Jaundice pp 175-188 | Cite as

Protein Binding and Conjugation of Bilirubin in the Liver Cell

  • Irwin M. Arias
  • Peter Jansen
Part of the Hepatology book series (H, volume 2)


For over 40 years, it has been known that following injection of “physiologic” amounts of bilirubin and a variety of other organic anions, a large proportion of the injected dose is recovered within the liver in a matter of minutes. Complete elucidation of the mechanism responsible for this rapid and seemingly selective transfer from plasma into the liver remains unknown; however, experimental studies suggest several hypotheses; (i) bilirubin is noncovalently bound to plasma albumin and enters the liver by pinocytosis as a pigment: albumin complex; (ii) “unbound” bilirubin in plasma is transferred across the plasma membrane of the liver cell by non-ionic diffusion and net uptake flux is determined by intracellular binding and/or subsequent metabolism and biliary excretion; (iii) a plasma membrane carrier system exists with relative specificity for bilirubin; (iv) net hepatic uptake of bilirubin is largely determined by hepatic blood flow and a high extraction ratio of the bile pigment, and (v) an active transport system for bilirubin and other organic anions exists in the portion of the plasma membrane of the parenchymal liver cells which faces the sinusoid.


Hepatic Uptake Glucuronyl Transferase Unconjugated Hyperbilirubinemia Bilirubin Conjugate Bilirubin Binding 
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  1. 1.
    LEVI AJ, GATMAITAN Z, ARIAS IM: The role of two hepatic cytoplasmic proteins (Y and Z) in the transfer of sulpho-biromophthalein (BSP) and bilirubin from plasma into the liver. J Clin Invest 48: 2156–2167, 1969.PubMedCrossRefGoogle Scholar
  2. 2.
    LEVI AJ, GATMAITAN Z, ARIAS IM: Deficiency of hepatic organic anion binding protein, impaired organic anion uptake by liver andphysiologic jaundice in newborn monkeys. New Eng J Med 284: 1136–1139, 1970.CrossRefGoogle Scholar
  3. 3.
    LEVI AJ, GATMAITAN Z, ARIAS IM: Deficiency of hepatic organic anion binding protein: a possible cause of non-hemolytic unconjugated hyperbilirubinemia in the newborn. Lancet 297: 139–140, 1969.CrossRefGoogle Scholar
  4. 4.
    REYES H, LEVI AJ, GATMAITAN Z, ARIAS IM: Organic anion-binding protein in rat liver: Drug induction and its physiologic consequence. Proc Nat Acad Sci 64: 168–170, 1969.PubMedCrossRefGoogle Scholar
  5. 5.
    REYES H, LEVI AJ, ARIAS IM: Studies of Y and Z, two hepatic cytoplasmic organic anion-binding proteins: effect of drugs, chemicals, hormones and cholestasis. J Clin Invest 50: 2242–2252, 1971.PubMedCrossRefGoogle Scholar
  6. 6.
    REYES H, LEVINE R, LEVI AJ et al: Bilirubin: a model for studies of drug metabolism in man. Ann NY Acad Sci 179: 520–528, 1971.PubMedCrossRefGoogle Scholar
  7. 7.
    FLEISCHNER G, ROBBINS J, ARIAS IM: Immunologic studies of Y, a major cytoplasmic organic anion-binding protein in rat liver. J Clin Invest 51: 677–684, 1972.PubMedCrossRefGoogle Scholar
  8. 8.
    FLEISCHNER G, ARIAS IM: Recent advances in bilirubin formation, transport, metabolism and excretion. Am J Med 49: 576–589, 1970.PubMedCrossRefGoogle Scholar
  9. 9.
    LITWACK G, KETTERER B, ARIAS IM: Ligandin: An abundant liver protein which binds steroids, bilirubin, carcinogens and a number of exogenous anions. Nature 234: 466–467, 1971.PubMedCrossRefGoogle Scholar
  10. 10.
    ARIAS IM: Pathogenesis ofphysiologic jaundice of the newborn: a re-evaluation. In Birth Defects, edited by D. Bergsma, Baltimore, Williams and Wilkins, 1970. Volume VI, pp. 55–59.Google Scholar
  11. 11.
    ARIAS IM: Transfer of bilirubin from blood to bile. Seminars of Hematology 9: 55–70, 1972.Google Scholar
  12. 12.
    KAMISAKA K, LISTOWSKY I, ARIAS IM: Circular dichroism studies of Y protein (Ligandin), a major organic anion binding protein in liver, kidney, and small intestine. Annals NY Acad Sci 226: 148–153, 1973.CrossRefGoogle Scholar
