Location of Repository

Transport and Metabolism at Blood–Brain Interfaces and in Neural Cells: Relevance to Bilirubin-Induced Encephalopathy

By Silvia Gazzin, Nathalie Strazielle, Claudio Tiribelli and Jean-François Ghersi-Egea


Bilirubin, the end-product of heme catabolism, circulates in non-pathological plasma mostly as a protein-bound species. When bilirubin concentration builds up, the free fraction of the molecule increases. Unbound bilirubin then diffuses across blood–brain interfaces (BBIs) into the brain, where it accumulates and exerts neurotoxic effects. In this classical view of bilirubin neurotoxicity, BBIs act merely as structural barriers impeding the penetration of the pigment-bound carrier protein, and neural cells are considered as passive targets of its toxicity. Yet, the role of BBIs in the occurrence of bilirubin encephalopathy appears more complex than being simple barriers to the diffusion of bilirubin, and neural cells such as astrocytes and neurons can play an active role in controlling the balance between the neuroprotective and neurotoxic effects of bilirubin. This article reviews the emerging in vivo and in vitro data showing that transport and metabolic detoxification mechanisms at the blood–brain and blood–cerebrospinal fluid barriers may modulate bilirubin flux across both cellular interfaces, and that these protective functions can be affected in chronic unconjugated hyperbilirubinemia. Then the in vivo and in vitro arguments in favor of the physiological antioxidant function of intracerebral bilirubin are presented, as well as the potential role of transporters such as ABCC1 and metabolizing enzymes such as cytochromes P-450 in setting the cerebral cell- and structure-specific toxicity of bilirubin following hyperbilirubinemia. The relevance of these data to the pathophysiology of bilirubin-induced neurological diseases is discussed

Topics: Pharmacology
Publisher: Frontiers Research Foundation
OAI identifier: oai:pubmedcentral.nih.gov:3355510
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles



    1. (2003).Transportacrossthechoroid plexuses in vivo and in vitro.
    2. (2004).ExpressionofP-glycoprotein (ABCB1) and Mrp1 (ABCC1) in adult rat brain: focus on astrocytes.
    3. (2005). [Cytoprotective effects of bilirubin].
    4. (2000). 1protectsthechoroidplexusepithelium and contributes to the bloodcerebrospinal fluid barrier.
    5. (1988). A new aspect of the protective functions of the bloodbrainbarrier:activitiesof fourdrugmetabolizing enzymes in isolated rat brain microvessels.
    6. (2008). ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood-brain barrier.
    7. (2012). accepted: 25
    8. (2003). Administration of drugs known to inhibit P-glycoprotein increases brain bilirubin and alters the regional distribution of bilirubin in rat brain.
    9. (2001). Affinity of human serum albumin for bilirubin varies with albumin concentration and buffer composition: results of a novel ultrafiltration method.
    10. (2010). Altered occludin expression in brain capillaries induced by obstructive jaundice in rats. Brain Res.
    11. and Strazielle,N.(2009a).Blood-braininterfaces and bilirubin-induced neurological diseases.
    12. andBendayan,R.(2001).Functional expression of P-glycoprotein in rat brain microglia.
    13. andBrito,M.A.(2011).Elevatedlevels of bilirubin and long-term exposure impair human brain microvascular endothelial cell integrity.
    14. andScherrmann,J.M.(2000).Functional expression of P-glycoprotein and multidrug resistance-associated protein (Mrp1) in primary cultures of rat astrocytes.
    15. andVitek,L.(2008).Highlysensitive method for quantitative determination of bilirubin in biological fluids and tissues.
    16. (1989). Antioxidant enzymes and related trace elements in aging brain capillaries and choroid plexus.
    17. (2005). Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radicalscavenging activity.
    18. (2011). Aryl hydrocarbon receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier.
    19. (1991). Bilirubin accumulation by the rabbit choroid plexus in vitro.
    20. (2009). Bilirubin and glutathione have complementary antioxidant and cytoprotective roles.
    21. (2005). Bilirubin and the risk of common non-hepatic diseases.
    22. (2003). Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implicationsfortheroleof oxidative stress in the development of multiple sclerosis.
    23. (2009). Bilirubin chemistry and metabolism;harmfulandprotectiveaspects.
    24. (2006). Bilirubin degradation by uncoupled cytochrome P450. Comparison with a chemical oxidation system and characterization of the products by highperformance liquid chromatography/electrospray ionization mass spectrometry. Rapid Commun.
    25. (2002). Bilirubin produces apoptosis in cultured bovine brain endothelial cells. Brain Res.
