, Volume 40, Supplement 3, pp 84–97 | Cite as

Cellular Mechanisms of Intrahepatic Cholestasis

  • Peter J. Meier-Abt


Most forms of intrahepatic cholestasis are caused by a failure of hepatocytes to secrete osmotically active bile constituents into the minute channels of bile canaliculi. This overall vectorial bile secretory process is dependent upon a variety of polarised active transport functions at the basolateral (sinusoidal and lateral) and canalicular plasma membrane domains, as well as upon the coordinated vectorial movement of intracellular vesicles. Although considerable progress has been made in recent years in the identification, characterisation and exact localisation of a number of polarised hepatocellular transport systems, the primary mechanisms and targets leading to defective bile secretion and cholestasis are still not completely understood. For example, not all reported experimental data are compatible with the concept that estrogen-induced cholestasis represents a predominant sinusoidal disease process. In addition, the pathophysiological significance of disturbed transcytotic pathways and/or disrupted intracellular calcium homeostasis are not yet clear. For many forms of cholestasis, it remains uncertain as to whether leaky tight junctions represent a primary cause rather than a secondary phenomenon of the cholestatic state. However, the ongoing progress in the understanding of the normal mechanisms involved in the establishment, maintenance and regulation of ion homeostasis and polar transport functions in hepatocytes will, undoubtedly, improve our knowledge of the pathogenesis of intrahepatic cholestasis and, it is hoped, lead to better therapeutic strategies in the near future.


Bile Acid Bile Salt Cholestasis Bile Flow Intrahepatic Cholestasis 
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  1. Adinolfi LE, Utili R, Gaeta GB, Abenathy ChO, Zimmerman HJ. Cholestasis induced by estradiol-17β—D-glucuronide: mechanisms and prevention by sodium taurocholate. Hepatology 4: 30–37, 1984PubMedGoogle Scholar
  2. Ali N, Milligan G, Evans WH. Distribution of G-proteins in rat liver plasma-membrane domains and endocytic pathways. Biochemical Journal 261: 905–912, 1989aPubMedGoogle Scholar
  3. Ali N, Milligan G, Evans WH. G-proteins of rat liver membranes. Subcellular compartmentation and disposition in the plasma membrane. Molecular and Cellular Biochemistry 91: 75–84, 1989bPubMedGoogle Scholar
  4. Ananthanarayanan M, von Dippe P, Levy D. Identification of the hepatocyte Na+-dependent bile acid transport protein using monoclonal antibodies. Journal of Biological Chemistry 263: 8338–8343, 1988PubMedGoogle Scholar
  5. Anderson JM, Glade JL, Stevenson BR, Boyer JL, Mooseker MS. Hepatic immunohistochemical localisation of the tight junction protein ZO-1 in rat models of cholestasis. American Journal of Experimental Pathology 134: 1055–1062, 1989Google Scholar
  6. Anwer MS, Engelkind LR, Nolan K, Sullivan D, Zimniak P, et al. Hepatotoxic bile acids increase cytosolic Ca++ activity of isolated rat hepatocytes. Hepatology 8: 887–891, 1988PubMedGoogle Scholar
  7. Apstein MD, Robins SJ. Effect of organic anions on biliary lipids in the rat. Gastroenterology 83: 1120–1126, 1982PubMedGoogle Scholar
  8. Apstein MD, Russo AR. Ampicillin inhibits biliary cholesterol secretion. Digestive Diseases and Sciences 30: 253–256, 1985PubMedGoogle Scholar
  9. Arias IM, Forgac M. The sinusoidal domain of the plasma membrane of rat hepatocytes contains an amiloride-sensitive Na+/H+ antiport. Journal of Biological Chemistry 259: 5406–5408, 1984PubMedGoogle Scholar
  10. Ayotte P, Plaa GL. Biliary excretion in Sprague-Dawley and Gunn rats during manganese-bilirubin induced cholestasis. Hepatology 8: 1069–1078, 1988PubMedGoogle Scholar
  11. Ballatori N, Jacob R, Barrett C, Boyer JL. Biliary catabolism of glutathione and differential reabsorption of its amino acid constituents. American Journal of Physiology 254: G1–G7, 1988PubMedGoogle Scholar
  12. Ballatori N, Jacob R, Boyer JL. Intrabiliary glutathione hydrolysis. A source of glutamate in bile. Journal of Biological Chemistry 261: 7860–7865, 1986PubMedGoogle Scholar
  13. Ballatori N, Truong AT. Relation between biliary glutathione excretion and bile acid-independent bile flow. American Journal of Physiology 256: G482–G490, 1989PubMedGoogle Scholar
