Published online December 1, 2004
PEDIATRICS Vol. 114 No. 6 December 2004, pp. 1741-1742 (doi:10.1542/10.1542/peds.2004-1426)
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Bilirubin the Beneficent

Antony McDonagh, PhD
Division of Gastroenterology
University of California
San Francisco, CA 94143-0538

To the Editor.—

I wish to add a few corrections and comments to the recent timely review by Sedlak and Snyder on bilirubin,1 the born-again benignant pigment.

  1. It is not true that bilirubin formation is restricted to mammals. This is an obsolete, but frequently repeated, hypothesis that flies in the face of scientific evidence. Bilirubin and its conjugates occur in many nonmammals, although they may not be the principle bile pigments excreted in bile.2 For example, conjugates of bilirubin are excreted in bile in many fish species, and jaundice in fish is not unknown.3 Bilirubin conjugates are also present in bile of embryonic and adult chickens,4 and the observation in 1886 by Minkowski and Naunyn5 that arsine poisoning produced marked jaundice in normal but not hepatectomized geese was a key observation in the elucidation of the physiologic pathway of heme catabolism and the role of the reticuloendothelial system. Similarly, observations on the biosynthesis of bilirubin in ducks were important in elucidating bilirubin-formation pathways in humans.6 Bilirubin pigments also occur in alligators, snakes, and turtles,2 and a biliverdin reductase with substantial sequence homology to the human enzyme is present even in the lowly unicellular cyanobacterium Synechocystis.7 Therefore, the hoary idea that bilirubin occurs uniquely in mammals8 is unfounded and should be laid to rest. The puzzle is not so much why mammals make bilirubin but rather why biliverdin reductase evolved and why many animals do without it.
  2. Similarly, it is not true that the principle isomer of bilirubin formed in the fetus is bilirubin IXß rather than the IX{alpha} isomer produced postnatally.1,8 This notion seems to have evolved from an incorrect interpretation of observations that the predominant isomer of bilirubin in meconium and fetal bile is IXß.9,10 However, the IXß isomer in fetal bile is probably but a small residual fraction of the total amount of bile pigment produced, most of which is the IX{alpha} isomer. The IX{alpha} isomer, being relatively lipophilic, does not accumulate because of its easy egress across the placenta.9,11 In contrast, the less lipophilic IXß isomer is less likely to diffuse across the placenta but can be excreted relatively easily in bile without the need for hepatic conjugation.12 Therefore, the fact that the IXß isomer is the principle isomer in fetal bile does not indicate that it is the major isomer made in the fetus. Similarly, the presence of an IXß-specific reductase in the fetus does not mean that the IX{alpha}-specific enzyme is not present or unimportant. Quite the contrary. The IX{alpha}-specific reductase is probably essential, because it facilitates transplacental excretion of bile pigment produced by heme cleavage during fetal life. There is no evidence that heme oxygenase is any less regioselective for the {alpha} bridge of heme in the fetus than it is in adults, where small amounts of the IXß isomer are also reportedly formed.13,14
  3. Because biliverdin reduction occurs in nonmammals and nonplacental mammals and a biliverdin reductase is present in Synechocystis, it is reasonable to assume that biliverdin reductases did not evolve solely to facilitate disposal of bilirubin across the placenta. However, that should not be interpreted to indicate that reduction is unimportant for fetal disposal of bile pigments in mammals. There is much experimental evidence in primates, guinea pigs, and rats that bilirubin IX{alpha} readily crosses the placenta and that reduction of biliverdin to unconjugated bilirubin really does facilitate fetal bile pigment disposal.11 Striking evidence for bidirectional flux of bilirubin across the placenta comes from the Gunn rat animal model, in which there is a recessive genetic defect in bilirubin conjugation. Heterozygous pups born to homozygous jaundiced mothers are icteric at birth but quickly lose their yellow pigmentation. In contrast, homozygous pups born to heterozygous nonjaundiced mothers are anicteric at birth but become jaundiced shortly thereafter. Early reports that bilirubin does not cross the placenta in the rat15 are not reliable, because they depended on the use of impure radioactive bilirubin prepared by a defective technique,16 which similarly has led to conflicting results in more recent investigations.17,18
  4. Although it is true that bilirubin is lipophilic, it is hardly correct to describe it as lipid soluble. Just try dissolving some in olive oil. As Brodersen19 showed, bilirubin does not dissolve to any significant extent in olive oil or classical lipids. Nevertheless, it does partition readily from aqueous solution to olive oil or octanol.20
  5. Recycling of bilirubin by biliverdin reductase reduction of biliverdin is an old idea. It would be significant only if biliverdin is a major product of the reaction of bilirubin with reactive oxygen species. Although formation of some biliverdin has been noted under certain conditions,8 there is much evidence that biliverdin is not formed stoichiometrically and is generally not a major product of the reaction of bilirubin with oxyradicals, dioxygen, or singlet oxygen. The importance of the proposed mechanism in vivo, therefore, must remain speculative. Furthermore, there are other plausible chemical mechanisms for regenerating bilirubin after it intercepts radical reactions that do not require biliverdin reductase reduction. For example, bilirubin undergoes oxygen-dependent free-radical reactions in water at pH 7.4 to 9.0, in which the pigment is regenerated without the intermediacy of biliverdin or enzyme.21
  6. As known for half a century, bilirubin is a potent antioxidant. However, evidence for its beneficial effects on human health,1 copious though it may be, remains fuzzy. It is surprising that so few studies have been done in Gunn rats. These animals permit comparative studies on icteric and anicteric littermates differing only in their glucuronosyl transferase (UGT1A1) activities and burden of unconjugated bilirubin. Although rats may be unreliable models for humans, experiments in Gunn rats might provide decisive or quantitative answers to some of the currently unresolved questions on the beneficial effects of bilirubin. Anybody wishing to obtain breeder pairs for starting their own research colony can contact me.
  7. Finally, although the antioxidant activity of bilirubin has been known for over half a century, credit for the first suggestion that bilirubin might be beneficial should perhaps go to Najib-Farah,22 who postulated in 1937, albeit for curious reasons, that the pigment forms part of a protective mechanism designed to overcome infection. Even by that date, however, the (probably ineffectual) use of bilirubin in traditional Asian medicines had become well established.23