    26. (2004). Bilirubin protects astrocytes from its own toxicity by inducing up-regulation and translocation of multidrugresistance-associatedprotein 1
    27. (2012). Bilirubin transport and metabolism
    28. (1999). Bilirubin, formed by activation of heme oxygenase-2, protectsneuronsagainstoxidativestress injury.
    29. (2004). Bilirubin: an endogenousproductof hemedegradationwithbothcytotoxicandcytoprotective properties.
    30. (2008). Biliverdin reductase is a transporter of haem into the nucleus and is essential for regulation of HO-1 gene expression by haematin.
    31. (1993). Biliverdin reductase is heat resistant and coexpressed with constitutive and heat shock forms of heme oxygenase in brain.
    32. (2002). Biliverdin reductase: a major physiologic cytoprotectant.
    33. Binding of bilirubin with lipid. A possiblemechanismof itstoxicreactionsinmitochondria.J.Biol.Chem.
    34. (2009). Blood-brain interfaces and cerebral drug bioavailability.
    35. (1995). Blood-brain interfaces: relevance to cerebral drug metabolism.
    36. (1998). Brain bilirubin content is increased in P-glycoproteindeficient transgenic null mutant mice.
    37. (2006). Brain protection at the blood-cerebrospinal fluid interface involves a glutathione-dependent metabolic barrier mechanism.
    38. (2006). Calculated in vivo free bilirubin levels in the central nervous system of Gunn rat pups.
    39. (2004). Cellular localization and functional expression of P-glycoprotein in rat astrocyte cultures.
    40. (2012). Cerebellar axon/myelin loss,angiogenic sprouting,and neuronal increase of vascular endothelialgrowthfactorinapreterminfant with kernicterus.
    41. (1985). Cerebellar hypoplasia in the Gunn rat is associated with quantitative changes in neurotypic and gliotypicproteins.J.Pharmacol.Exp.
    42. (2000). Choroid plexus in the central nervous system: biology and physiopathology.
    43. (1999). Circulation and energy metabolism of the brain,” in Basic Neurochemistry: Molecular, Cellular and Medical Aspects. eds
    44. (1985). Clearance of bilirubin from rat brain after reversible osmotic opening of the blood-brain barrier.
    45. (2005). Constitutive expression and localization of cytochrome P-450 1A1 in rat and human brain: presence of a splice variant form in human brain.
    46. (2010). Controversies in bilirubin biochemistry and their clinical relevance.
    47. (2000). Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ. Health Perspect.
    48. (2003). CYP1A1 and CYP1B1 in blood-brain interfaces: CYP1A1-dependent bioactivation of 7,12-dimethylbenz(a)anthracene in endothelial cells.
    49. (1996). Cytotoxicity of bilirubin for human fibroblasts and rat astrocytes in culture. Effect of the ratio of bilirubin to serum albumin.
    50. (1999). Demonstration of a coupled metabolism-efflux process at the choroid plexus as a mechanism of brain protection toward xenobiotics.
    51. (2004). Detoxification systems, passive and specific transport fordrugsattheblood-CSFbarrierin normal and pathological situations.
    52. (1995). Developmental changes in the cellular distribution of glutathione and glutathione S-transferases in the murine nervous system.
    53. (1995). Differential expression of heme oxygenase-1 in cultured cortical neurons and astrocytes determined by the aid of a new heme oxygenase antibody. Response to oxidative stress. Brain Res.
    54. (2008). Differential expression of the multidrug resistance-related proteinsABCb1andABCc1between blood-brain interfaces.
    55. (1998). Distribution and induction of cytochrome P450 1A1 and 1A2 in rat brain.
    56. Drug Deliv.
    57. (2009). Drug metabolizing enzyme expression in rat choroid plexus: effects of in vivo xenobiotics treatment.
    58. (2002). Drug-metabolizing cytochrome P450s in the brain.
    59. (2010). Early isomerization of bilirubin in phototherapyofneonataljaundice.Pediatr.
    60. (1993). Effects of bilirubin infusion on local cerebral glucose utilization in the immature rat.
    61. (1993). Effects of hyperbilirubinaemia on glutathioneS-transferaseisoenzymesin cerebellar cortex of the Gunn rat.
    62. (2005). Elevated plasma levels of bilirubin in patients with neurotrauma reflect its pathophysiological role in free radical scavenging.
    63. (2005). Essential fatty acids and the brain: from infancy to aging.Neurobiol.Aging 26(Suppl.1), 98–102. Yong,V.W.,Wells,J.,Giuliani,F.,Casha, S.,Power,C.,andMetz,L.M.(2004). The promise of minocycline in neurology.