  14. Barnwell SG, Lowe PJ, Coleman R. The effects of colchicine on secretion into bile of bile salts, phospholipids, cholesterol and plasma membrane enzymes: bile salts are secreted unaccompanied by phospholipids and cholesterol. Biochemical Journal 220: 773–731, 1984Google Scholar
  15. Bartles JR, Braiterman LS, Hubbard AL. Biochemical characterization of domain-specific glycoproteins of the rat hepatocyte plasma membrane. Journal of Biological Chemistry 260: 12792–12802, 1985PubMedGoogle Scholar
  16. Bellringer ME, Steele NJ, Rahman K, Coleman R. Ampicillin inhibits the movement of biliary secretory vesicles in rat hepatocytes. Biochimica et Biophysica Acta 941: 71–75, 1988PubMedGoogle Scholar
  17. Berk PD, Potter BJ, Stemmel W. Role of plasma membrane ligand-binding proteins in the hepatocellular uptake of albumin-bound organic anions. Hepatology 7: 165–176, 1987PubMedGoogle Scholar
  18. Berr F, Simon FR, Reichen J. Ethinylestradiol impairs bile salt uptake and Na-K pump function of rat hepatocytes. American Journal of Physiology 247: G437–G443 1984PubMedGoogle Scholar
  19. Berr F, Stellaard F, Goetz A, Hammer C, Paumgartner G. Ethinylestradiol stimulates a biliary cholesterol-phospholipid cosecretion mechanism in the hamster. Hepatology 8: 619–624, 1988PubMedGoogle Scholar
  20. Blitzer BL, Terzakis C, Scott KA. Hydroxyl/bile acid exchange. Journal of Biological Chemistry 261: 12042–12046, 1986PubMedGoogle Scholar
  21. Boelsterli UA, Rakhit G, Balazs T. Modulation by S-adenosyl-L-methionine of hepatic Na+, K+ ATPase, membrane fluidity, and bile flow in rats with ethinyl estradiol-induced cholestasis. Hepatology 3: 12–17, 1983PubMedGoogle Scholar
  22. Boyer JL. New concepts of mechanisms of hepatocyte bile formation. Physiological Reviews 60: 303–326, 1980PubMedGoogle Scholar
  23. Boyer JL. Tight junctions in normal and cholestatic liver: does the paracellular pathway have functional significance? Hepatology 3: 614–617, 1983PubMedGoogle Scholar
  24. Boyer JL. Contractile activity of bile canaliculi: contraction or collapse? Hepatology 7: 190–192, 1987Google Scholar
  25. Boyer JL, Gautam A, Graf J. Mechanisms of bile secretion: insights from the isolated rat hepatocyte couplet. Seminars in Liver Disease 8: 308–316, 1988PubMedGoogle Scholar
  26. Brock WJ, Vore M. The effect of pregnancy and treatment with estradiol-117β on the transport of organic anions into isolated rat hepatocytes. Drug Metabolism and Disposition 13: 695–699, 1984Google Scholar
  27. Caflisch C, Zimmerli B, Reichen J, Meier PJ. Cholate uptake in basolateral rat liver plasma membrane vesicles and in liposomes. Biochimica et Biophysica Acta 1021: 70–76, 1990PubMedGoogle Scholar
  28. Carraway KL, Carothers-Carraway CA. Membrane-cytoskeletal interactions in animal cells. Biochimica et Biophysica Acta 988: 147–171, 1989PubMedGoogle Scholar
  29. Cereijido M, Ponce A, Gonzalez-Mariscal L. Tight junctions and apical/basolateral polarity. Journal of Membrane Biology 110: 1–9, 1989Google Scholar
  30. Cohen DE, Angelico M, Carey MC. Quasielastic light scattering evidence for vesicular secretion of biliary lipids. American Journal of Physiology 257: G1–G8, 1989PubMedGoogle Scholar
  31. Coleman R. Biochemistry of bile secretion. Biochemical Journal 244: 249–261, 1987PubMedGoogle Scholar
  32. Combettes L, Berthon B, Doucet E, Erlinger S, Claret M. Characteristics of bile acid-mediated Ca2+ release from permeabilized liver cells and liver microsomes. Journal of Biological Chemistry 264: 157–167, 1989PubMedGoogle Scholar
  33. Combettes L, Dumont M, Berthon B, Erlinger S, Claret M. Release of calcium from the endoplasmic reticulum by bile acids in rat liver cells. Journal of Biological Chemistry 263: 2299–2303, 1988PubMedGoogle Scholar
  34. Cotting J, Zysset T, Reichen J. Biliary obstruction dissipates bioelectric sinusoidal-canalicular barrier without altering taurocholate uptake. American Journal of Physiology 256: G312–G318, 1989PubMedGoogle Scholar
  35. Crawford JM, Clifford AB, Gollan JL. Role of the hepatocyte microtubular system in the excretion of bile salts and biliary lipid: implications for intracellular vesicular transport. Journal of Lipid Research 29: 144–146, 1988PubMedGoogle Scholar
