Jaundice pp 85-102 | Cite as

Induction Mechanisms for Bile Pigment Formation

  • Brent A. Schacter
Part of the Hepatology book series (H, volume 2)


Detailed knowledge of the mechanisms by which bile pigment production may be stimulated has been accelerated by the recent delineation of the enzymatic mechanism for heme catabolism, microsomal heme oxygenase, and the regulatory processes which control this step in bile pigment production. Microsomal heme oxygenase catalyzes the conversion of heme to biliverdin by oxidative fission of the α-methene bridge of heme (1,2). This enzyme system is related to and dependent on the activity of the microsomal electron transport system (1–4) which comprises cytochrome P-450 and NADPH-cytochrome c reductase. Biliverdin formed is then converted to bilirubin by the soluble NADPH-dependent enzyme, biliverdin reductase (5). Although in rats hemoglobin administration enhances hepatic biliverdin reductase activity (6) this induction mechanism is probably of little importance in view of the fact that biliverdin reductase is present in excess and is not rate-limiting in the over-all conversion of heme to bilirubin.


Heme Oxygenase Induction Mechanism Bile Pigment Sinusoidal Cell Acute Intermittent Porphyria 
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  1. 1.
    TENHUNEN R, MARVER HS, SCHMID R: The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Nat Acad Sci USA 61: 748–754, 1968.PubMedCrossRefGoogle Scholar
  2. 2.
    TENHUNEN R, MARVER HS, SCHMID R: Microsomal heme oxygenase, characterization of the enzyme. J Biol Chem 244: 6388–6394, 1969.PubMedGoogle Scholar
  3. 3.
    SCHACTER BA, NELSON EB, MARVER HS et al: Immunochemical evidence for an association of heme oxygenase with the microsomal electron transport system. J Biol Chem 247: 3601–3607, 1972.PubMedGoogle Scholar
  4. 4.
    TENHUNEN R, MARVER H, PIMSTONE NR et al: Enzymatic degradation of heme. Oxygenative cleavage requiring cytochrome P-450. Biochem 11: 1716–1720, 1972.CrossRefGoogle Scholar
  5. 5.
    TENHUNEN R, ROSS ME, MARVER HS et al: Reduced nicotinamide- adenine dinucleotide phosphate dependent biliverdin reductase: Partial purification and characterization. Biochem 9 298–303, 1970.CrossRefGoogle Scholar
  6. 6.
    TENHUNEN R: The enzymatic degradation of heme. Sem Hemat 9: 19–29, 1972.Google Scholar
  7. 7.
    TENHUNEN R, MARVER HS, SCHMID R: The enzymatic catabolism of hemoglobin: Stimulation of microsomal heme oxygenase by hemin. J Lab Clin Med 75: 410–421, 1970.PubMedGoogle Scholar
  8. 8.
    PIMSTONE NR, ENGEL P, TENHUNEN R et al: Inducible heme oxygenase in the kidney: A model for the homeostatic control of hemoglobin catabolism. J Clin Invest 50: 2042–2050, 1971.PubMedCrossRefGoogle Scholar
  9. 9.
    BISSELL DM, HAMMAKER L, SCHMID R: Hemoglobin and erythrocyte catabolism in rat liver: The separate roles of parenchymal and sinusoidal cells. Blood 40: 812–822, 1972.PubMedGoogle Scholar
  10. 10.
    GEMSA D, WOO CH, FUDENBERG HH et al: Erythrocyte catabolism by macrophages in vitro. The effect of .hydrocortisone on erythrophagocytosis and on the induction of heme oxygenase. J Clin Invest 52: 812–822, 1973.PubMedCrossRefGoogle Scholar
  11. 11.
    GILLETTE JR: Biochemistry of drug oxidation and reduction by enzymes in hepatic endoplasmic reticulum. Advan Pharmacol4: 219–261, 1966.CrossRefGoogle Scholar
  12. 12.
    SLADEK NE, MANNERING GJ: Evidence for a new P-450 hemoprotein in hepatic microsomes from methylcholanthrene treated rats. Biochem Biophys Res Commun 24: 668–674, 1966.PubMedCrossRefGoogle Scholar
  13. 13.
    CONNEY AH: Pharmacological implications of microsomal enzyme induction. Pharmacol Rev 19: 317–366, 1967.PubMedGoogle Scholar
  14. 14.
    SCHACTER BA, MASON JI: The effect of phenobarbital, 3-methyl- cholanthrene, 3,4-benzpyrene, and pregnenolone-16-carbonitrile on microsomal heme oxygenase and splenic cytochrome P-450. Arch Biochem Biophys 160: 274–278, 1974.PubMedCrossRefGoogle Scholar