  13. 13.
    KAMISAKA K, LISTOWSKY I, BETHEIL J, ARIAS IM: Competitive binding of bilirubin, sulfobromophthalein, indocyanine green and other organic anions to human and bovine serum albumin. Biochem Biophys Acta (in press) 1975.Google Scholar
  14. 14.
    KAPLOWZ N, PIRCY-ROBB IW, JAVITNB: Role of hepatic anion-binding protein in bromsulphthalein conjugation. J Exp Med 183: 483–487, 1973.CrossRefGoogle Scholar
  15. 15.
    MISHKIN S, STEIN L, GATMAITAN Z, ARIAS IM: The binding of fatty acids to cytoplasmic proteins: binding to Z protein in liver and other tissues of the rat. Biochem Biophys Res Comm 47: 997–1003, 1972.PubMedCrossRefGoogle Scholar
  16. 16.
    OCKNER R, MANNING J, PAPPENHAUSEN R, HO W: A binding protein for fatty acids in cytosol of intestinal mucosa, liver myocardium and other tissues. Science 177: 56–58, 1972.PubMedCrossRefGoogle Scholar
  17. 17.
    MISHKIN S, STEIN L, GATMAITAN Z, ARIAS IM: Studies on the possible role of Z protein and other cytoplasmic proteins in the hepatic uptake of long-chain fatty acids. J Clin Invest 1975.Google Scholar
  18. 18.
    HEIRWEGH KPM, VAN HEES GP, LEROY P et al: Heterogeneity of bile pigment conjugates as revealed by chromatography of their ethyl anthranilate azopigments. Biochem J 120: 877–890, 1970.PubMedGoogle Scholar
  19. 19.
    COMPERNOLLE F, JANSEN FH, HEIRWEGH KFM: Mass-spectrcmetric study of the azopigments obtained from bile pigments with diazotized ethyl anthranilate. Biochem J 120: 891–894, 1970.PubMedGoogle Scholar
  20. 20.
    COMPERNOLLE F, VAN HEES GP, FEVERY J, HEIRWEGH KPM: Mass-spectrometric structure elucidation of dog bile azopigments as the acyl glycosides of glucopyranose and xylopyranose. Biochem J 125: 811–819, 1971.PubMedGoogle Scholar
  21. 21.
    FEVERY J, VAN HEES GP, LEROY P et al: Excretion in dog bile of glucose and xylose conjugates of bilirubin. Biochem J 125: 803–810, 1971.PubMedGoogle Scholar
  22. 22.
    KUENZLE CC, WEIBEL MH, PELLONI RR: The reaction of bilirubin with diazomethane. Biochem J 133: 357–368, 1973.PubMedGoogle Scholar
  23. 23.
    KUENZLE CC: Bilirubin conjugates of human bile. Chapter in Metabolic Conjugation and Hydrolysis. Ed. WH Fishman, vol. III, Academic Press, New York London, 1973.Google Scholar
  24. 24.
    CORNELIUS CE, KELLEY KC, HIMES JA: Heterogeneity of bilirubin conjugates in several animal, species. J Vet Res (in press) 1975.Google Scholar
  25. 25.
    FEVERY J, VAN DAMME B, MICHIELS R et al: Bilirubin conjugates in bile of man and rat in the normal state and in liver disease. J Clin Invest 51: 2482–2492, 1972.PubMedCrossRefGoogle Scholar
  26. 26.
    GRAHAM AB, WOODCOCK BG, WOOD GC: The phospholipid-dependence of uridine diphosphate glucuronyltransferase. Effect of protein deficiency on the phospholipid composition and enzyme activity of rat liver microsomal fraction. Biochem J 137: 567–574, 1974.PubMedGoogle Scholar
  27. 27.
    ZAKIM D, GOLDENBERG J, VESSEY DA: Influence of membrane lipids on the regulatory properties of UDP-glucuronyltransferase. Eur J Biochem 38: 59–63, 1973.PubMedCrossRefGoogle Scholar
  28. 28.
    VESSEY DA, ZAKIM D: Regulation of microsomal enzymes by phospholipids. II. Activation of hepatic uridine diphosphate-glucuronyltransferase. J Biol Chem 246: 4649–4656, 1971.PubMedGoogle Scholar
  29. 29.
    JANSEN PL: The isomerisation of bilirubin monoglucuronide. Clin Chim Acta 49: 233–240, 1973.PubMedCrossRefGoogle Scholar
  30. 30.
    JANSEN PL: The enzyme-catalyzed formation of bilirubin diglucuronide by a solubilized preparation from cat liver microsomes. Biochim Biophys Acta 338: 170–182, 1974.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1975

Authors and Affiliations

  • Irwin M. Arias
    • 1
  • Peter Jansen
    • 1
  1. 1.Liver Research CenterAlbert Einstein College of MedicineBronxUSA

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