Bilirubin: An endogenous product of heme degradation with both cytotoxic and cytoprotective properties

Molecular Pharmacology

Volumn 66, Issue 4, 2004, Pages 773-779

  Kapitulnik, Jaime ^a,b  

^a HEBREW UNIVERSITY OF JERUSALEM   (Israel)

^b HEBREW UNIVERSITY OF JERUSALEM   (Israel)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TOCOPHEROL; BILIRUBIN; BILIVERDIN; CYTOCHROME P450 1A1; HEME; LOW DENSITY LIPOPROTEIN; SCAVENGER; SERUM ALBUMIN;

ALLERGIC ENCEPHALOMYELITIS; ANTIOXIDANT ACTIVITY; APOPTOSIS; ASTROCYTE; ATHEROGENESIS; ATHEROSCLEROSIS; BACTERICIDAL ACTIVITY; BILIRUBIN BINDING; BILIRUBIN BLOOD LEVEL; BRAIN INJURY; BREATHING MUSCLE; CARBOHYDRATE METABOLISM; CELL PROTECTION; CHOLESTASIS; COGNITIVE DEFECT; CYTOTOXICITY; DEVELOPMENTAL STAGE; DNA SYNTHESIS INHIBITION; GLUCURONIDATION; HUMAN; ISCHEMIC HEART DISEASE; KERNICTERUS; LIVER TOXICITY; NERVE CELL; NEUROLOGIC DISEASE; NEUROPROTECTION; NEUROTOXICITY; NEUROTRANSMITTER RELEASE; NEUTROPHIL; NEWBORN JAUNDICE; NONHUMAN; OLIGODENDROGLIA; OXIDATION; OXIDATION REDUCTION STATE; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN SYNTHESIS INHIBITION; SHORT SURVEY;

ANIMALS; BILIRUBIN; CYTOPROTECTION; HEME; HEME OXYGENASE (DECYCLIZING); HUMANS; JAUNDICE;

EID: 4844219758     PISSN: 0026895X     EISSN: None     Source Type: Journal    
DOI: 10.1124/mol.104.002832     Document Type: Short Survey

References (84)