REFERENCES

  1. Sedlak T, Snyder SH. Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics. 2004;113 :1776 –1772[Free Full Text]
  2. Cornelius CE. Comparative bile pigment metabolism in vertebrates. In: Ostrow JD, ed. Bile Pigments and Jaundice. New York, NY: Marcel Dekker; 1986:601–647
  3. Cornelius CE. Bile pigments in fishes: a review. Vet Clin Pathol. 1991;20 :106 –115[Medline]
  4. Vajro P, Thaler MM, Blanckaert N. Bile pigment composition and bilirubin esterification in the developing chick. Pediatr Res. 1995;38 :349 –355[Web of Science][Medline]
  5. Minkowski O, Naunyn B. Beiträge zur Pathologie der Leber und des Icterus. Arch Exp Path Pharmakol. 1886;21 :1 –33[CrossRef]
  6. Israels LG, Novak W, Foerster J, Zipursky A. The early-appearing bilirubin in ducks. Can J Physiol Pharmacol. 1966;44 :864 –866[Web of Science][Medline]
  7. Schluchter WM, Glazer AN. Characterization of cyanobacterial biliverdin reductase. Conversion of biliverdin to bilirubin is important for normal phycobiliprotein biosynthesis. J Biol Chem. 1997;272 :13562 –13569[Abstract/Free Full Text]
  8. Barañano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci USA 2002;99 :16093 –16098[Abstract/Free Full Text]
  9. Aziz S, Kotal P, Leroy P, Servaes R, Eggermont E, Fevery J. Bilirubin-IXalpha and -IXbeta pigments, coproporphyrins and bile acids in meconium and stools from full-term and preterm neonates during the first month of life. Acta Paediatr. 2001;90 :81 –87[CrossRef][Web of Science][Medline]
  10. Yamaguchi T, Nakajima H. Changes in the composition of bilirubin-IX isomers during human prenatal development. Eur J Biochem. 1995;233 :467 –472[Web of Science][Medline]
  11. McDonagh AF, Palma LA, Schmid R. Reduction of biliverdin and placental transfer of bilirubin and biliverdin in the pregnant guinea pig. Biochem J. 1981;194 :273 –282[Web of Science][Medline]
  12. Blanckaert N, Heirwegh PM, Zaman Z. Comparison of the biliary excretion of the four isomers of bilirubin-IX in Wistar and homozygous Gunn rats. Biochem J. 1977;164 :229 –236[Web of Science][Medline]
  13. Hirota K. Urinary excretion of alpha- and beta-isomers of biliverdin-IX in humans. Biol Pharm Bull. 1995;18 :481 –484[Web of Science][Medline]
  14. Komuro A, Tobe T, Hashimoto K, et al. Molecular cloning and expression of human liver biliverdin-IX beta reductase. Biol Pharm Bull. 1996;19 :796 –804[Web of Science][Medline]
  15. Grodsky GM, Contopoulos AN, Fanska R, Carbone JV. Distribution of bilirubin-H3 in the fetal and maternal rat. Am J Physiol. 1963;204 :837 –841[Abstract/Free Full Text]
  16. McDonagh AF. Binding of tritiated bilirubin to albumin and plasma membrane vesicles. Biochem J. 1996;321 :262 –263
  17. Pascolo L, Del Vecchio S, Koehler RK, et al. Albumin binding of unconjugated [3H]bilirubin and its uptake by rat liver basolateral plasma membrane vesicles. Biochem J. 1996;316 :999 –1004
  18. Weisiger RA, Ostrow JD, Koehler RK, et al. Affinity of human serum albumin for bilirubin varies with albumin concentration and buffer composition: results of a novel ultrafiltration method. J Biol Chem. 2001;276 :29953 –29960[Abstract/Free Full Text]
  19. Brodersen R. Bilirubin. Solubility and interaction with albumin and phospholipid. J Biol Chem. 1979;254 :2364 –2369[Abstract/Free Full Text]
  20. McDonagh AF. Lyophilic properties of protoporphyrin and bilirubin. Hepatology. 2002;36 :1028 –1029[CrossRef][Web of Science][Medline]
  21. McDonagh AF, Assisi F. The ready isomerization of bilirubin IXa in aqueous solution. Biochem J. 1972;129 :797[Web of Science][Medline]
  22. Najib-Farah. Defensive role of bilirubinaemia in pneumococcal infection. Lancet. 1937;1 :505 –506
  23. Keji C, ed. Imperial Medicaments—Medical Prescriptions Written for Empress Dowager Cixi and Empero Guangxu With Commentary: Beijing, China: Foreign Languages Press; 1996
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics

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