  15. 15.
    ROTHWELL JD, LACROIX S, SWEENEY GD: Evidence against a regulatory role for heme oxygenase in hepatic heme synthesis. Biochim Biophys Acta 304: 871–874, 1973.PubMedCrossRefGoogle Scholar
  16. 16.
    HUPKA AL, KARLER R: Biotransformation of ethylmorphine and heme by isolated parenchymal and reticuloendothelial cells of rat liver. J Reticuloendothel Soc 14: 225–241, 1973.PubMedGoogle Scholar
  17. 17.
    KONDO T, NICHOLSON DC, JACKSON AH et al: Isotopic studies of the conversion of oxophlorins and their ferrihaems into bile pigments in the rat. Biochem J 121: 601–607, 1971.PubMedGoogle Scholar
  18. 18.
    GRANICK S: The induction in vitro of the synthesis of delta- aminolevulinic acid synthetase in chemical porphyria: A response to certain drugs, sex hormones, and foreign chemicals. J Biol Chem 241: 1359–1375, 1966.PubMedGoogle Scholar
  19. 19.
    MARVER HS: The role of heme in the synthesis and repression ofmicrosomal protein, in Microsomes and Drug Oxidations, edited by GILLETTE JR, CONNEY AH, COSMIDES GJ, ESTABROOK RW, FOUTS JR, MANNERING GJ, New York, Academic Press, 1969. p. 495.Google Scholar
  20. 20.
    REMMER H, MERKER HJ: Effect of drugs on the formation of smooth endoplasmic reticulum and drug-metabolizing enzymes. Ann NY Acad Sci 123: 79–97, 1965.PubMedCrossRefGoogle Scholar
  21. 21.
    DE LEON A, GARTNER LM, ARIAS IM: The effect of phenobarbital on hyperbilirubinemia in glucuronyl transferase deficient rats. J Lab Clin Med 70: 273–278, 1967.Google Scholar
  22. 22.
    CATZ C, YAFFE SJ: Barbiturate enhancement of bilirubin conjugation and excretion in young and adult animals. Pediat Res 2: 361–370, 1968.PubMedCrossRefGoogle Scholar
  23. 23.
    WINSNES A: Studies on the activation in vitro of glucuronyl transferase. Biochim Biophys Acta 91: 279–291, 1969.Google Scholar
  24. 24.
    POTREPKA RF, SPRATT JL: Effect of phenobarbital and 3-methyl- cholanthrene pretreatment on guinea pig hepatic microsomal bilirubin glucoronyltransferase activity. Biochem Pharm 20: 861–867, 1971.PubMedCrossRefGoogle Scholar
  25. 25.
    REYES H, LEVI AJ, GATMAITAN Z et al: 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
  26. 26.
    ROBERTS RJ, PLM GL: Effect of phenobarbital on the excretion of an exogenous bilirubin load. Biochem Pharm 16: 827–835, 1967.PubMedCrossRefGoogle Scholar
  27. 27.
    TROLLE D: Decrease of total serum bilirubin concentration in newborn infants after phenobarbitone treatment. Lancet 2 705–708, 1968.PubMedCrossRefGoogle Scholar
  28. 28.
    THOMPSON RPH, EDDLESTON ALWF, WILLIAMS R: Low plasma bilirubin in epileptics on phenobarbitone. Lancet 1: 21–22, 1969.PubMedCrossRefGoogle Scholar
  29. 29.
    YEUNG CY, FIELD CE: Phenobarbitone therapy in neonatal hyperbilirubinemia. Lancet 2: 135–140, 1969.PubMedCrossRefGoogle Scholar
  30. 30.
    BLACK M, SHERLOCK S: Treatment of Gilbert’s Syndrome with phenobarbitone. lancet 1 1359–1362, 1970.PubMedCrossRefGoogle Scholar
  31. 31.
    LEVITT M, SCHACTER BA, ZIPURSKY A et al: The nonerytropoietic component of early bilirubin. J Clin Invest 47: 1281–1294, 1968.PubMedCrossRefGoogle Scholar
  32. 32.
    WAXMAN AD, COLLINS A, TSCHUDY DP: Oscillations of hepatic delta-aminolevulinic acid synthetase produced in vivo by heme. Biochem Biophys Res Commun 24: 675–683, 1966.PubMedCrossRefGoogle Scholar
  33. 33.
    MARVER HS, TSCHUDY DP, PERLROTH MG et al: Coordinate synthesis of heme and apoenzyme in the formation of tryptophane pyrrolase. Science 154: 501–503, 1966.PubMedCrossRefGoogle Scholar
  34. 34.
    SCHOLNICK PL, HAMMAKER LE, MARVER HS: Soluble hepatic ALA synthetase: End-product inhibition of the partially purified enzyme. Proc Nat Acad Sci (USA) 63: 65–70, 1969.CrossRefGoogle Scholar
  35. 35.