1. Akin E, Clower B, Tibbs R, Tang J, and Zhang J (2002) Bilirubin produces apoptosis in cultured bovine brain endothelial cells. Brain Res 931:168-175.
2. Alayoff A, Kapitulnik J, Konijn A, Kaufmann NA, and Blondheim SH (1980) Bilirubin binding capacity of albumin isolated from cord-blood serum is less than that from serum of adults. Clin Chem 26:738-740.
3. Amit Y and Brenner T (1993) Age-dependent sensitivity of cultured rat glial cells to bilirubin toxicity. Exp Neurol 121:248-255.
4. Arai T, Yoshikai Y, Kamiya J, Nagino M, Uesaka K, Yuasa N, Oda K, Sano T, and Nimura Y (2001) Bilirubin impairs bactericidal activity of neutrophils through an antioxidant mechanism in vitro. J Surg Res 96:107-113.
5. Barañano DE, Rao M, Ferris CD, and Snyder SH (2002) Biliverdin reductase: A major physiologic cytoprotectant. Proc Natl Acad Sci USA 99:16093-16098.
6. Brito MA, Silva R, Tiribelli C, and Brites D (2000) Assessment of bilirubin toxicity to erythrocytes. Implication in neonatal jaundice management. Eur J Clin Invest 30:239-247.
7. Brito MA, Brondino CD, Moura JJG, and Brites D (2001) Effects of bilirubin molecular species on membrane dynamic properties of human erythrocyte membranes: A spin label electron paramagnetic resonance spectroscopy study. Arch Biochem Biophys 387:57-65.
8. Brito MA, Silva RF, and Brites D (2002) Bilirubin induces loss of membrane lipids and exposure of phosphatidylserine in human erythrocytes. Cell Biol Toxicol 18:181-192.
9. Brodersen R (1979) Binding of bilirubin to albumin: Implications for prevention of bilirubin encephalopathy in the newborn. Crit Rev Clin Lab Sci 11:305-399.
10. Chen J, Tu Y, Moon C, Nagata E, and Ronnett GV (2003) Heme oxygenase-1 and heme oxygenase-2 have distinct roles in the proliferation and survival of olfactory receptor neurons mediated by cGMP and bilirubin, respectively. J Neurochem 85:1247-1261.
11. Chiu H, Brittingham JA, and Laskin DL (2002) Differential induction of heme oxygenase-1 in macrophages and hepatocytes during acetaminophen-induced hepatotoxicity in the rat: Effects of hemin and biliverdin. Toxicol Appl Pharmacol 181:106-115.
12. Clark JE, Foresti R, Sarathchandra P, Kaur H, Green CJ, and Motterlini R (2000a) Heme oxygenase-1-derived bilirubin ameliorates postischemic myocardial dysfunction. Am J Physiol 278:H643-H651.
13. Clark JE, Foresti R, Green CJ, and Motterlini R (2000b) Dynamics of haem oxygen-ase-1 expression and bilirubin production in cellular protection against oxidative stress. Biochem J 348:615-619.
14. Cowger ML, Igo RP, and Labbe RF (1966) The mechanism of bilirubin toxicity studied with purified respiratory enzyme and tissue culture systems. Biochemistry 4:2763-2770.
15. Dennery PA, McDonagh AF, Spitz DR, Rodgers PA, and Stevenson DK (1996) Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia. Free Radic Biol Med 19:395-404.
16. Diamond I and Schmid R (1967) Oxidative phosphorylation in experimental bilirubin encephalopathy. Science (Wash DC) 155:1288-1289.
17. Doré S, Takahashi M, Ferris CD, Hester LD, Guastella D, and Snyder SH (1999) Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc Natl Acad Sci USA 96:2445-2450.
18. Foresti R, Clark JE, Green CJ, and Motterlini R (1997) Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells: involvement of superoxide and peroxynitrite anions. J Biol Chem 272:18411-18417.
19. Foresti R, Sarathchandra P, Clark JE, Green CJ, and Motterlini R (1999) Peroxynitrite induces haem oxygenase-1 in vascular endothelial cells: a link to apoptosis. Biochem J 339:729-736.
20. Foresti R, Goatly H, Green CJ, and Motterlini R (2001) Role of heme oxygenase-1 in hypoxia-reoxygenation: requirement of substrate heme to promote cardioprotection. Am J Physiol 281:H1976-H1984.
21. Foresti R, Hoque M, Bains S, Green CJ, and Motterlini R (2003) Haem and nitric oxide: synergism in the modulation of the endothelial haem oxygenase-1 pathway. Biochem J 372:381-390.