  36. Desmet VJ. Current problems in diagnosis of biliary disease and cholestasis. Seminars in Liver Disease 6: 233–245, 1986PubMedGoogle Scholar
  37. Drew R, Priestly BG. Choleretic and cholestatic effects of infused bile salts in the rat. Experientia 35: 809–811, 1979PubMedGoogle Scholar
  38. Dubin M, Maurice M, Feldmann G, Erlinger S. Influence of colchicine and phalloidin on bile secretion and hepatic ultrastructure in the rat. Possible interaction between microtubules and microfilaments. Gastroenterology 79: 646–654, 1980PubMedGoogle Scholar
  39. Duffy MC, Boyer JL. Pathophysiology of intrahepatic cholestasis and biliary obstruction. In Ostrow JD (Ed.) Bile pigments and jaundice. Molecular, metabolic and medical aspects, pp. 333–371, Marcel Dekker, Inc., New York and Basel, 1986Google Scholar
  40. Dumont M, Erlinger S, Uchman S. Hypercholeresis induced by ursodeoxycholic acid and 7-ketolithocholic acid in the rat: possible role of bicarbonate transport. Gastroenterology 79: 82–89, 1980PubMedGoogle Scholar
  41. Durand-Schneider AM, Maurice M, Dumont M, Feldmann G. Effect of colchicine and phalloidin on the distribution of three plasma membrane antigens in rat hepatocytes: comparison with bile duct ligation. Hepatology 7: 1239–1248, 1987PubMedGoogle Scholar
  42. Elias E, Boyer JL. Chlorpromazine and its metabolites alter polymerization and gelation of actin. Sciences 206: 1404–1406, 1979Google Scholar
  43. Erlinger S. What is cholestasis in 1985. Journal of Hepatology 1: 687–693, 1985PubMedGoogle Scholar
  44. Erlinger S. Bile flow. In Arias et al. (Eds) The liver: biology and pathobiology, 2nd ed., pp. 643–661, 1988Google Scholar
  45. Feldmann G. The cytoskeleton of the hepatocyte. Structure and functions. Journal of Hepatology 8: 380–386, 1989PubMedGoogle Scholar
  46. Fitz JG, Persico M, Scharschmidt BF. Electrophysiological evidence for Na+-coupled bicarbonate transport in cultured rat hepatocytes. American Journal of Physiology 256: G491–G500, 1989PubMedGoogle Scholar
  47. Fitz JG, Scharschmidt BF. Regulation of transmembrane electrical potential gradient in rat hepatocytes in situ. American Journal of Physiology 252: G56–G64, 1987aPubMedGoogle Scholar
  48. Fitz JG, Scharschmidt BF. Intracellular chloride activity in intact rat liver: relationship to membrane potential and bile flow. American Journal of Physiology 252: G699–G706, 1987bPubMedGoogle Scholar
  49. Fitz JG, Trouillot TE, Scharschmidt BF. Effect of pH on membrane potential and K+ conductance in cultured rat hepatocytes. American Journal of Physiology 257: G961–G968, 1989PubMedGoogle Scholar
  50. Fricker G, Landmann L, Meier PJ. Ethinylestradiol (EE) induced structural and functional alterations of rat liver plasma membranes and their reversal by S-adenosylmethionine (SAMe) in vitro. Hepatology 8: 1224, 1988Google Scholar
  51. Fricker G, Landmann L, Meier PJ. Extra-hepatic obstructive cholestasis reverses the bile salt secretory polarity of rat hepatocytes. Journal of Clinical Investigation 84: 876–885, 1989PubMedGoogle Scholar
  52. Frimmer M, Ziegler K. The transport of bile acids in liver cells. Biochimica et Biophysica Acta 947: 75–99, 1988PubMedGoogle Scholar
  53. Gleeson O, Smith ND, Boyer JL. Bicarbonate dependent and independent pH regulatory mechanisms in rat hepatocytes. Journal of Clinical Investigation 84: 312–321, 1989PubMedGoogle Scholar
  54. Goldman IS, Jones AL, Hradek GT, Huling S. Hepatocyte handling of immunoglobulin A in the rat: the role of microtubules. Gastroenterology 85: 130–140, 1983PubMedGoogle Scholar
  55. Goldsmith MA, Jones AL, Underdown BJ, Schiff J M. Alterations in protein transport events in rat liver after estrogen treatment. American Journal of Physiology 253: G195–G200, 1987PubMedGoogle Scholar
  56. Graf J. Canalicular bile salt-independent bile formation: concepts and clues from electrolyte transport in rat liver. American Journal of Physiology 244: G233–G246, 1983PubMedGoogle Scholar
  57. Graf J, Henderson RM, Krumpholz B, Boyer JL. Cell membrane and transepithelial voltages and resistances in isolated rat hepatocyte couplets. Journal of Membrane Biology 95: 241–254, 1987PubMedGoogle Scholar
