Bilirubin is an endogenous compound that can be toxic under certain conditions but, on the other hand, mild unconjugated hyperbilirubinaemia might protect against cardiovascular diseases and tumour development. Serum bilirubin levels are often enhanced under a variety of clinical conditions. These are discussed and the mechanisms are outlined.Bilirubin is an endogenous compound that can be toxic (1), especially in neonates. However, it has recently been recognized that unconjugated bilirubin (UCB) exerts a strong anti-oxidant activity, and that mild hyperbilirubinaemia might have positive health effects. Bilirubin is the ultimate breakdown product of haemoglobin and serves as a diagnostic marker of liver and blood disorders. It has a complex metabolism, which is important in relation to several processes involved in drug metabolism.
Bilirubin: chemical structure and formationAt first glance, bilirubin appears to be a simple molecule. However, the UCB IXa 4Z,15Z molecule, the major compound in mammals, has a peculiar stereo-chemical structure (Fig. 1). Indeed, all hydrophilic groups are involved in strong hydrogen bonds, and this turns the molecule into a closed molecule with a ridge-tile conformation (2, 3). These hydrogen bonds render UCB hydrophobic and they also shield the central -CH 2 -, which thus becomes inaccessible for the diazo-reagent (see further). Depending on the pH of the plasma, bile or urine, UCB can be present as uncharged diacid, as a monoanion or as a dianion (3). The uncharged diacid is by far the dominant species at low and physiological pH (4 80%) but the ionized fractions become more important in an alkaline milieu, because the pK'a values have been determined to be 8.12 and 8.44, respectively, for the first and for the second anion (3).Bilirubin is formed from haem by opening of the haem ring at the a carbon bridge. This cleavage is catalysed by the enzyme haem-oxygenase, and results in liberation of iron, and in the formation of carbonmonoxide and biliverdin IXa (Fig. 2). The latter is reduced by a cytosolic enzyme biliverdinreductase to bilirubin IXa. The haem-oxygenase can temporarily be inhibited by mesoporphyrins, and this suppression results in a decreased UCB production as was shown in neonates (4). Cleavage at non-a sites is possible; it is probably non-enzymic and occurs