22. Genc S, Genc K, Kumral A, Baskin H, and Ozkan H (2003) Bilirubin is cytotoxic to rat oligodendrocytes in vitro. Brain Res 985:135-141.
23. Gennuso F, Fernetti C, Tirolo C, Testa N, L'Episcopo F, Caniglia S, Morale MC, Ostrow JD, Pascolo L, Tiribelli C, et al. (2004) Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrug resistance-associated protein 1 (Mrp1). Proc Natl Acad Sci USA 101:2470-2475.
24. Ghatan S, Larner S, Kinoshita Y, Hetman M, Patel L, Xia Z, Youle RJ, and Morrison RS (2000) p38 mediates bax translocation in nitric oxide-induced apoptosis in neurons. J Cell Biol 150:335-347.
25. Gourley GR (1997) Bilirubin metabolism and kernicterus. Adv Pediatr 44:173-229.
26. Granato A, Gores G, Vilei MT, Tolando R, Ferraresso C, and Muraca M (2003) Bilirubin inhibits bile acid induced apoptosis in rat hepatocytes. Gut 52:1774-1778.
27. Grojean S, Koziel V, Vert P, and Daval J-L (2000) Bilirubin induces apoptosis via activation of NMDA receptors in developing rat brain neurons. Exp Neurol 166:334-341.
28. Grojean S, Lievre V, Koziel V, Vert P, and Daval J-L (2001) Bilirubin exerts additional toxic effects in hypoxic cultured neurons from the developing rat brain by the recruitment of glutamate neurotoxicity. Pediatr Res 49:507-513.
29. Gu Y-Z, Hogenesch JB, and Bradfield CA (2000) The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol 40:519-561.
30. Hahm JS, Ostrow JD, Mukerjee P, and Celic L (1992) Ionization and self-association of unconjugated bilirubin, determined by rapid solvent partition from chloroform, with further studies of bilirubin solubility. J Lipid Res 33:1123-1137.
31. 3H]bilirubin. Pediatr Res 49:203-207.
32. Kapitulnik J, Blondheim SH, and Kaufmann NA (1972) Sephadex adsorption of bilirubin from neonatal and adult serum. Clin Chem 18:43-47.
33. Kapitulnik J and Ostrow JD (1978) Stimulation of bilirubin catabolism in jaundiced Gunn rats by an inducer of microsomal mixed-function monooxygenases. Proc Natl Acad Sci USA 75:682-685.
34. Kapitulnik J, Hardwick JP, Ostrow JD, Webster CC, Park SS, and Gelboin HV (1987) Increase in a specific cytochrome P-450 isoenzyme in the liver of congenitally jaundiced Gunn rats. Biochem J 242:297-300.
35. Kapitulnik J and Gonzalez FJ (1993) Marked endogenous activation of the CYP1A1 and CYP1A2 genes in the congenitally jaundiced Gunn rat. Mol Pharmacol 43:722-725.
36. Kato Y, Shimazu M, Kondo M, Uchida K, Kumamoto Y, Wakabayashi G, Kitajima M, and Suematsu M (2003) Bilirubin rinse: A simple protectant against the rat liver graft injury mimicking heme oxygenase-1 preconditioning. Hepatology 38:364-373.
37. Kaufmann NA, Simcha AJ, and Blondheim SH (1967) The uptake of bilirubin by blood cells from plasma and its relationship to the criteria for exchange transfusion. Clin Sci 33:201-208.
38. Kaufmann NA, Kapitulnik J, and Blondheim SH (1969) The adsorption of bilirubin by Sephadex and its relationship to the criteria for exchange transfusion. Pediatrics 44:543-548.
39. Kaur H, Hughes MN, Green CJ, Naughton P, Foresti R, and Motterlini R (2003) Interaction of bilirubin and biliverdin with reactive nitrogen species. FEBS Lett 543:113-119.
40. Lin S, Yan C, Wei X, Paul SM, and Du Y (2003) p38 MAP kinase mediates bilirubin-induced neuronal death of cultured rat cerebellar granule neurons. Neurosci Lett 353:209-212.
41. Lindenblatt N, Bordel R, Schareck W, Menger MD, and Vollmar B (2004) Vascular heme oxygenase-1 induction suppresses microvascular thrombus formation in vivo. Arterioscl Thromb Vasc Biol 24:601-606.
42. Liu X-M, Chapman GB, Wang H, and Durante W (2002) Adenovirus-mediated heme oxygenase-1 gene expression stimulates apoptosis in vascular smooth muscle cells. Circulation 105:79-84.
43. Liu Y, Zhu B, Wang X, Luo L, Li P, Paty DW, and Cynader MS (2003) Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis. J Neuroimmunol 139:27-35.