  58. Gregory DH, Vlahcevic ZR, Prugh MF, Swell L. Mechanism of secretion of biliary lipids: role of a microtubular system in hepatocellular transport of lipids in the rat. Gastroenterology 74: 93–100, 1978PubMedGoogle Scholar
  59. Griffiths G, Simons K. The trans Golgi network: sorting at the exit site of the Golgi complex. Science 234: 438–443, 1986PubMedGoogle Scholar
  60. Gumbiner B. Structure, biochemistry, and assembly of epithelial tight junctions. American Journal of Physiology 253: C749–C758, 1987PubMedGoogle Scholar
  61. Gumbiner B, Louvard D. Localized barriers in the plasma membrane: a common way to form domains. Trends in Biochemical Sciences, November issue: 435–438, 1985Google Scholar
  62. Hardison WGM, Hatoff DE, Miyai K, Weiner RG. Nature of bile acid maximum secretory rate in the rat. American Journal of Physiology 241: G337–G343, 1981PubMedGoogle Scholar
  63. Henderson RM, Graf J, Boyer JL. Na-H exchange regulates intracellular pH in isolated rat hepatocyte couplets. American Journal of Physiology 252: G109–G113, 1987PubMedGoogle Scholar
  64. Hofmann AF, Gurantz D, Hagey LR, Schteingart C, Yoon YB, et al. The relationship between bile acid biotransformation and bile acid-dependent bile flow. In Paumgartner et al. (Eds) Bile acids and the liver, pp. 183–193, MTP Press Limited, Lancaster, England, 1987Google Scholar
  65. Hong W, Petell JK, Swank D, Sanford J, Hixson DC, et al. Expression of dipeptidylpeptidase IV in rat tissues is mainly regulated at the mRNA levels. Experimental Cell Research 182: 256–266, 1989PubMedGoogle Scholar
  66. Hubbard AL, Stieger B, Bartles JR. Biogenesis of endogenous plasma membrane proteins in epithelial cells. Annual Reviews of Physiology 51: 755–770, 1989Google Scholar
  67. Hugentobler G, Meier PJ. Multispecific anion exchange in basolateral (sinusoidal) rat liver plasma membrane vesicles. American Journal of Physiology 251: G656–G664, 1986PubMedGoogle Scholar
  68. Inoue M, Kinne R, Tran T, Biempica L, Arias IM. Rat liver canalicular membrane vesicles. Isolation and topological characterization. Journal of Biological Chemistry 258: 5183–5188, 1983PubMedGoogle Scholar
  69. Iqbal S, Mills OCH, Elias E. Biliary permeability during ethinylesradiol-induced cholestasis studied by segmented retrograde intrabiliary injections in rats. Journal of Hepatology 1: 211–219, 1985PubMedGoogle Scholar
  70. Jaeschke H, Trummer E, Krell E. Increase in biliary permeability subsequent to intrahepatic cholestasis by estradiol valerate in rats. Gastroenterology 93: 533–538, 1987PubMedGoogle Scholar
  71. Jones AL, Renston RH, Burwen SJ. Uptake and intracellular disposition of plasma-derived proteins and apoproteins by hepatocytes. Progress in Liver Diseases 7: 51–69, 1980aGoogle Scholar
  72. Jones AL, Schmucker DL, Renston RH, Murakami T. The architecture of bile secretion. A morphological perspective of physiology. Digestive Diseases and Sciences 25: 609–629, 1980bPubMedGoogle Scholar
  73. Kacich RL, Renston RH, Jones AL. Effects of cytochalasin D and colchicine on the uptake, translocation, and biliary secretion of horseradish peroxidase and 14C sodium taurocholate in the rat. Gastroenterology 85: 385–394, 1983PubMedGoogle Scholar
  74. Kakis G, Yousef IM. Pathogenesis of lithocholate- and taurocholate-induced intrahepatic cholestasis in rats. Gastroenterology 75: 595–607, 1978PubMedGoogle Scholar
  75. Kamimoto Y, Gaitmaitan Z, Hsu J, Arias IM. The function of Gp 170, the multidrug resistance gene product, in rat liver canalicular membrane vesicles. Journal of Biological Chemistry 264: 11693–11698, 1989PubMedGoogle Scholar
  76. Kan KS, Monte MJ, Parslow RA, Coleman R. Oestradiol 17β-glucuronide increases tight-junctional permeability in rat liver. Biochemical Journal 261: 297–300, 1989PubMedGoogle Scholar
  77. Kaplowitz N. Physiological significance of glutathione-S-transferases. American Journal of Physiology 239: G439–G444, 1980PubMedGoogle Scholar
  78. Kaplowitz N, Aw TY, Simon FR, Stolz A. Drug-induced hepatotoxicity. Annals of Internal Medicine 104: 826–839, 1986PubMedGoogle Scholar
  79. Keeffe EB, Blankenship N, Scharschmidt BF. Alteration of rat liver plasma membrane fluidity and ATPase activity by chlorpromazine hydrochloride and its metabolites. Gastroenterology 74: 222–231, 1980Google Scholar
  80. Kitani K, Kanai S. Effect of ursodeoxycholate on the bile flow in the rat. Life Sciences 31: 1973–1985, 1982PubMedGoogle Scholar
