Available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/cupe Bilirubin metabolism: Applied physiology Xia Wang, Jayanta Roy Chowdhury à , Namita Roy Chowdhury Albert Einstein College of Medicine, New York, USA KEYWORDS Bilirubin; Bilirubin glucuro- nides; UGT1A1; ABCC2 Summary Bilirubin is the breakdown product of the haem moiety of haemoglobin and other haemoproteins. Because of internal hydrogen bonding, bilirubin is water-insoluble and requires enzyme-mediated glucuronidation in the liver for biliary excretion. In normal circumstances, plasma bilirubin is mostly unconjugated and is tightly bound to circulating albumin. It is taken up by hepatocytes by facilitated diffusion, stored in hepatocytes bound to glutathione-S-transferases and conjugated to glucuronides by microsomal UGT1A1. Bilirubin glucuronides are actively transported into the bile canaliculi by the ATP-utilizing pump MRP2. Bilirubin is degraded in the intestine by bacteria into urobilinogens, which are partly excreted in the urine. Increased production, reduced uptake and low glucuronida- tion capacity can increase plasma unconjugated bilirubin levels. In cases of inherited or acquired deficiencies of bilirubin storage or excretion, both conjugated and unconjugated bilirubin accumulate in the plasma. Conjugated bilirubin is less tightly bound to albumin and is excreted in the urine. The capacities of the various steps of bilirubin throughput are finely balanced, and the expression of the gene products mediating these steps is coordinated by nuclear receptors. & 2005 Elsevier Ltd. All rights reserved. Practice points  In normal circumstances, plasma bilirubin is mostly unconjugated (96%)  The presence of a higher percentage of conjugated bilirubin suggests liver disease or inherited errors of bilirubin excretion. However, the ‘direct-reacting’ fraction in clinical tests slightly overestimates the conjugated fraction of bilirubin  Unconjugated bilirubin is not excreted in urine in the absence of proteinuria. Therefore, the excre- tion of conjugated bilirubin in the urine indicates the presence of an increased amount of conjugated bilirubin in the plasma  When conjugated bilirubin accumulates in the plasma over a long time, a fraction of the pigment may bind irreversibly to albumin, generating a complex that is not excreted in the bile or urine. Thus, after surgical correction of biliary obstruction, direct-reacting hyperbilirubinaemia may linger for several weeks Research directions  Bilirubin is toxic to cells when its molar concentra- tion in the plasma exceeds that of albumin. Mild ARTICLE IN PRESS 0957-5839/$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.cupe.2005.10.002 à Corresponding author. Tel.: +1 718 430 2265; fax: +1 718 430 8975. E-mail address: chowdhur@aecom.yu.edu (J.R. Chowdhury). Current Paediatrics (2006) 16, 70–74