44. Maines MD (1999) Characterization and regulation of heme oxygenase isozymes atthe molecular level, in Heme Oxygenase: Clinical Applications and Functions (Maines MD ed) pp 109-144, CRC Press, Boca Raton.
45. Maklakov A, Kohan M, Zilberman Y, Pongratz I, Poellinger L, and Kapitulnik J (2004) Bilirubin activates the aryl hydrocarbon/dioxin receptor by modifying the cellular redox state. The 15th International Symposium on Microsomes and Drug Oxidations; 2004 Jul 4-9; Mainz, Germany.
46. Mancuso C, Bonsignore A, Di Stasio E, Mordente A, and Motterlini R (2003) Bilirubin and S-nitrosothiols interaction: evidence for a possible role of bilirubin as a scavenger of nitric oxide. Biochem Pharmacol 66:2355-2363.
47. Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu H-Y, Laine J, Sakai T, Korsmeyer SJ, Casper RF, et al. (2001) Aromatic hydrocarbon receptor-driven Box gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet 28:355-360.
48. McDonald JW, Shapiro SM, Silverstein FS, and Johnston MV (1998) Role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat model. Exp Neurol 150:21-29.
49. Menken M and Weinbach EC (1967) Oxidative phosphorylation and respiratory control of brain mitochondria isolated from kernicteric rats. J Neurochem 14:189-193.
50. Minetti M, Mallozzi C, Di Stasi AMM, and Pietraforte D (1998) Bilirubin is an effective antioxidant of peroxynitrite-mediated protein oxidation in human blood plasma. Arch Biochem Biophys 352:165-174.
51. Morita T, Imai T, Yamaguchi T, Sugiyama T, Katayama S, and Yoshino G (2003) Induction of heme oxygenase-1 in monocytes suppresses angiotensin II-elicited chemotactic activity through inhibition of CCR2: Role of bilirubin and carbon monoxide generated by the enzyme. Antioxid Redox Signal 5:439-447.
52. Motterlini R, Foresti R, Intaglietta M, and Winslow RM (1996) NO-mediated activation of heme oxygenase: endogenous cytoprotection against oxidative stress to endothelium. Am J Physiol 270:H107-H114.
53. Mustafa MG, Cowger ML, and King TE (1969) Effects of bilirubin on mitochondrial reactions. J Biol Chem 244:6403-6414.
54. Neuzil J and Stocker R (1993) Bilirubin attenuates radical-mediated damage to serum albumin. FEBS Lett 331:281-284.
55. Neuzil J and Stocker R (1994) Free and albumin-bound bilirubin are efficient co-antioxidants for α-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J Biol Chem 269:16712-16719.
56. Noriega GO, Ossola JO, Tomaro ML, and del Batlle AMC (2000) Effect of acetamin-ophen on heme metabolism in rat liver. Int J Biochem Cell Biol 32:983-991.
57. Novotny L and Vitek L (2003) Inverse relationship between serum bilirubin and atherosclerosis in men: A meta-analysis of published studies. Exp Biol Med 228:568-571.
58. Oberle S, Abate A, Grosser N, Hemmerle A, Vreman HJ, Dennery PA, Schneider HT, Stalleicken D, and Schroder H (2003) Endothelial protection by pentaerithrityl trinitrate: Bilirubin and carbon monoxide as possible mediators. Exp Biol Med 228:529-534.
59. O'Callaghan JP and Miller DB (1985) Cerebellar hypoplasia in the Gunn rat is associated with quantitative changes in neurotypic and gliotypic proteins. J Pharmacol Exp Ther 234:522-533.
60. Ostrow JD and Tiribelli C (2001) New concepts in bilirubin neurotoxicity and the need for studies at clinically relevant bilirubin concentrations. J Hepatol 34:467-470.
61. Ostrow JD, Pascolo L, Shapiro SM, and Tiribelli C (2003a) New concepts in bilirubin encephalopathy. Eur J Clin Investis 33:988-997.
62. Ostrow JD, Pascolo L, and Tiribelli C (2003b) Reassessment of the unbound concentrations of unconjugated bilirubin in relation to neurotoxicity in vitro. Pediatr Res 54:98-104.
63. Phelan D, Winter GM, Rogers WJ, Lam JC, and Denison MS (1998) Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch Biochem Biophys 357:155-163.