  81. Kloppel TM, Brown WR, Reichen J. Mechanisms of secretion of proteins into bile: studies in the perfused rat liver. Hepatology 6: 587–594, 1986PubMedGoogle Scholar
  82. Krell H, Höke H, Pfaff E. Development of intrahepatic cholestasis by α-naphthylisothiocyanate in rats. Gastroenterology 82: 507–514, 1982PubMedGoogle Scholar
  83. Kuipers F, Enserink M, van der Steen Ad BM, Hardonk MJ, Fevery J, et al. Separate transport systems for biliary secretion of sulfated and unsulfated bile acids. Journal of Clinical Investigation 81: 1593–1599, 1988PubMedGoogle Scholar
  84. Lake JR, Licko V, Van Dyke RW, Scharschmidt BF. Biliary secretion of fluid-phase markers by the isolated perfused rat liver. Role of transcellular vesicular transport. Journal of Clinical Investigation 76: 676–684, 1985PubMedGoogle Scholar
  85. Lake JR, Renner EL, Scharschmidt BF, Cragoe Jr EJ, Hagey LR, et al. Inhibition of Na+/H+ exchange in the rat is associated with decreased ursodeoxycholate hypercholeresis, decreased secretion of unconjugated ursodeoxycholate, and increased ursodeoxycholate glucuronidation. Gastroenterology 95: 454–463, 1988PubMedGoogle Scholar
  86. Lamri Y, Roda A, Dumont M, Feldmann G, Erlinger S. Immunoperoxidase localization of bile salts in rat liver cells. Evidence for a role of the Golgi apparatus in bile salt transport. Journal of Clinical investigation 82: 1173–1182, 1988PubMedGoogle Scholar
  87. La Russo NF. Proteins in bile: how they get there and what they do. American Journal of Physiology 247: G199–G205, 1984Google Scholar
  88. Lin SH. Localization of the ecto-ATPase (Ecto-nucleotidase) in the rat hepatocyte plasma membrane. Journal of Biological Chemistry 264: 14403–14407, 1989PubMedGoogle Scholar
  89. Lin SH, Guidotti G. Cloning and expression of a cDNA coding for a rat liver plasma membrane ecto-ATPase. Journal of Biological Chemistry 264: 14408–14414, 1989PubMedGoogle Scholar
  90. Low MG. The glycosyl-phosphatidylinositol anchor of membrane proteins. Biochimica et Biophysica Acta 988: 427–454, 1989PubMedGoogle Scholar
  91. Lowe PJ, Kan KS, Barnwell SG, Sharma RK, Coleman R. Trancytosis and paracellular movements of horse-radish peroxidase across liver parenchymal tissue from blood to bile. Biochemical Journal 229: 529–537, 1985PubMedGoogle Scholar
  92. Lowe PJ, Miyai K, Steinbach JH, Hardison WGM. Hormonal regulation of hepatocyte tight junctional permeability. American Journal of Physiology 255: G454–G461, 1988PubMedGoogle Scholar
  93. Lynch CJ, Wilson PB, Blackmore PF, Eston JH. The hormone-sensitive hepatic Na+-pump. Journal of Biological Chemistry 261: 14551–14556, 1986PubMedGoogle Scholar
  94. Margolis RN, Schell MJ, Taylor SI, Hubbard AL. Hepatocyte plasma membrane ecto-ATPase (pp 120/HA4) is a substrate for tyrosine kinase activity of the insulin receptor. Biochemical and Biophysical Research Communications 166: 562–566, 1990PubMedGoogle Scholar
  95. Marinelli RA, Luguita MG, Garay EAR. Bile salt related secretion of acid phosphatase in rat bile. Canadian Journal of Physiology and Pharmacology 64: 1347–1352, 1985Google Scholar
  96. Meier PJ. Transport polarity of hepatocytes. Seminars in Liver Disease 8: 293–307, 1988PubMedGoogle Scholar
  97. Meier PJ. The bile salt secretory polarity of hepatocytes. Journal of Hepatology 9: 124–129, 1989PubMedGoogle Scholar
  98. Meier PJ, Knickelbein R, Moseley RH, Dobbins JW, Boyer JL. Evidence for carrier-mediated chloride/bicarbonate exchange in canalicular rat liver plasma membrane vesicles. Journal of Clinical Investigation 75: 1256–1263, 1985PubMedGoogle Scholar
  99. Meier PJ, Sztul ES, Reuben A, Boyer JL. Structural and functional polarity of canalicular and basolateral plasma membrane vesicles isolated in high yield from rat liver. Journal of Cell Biology 98: 991–1000, 1984PubMedGoogle Scholar
  100. Meier PJ, Valantinas J, Hugentobler G, Rahm I. Bicarbonate sulfate exchange in canalicular rat liver plasma membrane vesicles. American Journal of Physiology 253: G461–G468, 1987PubMedGoogle Scholar
  101. Miccio M, Baldini G, Basso V, Gazzin B, Lunazzi GC, et al. Bilitranslocase is the protein responsible for the electrogenic movement of sulfobromophthalein in plasma membrane vesicles from rat liver: immunological evidence using mono and poly-clonal antibodies. Biochimica et Biophysica Acta 981: 115–120, 1989PubMedGoogle Scholar
