale sheep [87,88] and TR -/GY rats [11,39,48] show impaired secretion of bilirubin-glucuronide, bromosulfophthalein-S-glutathione (GS-BSP), and indocyanine green (among various other organic anions; Table 1), substrates which have shown to be transported by the cMOAT protein; bile salt transport is unaffected. In Dubin-Johnson patients the hepatobiliary transport of these nonbile salt organic anions is impaired as well; hepatic uptake and storage of these compounds is not affected, indicating that the defect in Dubin-Johnson patients is caused primarily by a defect in a canalicular transport system [16,17,89].…”

Section: Dubin-johnson Syndromementioning

confidence: 99%

The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man

Paulusma

Elferink

1997

Journal of Molecular Medicine

104

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The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man Paulusma, C.C.; Oude Elferink, R.P.J. Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 22 Mar 2019& p . 1 : Abstract The human Dubin-Johnson syndrome is an autosomal recessive liver disease characterized by a chronic conjugated hyperbilirubinemia. Patients have impaired hepatobiliary transport of many endogenous and xenobiotic compounds. A similar disease phenotype has been described for a naturally occurring mutant Wistar rat strain, the TR -rat, which is defective in the, functionally defined, canalicular multispecific organic anion transporter (cMOAT). The complementary DNA encoding this protein has been cloned from rat and recently from human liver. cMOAT is a new member of the ATPbinding cassette transporter family, and homologous to the multidrug resistance-associated protein 1. A mutation in the cMOAT gene is responsible for the phenotype observed in TR -rats. This information should soon lead to a complete genetic characterization of the human DubinJohnson syndrome.

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“…Conventional bile acids are conjugated primarily with glycine and taurine (24), while minimal amounts of glucuronide conjugates are found normally, and bile acid glucuronides appear in quantity only in cholestatic liver disease (25)(26)(27)(28). Thus, while the biliary secretory pattern observed for etianic acid is similar to that of conventional bile acids, secretion via mechanisms more closely related to those for bilirubin, bromsul phalein, and other organic anions (29,30) is an alternative possibility. In this regard, studies examining competition between short-chain and conventional bile acids for hepatic uptake and/or secretion would be of interest.…”

Section: Discussionmentioning

confidence: 92%

Hepatic metabolism of 3 alpha-hydroxy-5 beta-etianic acid (3 alpha-hydroxy-5 beta-androstan-17 beta-carboxylic acid) in the adult rat.

Little¹,

Pyrek²,

Lester³

1983

J. Clin. Invest.

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A B S T R A C T Normal human meconium has been shown to contain short-chain (C20-C22) bile acids and, recently, these compounds have been identified in sera of patients with cholestasis. This suggests that shortchain bile acids may be secreted in bile. We have examined this point by studying the hepatic metabolism and biliary secretion of one naturally occurring C20 bile acid, 3a-hydroxy-5,3-etianic acid (3a-hydroxy-5fB-androstan-17f3-carboxylic acid).[3-3H]-3a-hydroxy-5,3-etianic acid was prepared and administered intravenously to rats prepared with an external biliary fistula. 85.5±1.2% of the administered dose was recovered in bile over 20 h with 71.5±1.3% appearing in the first hour. 11.9±1.6% of the dose was estimated to be distributed in body water and 0.6±0.2% was recovered as organic matter in urine. Total recovery of label was 98.0±2.6%. Administration of milligram quantities of 3a-hydroxy-5#3-etianic acid produced an increase in bile flow (58.9±7.1% over basal levels) within 20 min after injection of the steroid.The radiolabeled material in bile was shown by thinlayer chromatography (TLC) to be a polar conjugate which, after 13-glucuronidase hydrolysis, cochromatographed with authentic free 3a-hydroxy-5f3-etianic acid. After purification, and derivatization, the steroid moiety was proven by gas chromatography-mass spectrometry to be identical to 3a-hydroxy-513-etianic acid.Characterization of the conjugate by TLC and by 3a-hydroxysteroid dehydrogenase assay, before and after 3-glucuronidase hydrolysis, indicated that the steroid was secreted in bile as the 3-O-f3-glucuronide.These results were presented in part at the Annual Meeting of the American Society for Clinical Investigation, Washington, DC, 8 May 1982, and were published in abstract form (Clin. Res. 30: 497a).Received for publication 7 June 1982 and in revised form 28 September 1982. It is concluded that 3a-hydroxy-5f-etianic acid is cleared from the plasma, conjugated with glucuronic acid, and secreted into bile rapidly and in high concentration. The choleretic properties of this shortchain bile acid contrast with the cholestatic effects of lithocholic acid, its C24 analog. Both the form of conjugation of etianic acid and its effect on bile flow suggest that the shortened side chain of this steroid markedly alters its hepatic metabolism and physiology. INTRODUCTION The bile acids are bioactive compounds that serve essential normal digestive functions and have disruptive effects when they accumulate in tissues in excess. Although bile acids frequently are considered a homogeneous group, each has peculiar physical characteristics and each is capable of exerting distinctive biological effects.The application of sophisticated computerized gas chromatography-mass spectrometry (GC-MS)' technology to the analysis of bile acids has increased the number and variety identified in biological materials. It is now recognized that the spectrum of naturally occurring compounds that have a hydroxylated steroid nucleus and an acidic side-chain is more co...

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Multiplicity of Hepatic Excretory Mechanisms for Organic Anions

Cited by 104 publications

References 9 publications

Alteration of Bile Canalicular Enzymes in Cholestasis. A POSSIBLE CAUSE OF BILE SECRETORY FAILURE

Alteration of Bile Canalicular Enzymes in Cholestasis. A POSSIBLE CAUSE OF BILE SECRETORY FAILURE

The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man

Hepatic metabolism of 3 alpha-hydroxy-5 beta-etianic acid (3 alpha-hydroxy-5 beta-androstan-17 beta-carboxylic acid) in the adult rat.

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