64. Quan S, Kaminski PM, Yang L, Morita T, Inaba M, Ikehara S, Goodman AI, Wolin MS, and Abraham NG (2004) Heme oxygenase-1 prevents superoxide anion-associated endothelial cell sloughing in diabetic rats. Biochem Biophys Res Commun 315:509-516.
65. Rodrigues CMP, Sola S, and Brites D (2002a) Bilirubin induces apoptosis via the mitochondrial pathway in developing rat brain neurons. Hepatology 35:1186-1195.
66. Rodrigues CMP, Sola S, Brito MA, Brites D, and Moura JJG (2002b) Bilirubin directly disrupts membrane lipid polarity and fluidity, protein order and redox status in rat mitochondria. J Hepatol 36:335-341.
67. Rodrigues CMP, Sola S, Castro RE, Laires PA, Brites D, and Moura JJG (2002c) Perturbation of membrane dynamics in nerve cells as an early event during bilirubin-induced apoptosis. J Lipid Res 43:885-894.
68. Rodrigues CMP, Sola S, Silva RFM, and Brites D (2002d) Aging confers different sensitivity to the neurotoxic properties of unconjugated bilirubin. Pediatr Res 51:112-118.
69. Samb A, Taille C, Almolki A, Megret J, Staddon JM, Aubier M, and Boczkowski J (2002) Heme oxygenase modulates oxidant-signaled airway smooth muscle contractility: role of bilirubin. Am J Physiol 283:L596-L603.
70. Seubert JM, Darmon AJ, El-Kadi AOS, D'Souza SJA, and Bend JR (2002) Apoptosis in murine hepatoma Hepa Iclc7 wild-type, C12 and C4 cells mediated by bilirubin. Mol Pharmacol 62:257-264.
71. Shapiro SM (2003) Bilirubin toxicity in the developing nervous system. Pediatr Neurol 29:410-421.
72. Shibahara S, Kitamuro T, and Takahashi K (2002) Heme degradation and human disease: Diversity is the soul of life. Antioxid Redox Signal 4:593-602.
73. Silva R, Mata LR, Gulbenkian S, Brito MA, Tiribelli C, and Brites D (1999) Inhibition of glutamate uptake by unconjugated bilirubin in cultured cortical rat astrocytes: role of concentration and pH. Biochem Biophys Res Commun 265:67-72.
74. Silva RFM, Rodrigues CMP, and Brites D (2001) Bilirubin-induced apoptosis in cultured rat neural cells is aggravated by chenodeoxycholic acid but prevented by ursodeoxycholic acid. J Hepatol 34:402-408.
75. Silva RFM, Rodrigues CMP, and Brites D (2002) Rat cultured neuronal and glial cells respond differently to toxicity of unconjugated bilirubin. Pediatr Res 51:535-541.
76. Sinal CJ and Bend JR (1997) Aryl hydrocarbon receptor-dependent induction of Cyp1a1 by bilirubin in mouse hepatoma Hepa 1c1c7 cells. Mol Pharmacol 52:590-599.
77. Siow RCM, Sato H, and Mann GE (1999) Heme oxygenase-carbon monoxide signaling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide? Cardiovasc Res 41:385-394.
78. Stocker R, Glazer AN, and Ames BN (1987a) Antioxidant activity of albumin-bound bilirubin. Proc Natl Acad Sci USA 84:5918-5922.
79. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, and Ames BN (1987b) Bilirubin is an antioxidant of possible physiological importance. Science (Wash DC) 235:1043-1046.
80. Taillé C, Almolki A, Benhamed M, Zedda C, Megret J, Berger P, Leseche G, Fadel E, Yamaguchi T, Marthan R, et al. (2003) Heme oxygenase inhibits human airway smooth muscle proliferation via a bilirubin-dependent modulation of ERK1/2 phosphorylation. J Biol Chem 278:27160-27168.
81. Vitek L, Jirsa M, Brodanova M, Kalab M, Marecek Z, Danzig V, Novotny L, and Kotal P (2002) Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 160:449-456.
82. Wu T-W, Fung KP, Wu J, Yang C-C, and Weisel RD (1996) Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins. Biochem Pharmacol 51:859-862.
83. Yamashita K, McDaid J, Ollinger R, Tsui T-Y, Berberat PO, Usheva A, Csizmadia E, Smith RN, Soares MP, and Bach FH (2004) Biliverdin, a natural product of heme catabolism, induces tolerance to cardiac allografts. FASEB J 18:765-766.
84. Zetterstrom R and Ernster L (1906) Bilirubin, an uncoupler of oxidative phosphorylation in isolated mitochondria. Nature (Lond) 178:1335-1337.