  102. Miyairi M, Oshio C, Watanabe S, Smith CR, Yousef IM, et al. Taurocholate accelerates bile canalicular contractions in isolated rat hepatocytes. Gastroenterology 87: 788–792, 1984PubMedGoogle Scholar
  103. Molitoris BA, Nelson WJ. Alterations in the establishment and maintenance of epithelial cell polarity as a basis for disease processes. Journal of Clinical Investigation 85: 3–9, 1990PubMedGoogle Scholar
  104. Moseley RH, Meier PJ, Aronson PS, Boyer JL: Na+/H+ exchange in rat liver basolateral but not canalicular plasma membrane vesicles. American Journal of Physiology 250: G35–G43, 1986PubMedGoogle Scholar
  105. Mostov KE, Simister NE. Transcytosis. Cell 43: 389–390, 1985PubMedGoogle Scholar
  106. Nicotera P, Baldi C, Svensson St Å, Larsson R, Bellomo G, et al. Glutathione S-conjugates stimulate ATP hydrolysis in the plasma membrane fraction of rat hepatocytes. FEBS Letters 187: 121–125, 1985PubMedGoogle Scholar
  107. Oda M, Price VM, Fisher MM, Phillips MJ. Ultrastructure of bile canaliculi, with special reference to the surface coat and the pericanalicular web. Laboratory Investigations 31: 314–323, 1974Google Scholar
  108. Oelberg DG, Chari MV, Little JM, Adcock EW, Lester R. Lithocholate glucuronide is a cholestatic agent. Journal of Clinical Investigation 73: 1507–1514, 1984aPubMedGoogle Scholar
  109. Oelberg DG, Dubinsky WP, Adcock EW, Lester R. Calcium binding of lithocholic acid derivatives. American Journal of Physiology 247: G112–G115, 1984bPubMedGoogle Scholar
  110. Oelberg DG, Lester R. Cellular mechanisms of cholestasis. Annual Reviews of Medicine 37: 297–317, 1986Google Scholar
  111. Okolicsanyi L, Lirussi F, Strazzaboso M, Jemmolo RM, Orlando R, et al. The effect of drugs on bile flow and composition. An overview. Drugs 31: 430–448, 1986PubMedGoogle Scholar
  112. Oshio C, Phillips MJ, Contractility of bile canaliculi, implications for liver function. Science 212: 1041–1042, 1981PubMedGoogle Scholar
  113. Oude Elferink RPJ, Ottenhoff R, Liefting W, Haan de J, Jansen PLM. Hepatobiliary transport of glutathione and glutathione conjugate in rats with hereditary hyperbilirubinemia. Journal of Clinical Investigation 84: 476–483, 1989Google Scholar
  114. Phillips DJ, Poucell S, Oda M. Biology of disease. Mechanism of cholestasis. Laboratory Investigations 54: 593–608, 1986Google Scholar
  115. Plaa GL, De Lamirande E, Lewittes M, Yousef IM. Liver cell plasma membrane lipids in manganese-bilirubin-induced intrahepatic cholestasis. Biochemical Pharmacology 31: 3698–3701, 1982PubMedGoogle Scholar
  116. Plaa GL, Priestly BG. Intrahepatic cholestasis induced by drugs and chemicals. Pharmacological Reviews 28: 207–273, 1976PubMedGoogle Scholar
  117. Popper H, Schaffner F. Cholestasis. In Berk et al. (Eds) Bockus gastroenterology. 4th ed., Vol. 5, pp. 2697–2731, WB Saunders Company, Philadelphia, 1985Google Scholar
  118. Potter BJ, Blades BF, Shepard MD, Thung SM, Berk PD. The kinetics of sulfobromophthalein uptake by rat liver sinusoidal vesicles. Biochimica et Biophysica Acta 898: 159–171, 1989Google Scholar
  119. Reichen J, Berman MD, Berk PD. The role of microfilaments and microtubules in taurocholate uptake by isolated rat liver cells. Biochimica et Biophysica Acta 643: 126–133, 1981PubMedGoogle Scholar
  120. Reichen J, Le M. Taurocholate, but not taurodehydrocholate, increases biliary permeability to sucrose. American Journal of Physiology 245: G651–G655, 1983PubMedGoogle Scholar
  121. Reichen J, Simon FR. Cholestasis. In Arias et al. (Eds) The liver: biology and pathobiology, 2nd ed., pp. 1105–1124, Raven Press Ltd, New York, 1988Google Scholar
  122. Renner EL, Lake JR, Persico M, Scharschmidt BF. Na+/H+ exchange activity in rat hepatocytes: role in regulation of intracellular pH. American Journal of Physiology 256: G44–G52, 1989aPubMedGoogle Scholar
  123. Renner EL, Lake JR, Scharschmidt BF, Zimmerli B, Meier PJ. Rat hepatocytes exhibit basolateral Na+/HCO3 cotransport. Journal of Clinical Investigation 83: 1225–1235, 1989bPubMedGoogle Scholar
  124. Rosario J, Sutherland E, Zaccaro L, Simon FR. Ethinylestradiol administration selectively alters liver sinusoidal membrane lipid fluidity and protein composition. Biochemistry 27: 3939–3946, 1988PubMedGoogle Scholar