    64. (2005). Evidence for induced microsomal bilirubin degradation by cytochrome P450 2A5.
    65. Expression and functional activity of the ABC-transporter proteins P-glycoprotein and multidrugresistance protein 1 in human brain tumor cells and astrocytes.
    66. (2002). Expression of mRNAs of multidrug resistance proteins (Mrps) in cultured rat astrocytes, oligodendrocytes, microglial cells and neurones.
    67. (2005). Expressionofmultidrugresistanceproteins (Mrps) in astrocytes of the mouse brain: a single cell RT-PCR study.
    68. (2005). Factors affecting delivery of antiviral drugs to the brain.
    69. (2006). Functional effectiveness of the blood-brain barrier to small watersoluble molecules in developing and adult opossum (Monodelphis domestica).
    70. (2003). Functional expression of the multidrug resistance protein 1 in microglia.
    71. (2000). Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype.
    72. (2000). Glial cell type-specific responses to menadione-induced oxidative stress. Free Radic.
    73. (1997). Glutathione in the brain: disorders of glutathione metabolism,”
    74. (1990). Glutathione S-transferase in human brain.
    75. (2004). Heme oxygenase and its products in the nervous system.
    76. (2005). Heme oxygenase-2 protects against glutathione depletion-induced neuronal apoptosis mediated by bilirubinandcyclicGMP.Curr.Neurovasc.
    77. (1999). Hemoglobin and iron-evoked oxidative stress in the brain: protection by bile pigments, manganese and S-nitrosoglutathione. Free Radic.
    78. (1997). Histochemical localization of heme oxygenase-2 protein and mRNA expression in rat brain. Brain Res. Brain Res.
    79. (1995). Hyperbilirubinemia results in reduced oxidative injury in neonatal Gunn rats exposed to hyperoxia. Free Radic.
    80. (2005). Impact of serum bilirubin on human diseases.
    81. (2000). Implication of bloodbrain interfaces in cerebral drug metabolism and drug metabolite disposition,”
    82. (1987). Increase in a specific cytochrome P-450 isoenzyme in the liver of congenitally jaundiced Gunn rats.
    83. (1994). Induction and immunological characterization of the uridine diphosphateglucuronosyltransferaseconjugating 1-naphtholintheratchoroidplexus.
    84. (1993). Inhibition of thyroxine transport into cultured rat hepatocytes by serum of nonuremic critically ill patients: effects of bilirubin and nonesterified fatty acids.
    85. (2009). Intervention guidelines for neonatal hyperbilirubinemia: an evidence based quagmire.
    86. (2006). Kernicterus and the molecular mechanisms of bilirubin-induced CNS injury in newborns.
    87. (1986). Kinetics of protein binding determine rates of uptake of drugs by brain.
    88. (1994). Localization of drugmetabolizing enzyme activities to blood-brain interfaces and circumventricularorgans.J.Neurochem.62,
    89. (1995). Mapping of the consequences of bilirubin exposure in the immature rat: local cerebral metabolic rates for glucose during moderateandseverehyperbilirubinemia. Early Hum.
    90. (1999). Mechanism of organic anion transport across the apical membrane of choroid plexus.
    91. (2002). Mechanisms of bilirubin neurotoxicity.
    92. (1994). Metabolismdependent binding of the heterocyclic amine Trp-P-1 in endothelial cells of choroid plexus and in large cerebral veins of cytochrome P450-inducedmice.BrainRes.659,91–98.
    93. (1997). Mice deficient in cellular glutathione peroxidase develop normally and show noincreasedsensitivitytohyperoxia.
    94. (2005). Minocycline blocks bilirubin neurotoxicity and prevents hyperbilirubinemiainduced cerebellar hypoplasia in the Gunnrat.Eur.J.Neurosci.22,21–27.
    95. (1997). Mitochondrial content of choroid plexus epithelium.
    96. (1985). Mode of prevention by phototherapy of cerebellar hypoplasia in a new Sprague-Dawley strain of jaundiced Gunn rats.
    97. (2011). Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by bilirubin at the bloodCSF and blood-brain barriers in the Gunn rat.
    98. (2006). Multidrug resistance associated protein 1 protectsagainstbilirubin-inducedcytotoxicity.
    99. (2005). Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2,andBCRP(ABCG2)intissue defense.
    100. (1999). Neuroprotective action of bilirubin against oxidative stress in primary hippocampal cultures.
    101. (2005). New insights into biliverdin reductase functions: linking heme metabolism to cell signaling.
    102. (2005). Nomenclature for mammalian soluble glutathione transferases.