    PIMSTONE NR, TENHUNEN R, SEITZ PT et al: The enzymatic degradation of hemoglobin to bile pigments by macrophages. J Exp Med 133: 1264–1281, 1971.PubMedCrossRefGoogle Scholar
  36. 36.
    SCHACTER BA: Unpublished observations.Google Scholar
  37. 37.
    BAKKEN AF, THALER MM, SCHMID R: Metabolic regulation of heme catabolism and bilirubin production. I Hormonal control of hepatic heme oxygenase activity. J Clin Invest 51530–536, 1972.PubMedCrossRefGoogle Scholar
  38. 38.
    THALER MM, GEMES DL, BAKKEN AF: Enzymatic conversion of heme to bilirubin in normal and starved fetuses and newborn rats. Pediat Res 6: 197–201, 1972..PubMedCrossRefGoogle Scholar
  39. 39.
    DAWBER NH, BAKKEN A, SCHMID R et al: Stimulation of bilirubin production by epineprin and glucagon. (Abstract). Gastroenterology 66: 881, 1974.Google Scholar
  40. 40.
    LUNDH B, JOHANSSON B, MERCKE C et al: Enhancement of heme catabolism by caloric restriction in man. Scand J Lab Clin Invest 30: 421–427, 1972.CrossRefGoogle Scholar
  41. 41.
    GILBERT A, HERSCHER M: Sur les variations de la cholemie physiologique. Presse Med 14: 209–211, 1906.Google Scholar
  42. 42.
    BARRETT PVD: Hyperbilirubinemia of fasting. J A M A 217: 1349–1353, 1971.PubMedCrossRefGoogle Scholar
  43. 43.
    BLOOMER JR, BARRET PV, RODKEY FL et al: Studies on the mechanism of fasting hyperbilirubinemia. Gastroenterol61: 479–487, 1971.Google Scholar
  44. 44.
    FELSHER BF, RICKARD D, REDEKER AG: The reciprocal relation between caloric intake and the degree of hyperbilirubinemia in Gilbert’s syndrome. New Engl J Med 283: .170–172, 1970.PubMedCrossRefGoogle Scholar
  45. 45.
    SOKAL, JE: Glucagon, an essential hormone. Amer J Med 41: 331–341, 1966.PubMedCrossRefGoogle Scholar
  46. 46.
    TSCHUDY DP, WELLAND FH, COLLINS A et al: The effect of carbohydrate feeding on the induction of delta-aminolevulinic acid synthetase. Metabolism 13 396–406, 1964.PubMedCrossRefGoogle Scholar
  47. 47.
    MARVER HS, COLLINS A, TSCHUDY DP et al: Delta-aminolevulinic acid synthetase. II Induction in rat liver. J Biol Chem 241: 1359–1375, 1966.Google Scholar
  48. 48.
    WELLAND FH, HELLMAN ES, GADDIS EM et al: Factors affecting the excretion of porphyrin precursors by patients with acute intermittent porphyria. I The effect of diet. Metabolism 13: 232–250, 1964.PubMedCrossRefGoogle Scholar
  49. 49.
    FELSHER BF, REDEKER AG: Acute intermittent porphyria: Effect of diet and griseofulvin. Medicine (Baltimore) 46: 217–223, 1967.CrossRefGoogle Scholar
  50. 50.
    GOLDSTEIN GW, HAMMAKER L, SCHMID R: The catabolism of Heinz bodies; An experimental model demonstrating conversion to non-bilirubin catabolites. Blood 31; 388–395, 1968.PubMedGoogle Scholar
  51. 51.
    LANAW SA, CALLAHAN EW, SCHMID R: Catabolism of heme in vivo: Comparison of the simultaneous production of bilirubin and carbon monoxide. J Clin Invest M-9: 914–925, 1970.CrossRefGoogle Scholar
  52. 52.
    SCHACTER BA, MARVER HS, MEYER UA: Hemoprotein catabolism during stimulation of microsomal lipid peroxidation. Biochim Biophys Acta 279: 221–227, 1972.PubMedCrossRefGoogle Scholar
  53. 53.
    KATZ RM, DUCCI H, ALESSANDRI H: Influence of cortisone and prednisolone on hyperbilirubinemia. J Clin Invest 361370–1374, 1957.PubMedCrossRefGoogle Scholar
  54. 54.
    SCHIFF L: The use of steroids in liver disease. Medicine (Baltimore) 45: 565–573, 1966.CrossRefGoogle Scholar
  55. 55.
    GEMSA D, WOO CH, HJDENBERG HH et al: Stimulation of heme oxygenase in macrophages and liver by endotoxin. J Clin Invest 53: 647–651, 1974.PubMedCrossRefGoogle Scholar
  56. 56.
    VERMILLION SE, GREGG JA, BAGGENSTOSS AH et al: Jaundice associated with bacteremia. Arch Intern Med 124: 611–618, 1969.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1975

Authors and Affiliations

  • Brent A. Schacter
    • 1
  1. 1.University of Manitoba and The Manitoba Institute of Cell BiologyWinnipegCanada

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