  125. Ruetz St, Fricker G, Hugentobler G, Winterhalter K, Kurz G, Meier PJ. Isolation and characterization of the putative canalicular bile salt transport system of rat liver. Journal of Biological Chemistry 262: 11324–11330, 1987PubMedGoogle Scholar
  126. Ruetz St, Hugentobler G, Meier PJ. Functional reconstitution of the canalicular bile salt transport system of rat liver. Proceedings of the National Academy of Science USA 85: 6147–6151, 1988Google Scholar
  127. Sakisaka S, Ng O CH, Boyer JL. Tubulovesicular transcytotic pathway in isolated rat hepatocyte couplets in culture. Gastroenterology 95: 793–804, 1988PubMedGoogle Scholar
  128. Schachter D. Fluidity and function of hepatocyte plasma membranes. Hepatology 4: 140–151, 1984PubMedGoogle Scholar
  129. Scharschmidt BF. Bile formation and cholestasis, metabolism and enterohepatic circulation of bile acids, and gallstone formation. In Zakim & Boyer (Eds) Hepatology. A textbook of liver disease, pp. 297–351, WB Saunders Co., Philadelphia, 1982Google Scholar
  130. Scharschmidt BF, Lake JR. Hepatocellular bile acid transport and ursodeoxycholic acid hypercholeresis. Digestive Diseases and Sciences 34: 5S–15S, 1989PubMedGoogle Scholar
  131. Scharsmidt BF, Van Dyke R. Mechanisms of hepatic electrolyte transport. Gastroenterology 85: 1199–1214, 1983Google Scholar
  132. Schwarz SM, Bostwick HE, Medow MS. Estrogen modulates ileal basolateral membrame lipid dynamics and Na+K+-ATPase activity. American Journal of Physiology 254: G687–G694, 1988PubMedGoogle Scholar
  133. Schwarz SM, Watkins JB, Ling SC, Fayer JC, Mone M. Effects of ethinyl estradiol on intestinal membrane structure and function in the rabbit. Biochimica et Biophysica Acta 860: 411–419, 1986PubMedGoogle Scholar
  134. Shears SB, Evans WH, Kirk ChJ, Michell RH. Preferential localization of rat liver D-myo-inositol 1,4,5-triphosphate/1,3,4,5-tetrakisphosphate 5-phosphatase in bile-canalicular plasma membrane and ‘late’ endosomal vesicles. Biochemical Journal 256: 363–369, 1988PubMedGoogle Scholar
  135. Simion FA, Fleischer B, Fleischer S. Subcellular distribution of bile acids, bile salts, and taurocholate binding sites in rat liver. Biochemistry 23: 6459–6466, 1984aPubMedGoogle Scholar
  136. Simion FA, Fleischer B, Fleischer S. Two distinct mechanisms for taurocholate uptake in subcellular fractions from rat liver. Journal of Biological Chemistry 259: 10814–10822, 1984bPubMedGoogle Scholar
  137. Simon FR, Sutherland E, Sutherland J. Selective modulation of hepatic and ileal Na+-K+-ATPase by bile salts in the rat. American Journal of Physiology 254: G761–G767, 1988PubMedGoogle Scholar
  138. Simons K, Fuller St D. Cell surface polarity in epithelia. Annual Reviews of Cell Biology 1: 243–288, 1985Google Scholar
  139. Simons K, van Meer G. Lipid sorting in epithelial cells. Biochemistry 27: 6197–6202, 1988PubMedGoogle Scholar
  140. Smith DJ, Gordon ER. Role of liver plasma membrane fluidity in the pathogenesis of estrogen-induced cholestasis. Journal of Laboratory and Clinical Medicine 112: 679–685, 1988PubMedGoogle Scholar
  141. Smith CR, Oshio C, Miyairi M, Katz M, Phillips MJ. Coordination of the contractile activity of bile canaliculi, evidence from spontaneous contractions in vitro. Laboratory Investigations 53: 270–274, 1985Google Scholar
  142. Stolz A, Takikawa H, Ookhtens M, Kaplowitz N. The role of cytoplasmic proteins in hepatic bile acid transport. Annual Reviews of Physiology 51: 161–176, 1989Google Scholar
  143. Suchy FJ, Balistreri WF, Hung J, Miller P, Garfield SA. Intracellular bile acid transport in rat liver as visualized by electron microscope autoradiography using a bile acid analogue. American Journal of Physiology 245: G681–G689, 1983PubMedGoogle Scholar
  144. Sutherland E, Dixon BS, Leffert HL, Skally H, Zaccaro L, et al. Biochemical localization of hepatic surface-membrane Na+, K+-ATPase activity depends on membrane lipid fluidity. Proceedings of the National Academy of Sciences USA 85: 8673–8677, 1988Google Scholar
  145. Sztul ES, Biemesderfer D, Caplan MJ, Kashgarian M, Boyer JL. Localization of Na+, K+-ATPase α-subunit to the sinusoidal and lateral but not canalicular membranes of rat hepatocytes. Journal of Cell Biology 104: 1239–1248, 1987PubMedGoogle Scholar
