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American Academy of Pediatrics
Special Article

Bilirubin Benefits: Cellular Protection by a Biliverdin Reductase Antioxidant Cycle

Thomas W. Sedlak and Solomon H. Snyder
Pediatrics June 2004, 113 (6) 1776-1782; DOI: https://doi.org/10.1542/peds.113.6.1776
Thomas W. Sedlak
*Departments of Neuroscience and Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
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Solomon H. Snyder
*Departments of Neuroscience and Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
‡Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland
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Bilirubin is widely known as an end product of heme metabolism. Very high levels of serum bilirubin lead to its accumulation in the brain, causing kernicterus.1,2 Almost all newborns display some level of jaundice, and some display high enough serum bilirubin levels that phototherapy or exchange transfusion is considered.

What most of the medical profession has not appreciated is that, from a teleologic perspective, biosynthesis of bilirubin as the key catabolite of heme does not seem to make sense. Bilirubin is a secondary degradation product of heme. Heme is best known as a constituent of hemoglobin, which is released in association with the breakdown of aging red blood cells. Heme also is contained in a wide range of enzymes whose turnover also leads to free heme release. Free heme can be toxic, so nature evolved a family of heme oxygenase enzymes to degrade heme,3,4 and their blockade leads to greatly increased excretion of unmetabolized heme in the bile.5 These enzymes cleave the heme ring to form biliverdin, iron, and a 1-carbon fragment as carbon monoxide (CO; Fig 1). CO is increasingly appreciated as a neurotransmitter,6,7 and iron, itself toxic, is excreted from cells by a recently characterized pump.8–11 Biliverdin would seem to be an appropriate end product of the pathway, being readily excreted in the bile to enter the intestine and leave the body in the feces. Indeed, in birds, reptiles, and amphibians, biliverdin is the predominant end product of heme degradation.12 For reasons that until now have seemed obscure, in mammals, biliverdin undergoes additional metabolism, being reduced by biliverdin reductase (BVR) to bilirubin, a step that consumes the energy resource nicotinamide adenine dinucleotide phosphate (NADPH).13 As bilirubin is more hydrophobic and insoluble than biliverdin, …

Reprint requests to (S.H.S.) Department of Neuroscience, Johns Hopkins School of Medicine, 725 North Wolfe St, Baltimore, MD 21205. E-mail: ssnyder{at}bs.jhmi.edu

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In this issue

Pediatrics
Vol. 113, Issue 6
1 Jun 2004
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Bilirubin Benefits: Cellular Protection by a Biliverdin Reductase Antioxidant Cycle
Thomas W. Sedlak, Solomon H. Snyder
Pediatrics Jun 2004, 113 (6) 1776-1782; DOI: 10.1542/peds.113.6.1776

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Bilirubin Benefits: Cellular Protection by a Biliverdin Reductase Antioxidant Cycle
Thomas W. Sedlak, Solomon H. Snyder
Pediatrics Jun 2004, 113 (6) 1776-1782; DOI: 10.1542/peds.113.6.1776
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  • Article
    • BILIVERDIN REDUCTASE CYCLE
    • CLINICAL RELEVANCE
    • CONCLUSIONS
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  • Developmental hyperbilirubinemia and CNS toxicity in mice humanized with the UDP glucuronosyltransferase 1 (UGT1) locus
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  • Biliverdin Administration Prevents the Formation of Intimal Hyperplasia Induced by Vascular Injury
  • Impact of Serum Bilirubin on Human Diseases
  • Bilirubin the Beneficent
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  • Conflict of Interest and Purpose in Bilirubin Screening
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Subjects

  • Fetus/Newborn Infant
    • Fetus/Newborn Infant
  • Endocrinology
    • Endocrinology

Keywords

  • CO, carbon monoxide
  • BVR, biliverdin reductase
  • NADPH, nicotinamide adenine dinucleotide phosphate (reduced form)
  • HO1, heme oxygenase 1
  • HO2, heme oxygenase 2
  • GSH, glutathione
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