    103. (2010). Omega-3 and omega-6 fatty acids suppress ER- and oxidative stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1.
    104. (2004). Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch.
    105. (2000). Organic aniontransporting polypeptides mediate transport of opioid peptides across blood-brain barrier.
    106. (2010). Pericytes are required for blood-brain barrier integrity during embryogenesis.
    107. (1996). Pglycoprotein in the blood-brain barrierofmiceinfluencesthebrainpenetration and pharmacological activity of many drugs.
    108. (2000). Pioneers in the scientific study of neonatal jaundice and kernicterus. Pediatrics 106,E15.
    109. (2001). Plasma membranetransportof thyroidhormones and its role in thyroid hormone metabolism and bioavailability.
    110. (2005). Polymorphisms in human organic anion-transporting polypeptide1A2(OATP1A2):implications for altered drug disposition and central nervous system drug entry.
    111. (2012). Postnatal changes of bilirubin accumulation in selective brain regions of hyperbilirubinemic Gunn rat.
    112. (2004). Presence and functional activity of the aryl hydrocarbon receptor in isolated murine cerebral vascular endothelial cells and astrocytes.
    113. (2005). Presence of splice variant forms of cytochrome P4502D1inratbrainbutnotinliver.
    114. (1993). Purification and characterization of human biliverdin reductase.
    115. (2006). Redox regulation of heat shock protein expression by signaling involving nitric oxide and carbon monoxide: relevance to brain aging, neurodegenerative disorders, and longevity.
    116. (2006). reductase, a major physiologic cytoprotectant, suppresses experimental autoimmune encephalomyelitis. Free Radic.
    117. (2008). Reduction of cerebral Frontiers
    118. (2010). Regional Pglycoprotein activity and inhibition at the human blood-brain barrier as imagedbypositronemissiontomography.
    119. (1993). Regiospecific expression of cytochrome P-450s and microsomal epoxide hydrolase in human brain tissue.
    120. (2009). Role of bilirubin as antioxidant in neonatal jaundice and effect of ethanolic extract of sweet limepeelonexperimentallyinduced jaundice in rat.
    121. (2007). Role of multidrug resistance-associated protein 1 expression in the in vitro susceptibility of rat nerve cell to unconjugated bilirubin.
    122. (2011). Selectivevulnerabilityof ratbrainregions to unconjugated bilirubin.
    123. (2005). Small interference RNAmediated gene silencing of human biliverdin reductase, but not that of heme oxygenase-1, attenuates arsenite-mediated induction of the oxygenaseandincreasesapoptosisin 293Akidneycells.J.Biol.Chem.280,
    124. (1994). Structure and binding of unconjugated bilirubin: relevance for physiological and pathophysiological function.
    125. (1993). Subcellular localization of cytochrome P450, and activities of several enzymes responsible for drug metabolism in the human brain.
    126. (2000). The blood-brain barrier and bilirubin encephalopathy.
    127. (2008). The blood-CSF barrier explained: when development is not immaturity.
    128. (1993). The bloodbrain barrier: morphology, molecules, and neurothelin.
    129. (2009). The cytotoxic effect of unconjugated bilirubin in human neuroblastoma SH-SY5Y cells is modulatedbytheexpressionlevelof MRP1 but not MDR1.
    130. (2012). The human multidrug-resistanceassociated protein MRP1 mediates ATP-dependent transport of Frontiers
    131. (2004). The structure of the choroid plexus and the physiology of the choroid plexus epithelium.
    132. (2008). The tight junction protein complex undergoes rapid and continuous molecular remodeling at steady state.
    133. (2008). Tight junction biogenesis during early development.
    134. (2003). Tissue mRNA expression of the rat UDPglucuronosyltransferase gene family. Drug Metab.
    135. (1999). Tissue- and cell typespecific expression of cytochrome P4501A1andcytochromeP4501A2 mRNAinthemouselocalizedinsitu hybridization.
    136. (2011). Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels.
    137. (2012). Transport andmetabolismatblood–braininterfaces andinneuralcells:relevancetobilirubininduced encephalopathy.
    138. Uhler (Philadelphia: Lippincott-Raven), 637–669. Conlee,J.W.,andShapiro,S.M.(1997). Development of cerebellar hypoplasia in jaundiced Gunn rats: a quantitative light microscopic analysis.
    139. (2009). Unbound (free) bilirubin: improving the paradigm for evaluating neonatal jaundice.
    140. (2008). Unconjugated bilirubin differentially affects the redox status of neuronal and astroglial cells.
    141. (1999). Unconjugated bilirubin exhibits spontaneous diffusion through model lipid bilayers andnativehepatocytemembranes.J.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.