  146. Tarao K, Olinger ET, Ostrav D, Balisheri WF. Impaired bile acid efflux from hepatocytes isolated from the liver of rats with cholestasis. American Journal of Physiology 243: 6253–6258, 1982Google Scholar
  147. Tashiro Y, Omori K, Yamamoto A. Absence of the α-subunit of (Na+, K+) ATPase on luminal cell membranes. Journal of Histochemistry and Cytochemistry 36: 221–222, 1988PubMedGoogle Scholar
  148. Tuchweber B, Weber A, Roy CC, Yousef IM. Mechanisms of experimentally induced intrahepatic cholestasis. Progress in Liver Diseases 8: 161–178, 1986PubMedGoogle Scholar
  149. Van Dyke RW, Scharschmidt BF. (Na-K)-ATPase-mediated cation pumping in cultured rat hepatocytes. Journal of Biological Chemistry 258: 12912–12919, 1983PubMedGoogle Scholar
  150. Van Dyke RW, Scharschmidt BF. Effects of chlorpromazine on Na+, K+-ATPase pumping and solute transport in rat hepatocytes. American Journal of Physiology 253: G613–G621, 1987PubMedGoogle Scholar
  151. Van Dyke RW, Stephens JE, Scharschmidt BF. Bile acid transport in cultured rat hepatocytes. American Journal of Physiology 243: G484–G492, 1982PubMedGoogle Scholar
  152. van Meer G. Lipid traffic in animal cells. Annual Reviews of Cell Biology 5: 247–275, 1989Google Scholar
  153. van Meer G, Simons K. Lipid polarity and sorting in epithelial cells. Journal of Cellular Biochemistry 36: 51–58, 1988PubMedGoogle Scholar
  154. Vore M. Estrogen cholestasis. Membranes, metabolites, or receptors. Gastroenterology 93: 643–649, 1987PubMedGoogle Scholar
  155. Watanabe S, Phillips MJ. Ca2+ causes active contraction of bile canaliculi: direct evidence from microinjection studies. Proceedings of the National Academy of Science USA 81: 6164–6168, 1984Google Scholar
  156. Watanabe S, Smith CR, Phillips MJ. Coordination of the contractile activity of bile canaliculi: evidence from calcium microinjection of triplet hepatocytes. Laboratory Investigation 53: 275–279, 1985PubMedGoogle Scholar
  157. Weibel ER, Stäubli W, Gnägi HR, Hess FA. Correlated morphometric and biochemical studies on the liver cell. I. Morphometry model, stereologic methods, and normal morphometric data for rat liver. Journal of Cell Biology 42: 69–91, 1969Google Scholar
  158. Weinman SA, Graf J, Boyer JL. Voltage-driven taurocholate-dependent secretion in isolated hepatocyte couples. American Journal of Physiology 256: G826–G832, 1989PubMedGoogle Scholar
  159. Weintraub WH, Machen TE. pH regulation in hepatoma cells: roles for Na-H exchange, Cl-HCO3 exchange, and Na-HCO3 cotransport. American Journal of Physiology 257: G317–G327, 1989PubMedGoogle Scholar
  160. West JC. What determines the substrate specificity of the multi-drug-resistance pump? Trends in Biochemical Sciences 15: 42–46, 1990PubMedGoogle Scholar
  161. Wieland T, Nassal M, Kramer W, Fricker G, Bickel U, et al. Identity of hepatic membrane transport systems for bile salts, phalloidin, and antamanide by photoaffinity labeling. Proceedings of the National Academy of Sciences USA 81: 5232–5236, 1984Google Scholar
  162. Witzleben CL, Boyer JL, NG O Ch. Manganese-biljrubin cholestasis. Further studies in pathogenesis. Laboratory Investigation 56: 151–154, 1987PubMedGoogle Scholar
  163. Wolkoff AW, Samuelson AC, Johansen KL, Nakata R, Withers DM, et al. Influence of Cl on organic anion transport in short-term cultured rat hepatocytes and isolated perfused rat liver. Journal of Clinical Investigation 79: 1259–1268, 1987PubMedGoogle Scholar
  164. Yeagle PL. Lipid regulation of cell membrane structure and function. FASEB Journal 3: 1833–1842, 1989PubMedGoogle Scholar
  165. Zimmerli B, Valantinas J, Meier PJ. Multispecificity of Na+ dependent taurocholate uptake in basolateral (sinusoidal) rat liver plasma membrane vesicles. Journal of Pharmacology and Experimental Therapeutics 250: 301–308, 1989PubMedGoogle Scholar
  166. Zimmerman HJ, Lewis JH. Drug induced cholestasis. Medical Toxicology 2: 112–160, 1987PubMedGoogle Scholar

Copyright information

© Adis International Limited 1990

Authors and Affiliations

  • Peter J. Meier-Abt
    • 1
  1. 1.Division of Clinical Pharmacology, Department of Internal MedicineUniversity HospitalZurichSwitzerland

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