Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, it is here that bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes. The antioxidant activity of bilirubin increases as the experimental concentration of oxygen is decreased from 20% (that of normal air) to 2% (physiologically relevant concentration). Furthermore, under 2% oxygen, in liposomes, bilirubin suppresses the oxidation more than alpha-tocopherol, which is regarded as the best antioxidant of lipid peroxidation. The data support the idea of a "beneficial" role for bilirubin as a physiological, chain-breaking antioxidant.

North American Indians were appar¬ ently aware that exposure to sunlight reduced the yellow colour of babies. Bright indirect daylight is also effect¬ ive in bringing about this reduction and may account for the alleged lower incidence of hyperbilirubinemia in sunny regions.1 For some time labo¬ ratory technicians have known that bilirubin levels are lower in samples of plasma exposed to light than in samples stored in thedark. Biochemically the change that occurs is a par¬ tial breakdown of bilirubin with a resulting shift in the absorption spec¬ trum ofthe serum.2

Bilirubin, an insoluble yellow-orange pigment derived from heme catabolism, accumulates to toxic levels in individuals with impaired or immature liver function. The resulting jaundice may be managed with phototherapy to isomerize the biosynthetic 4Z,15Z-bilirubin-IXα to more soluble and excretable isomers, such as 4Z,15E-bilirubin. Bilirubin and its configurational isomers are transported to the liver by human serum albumin (HSA) but their precise binding location(s) on the protein have yet to be determined. To investigate the molecular details of their interaction, we co-crystallised bilirubin with HSA. Strikingly, the crystal structure—determined to 2.42 Å resolution—revealed the 4Z,15E-bilirubin-IXα isomer bound to an L-shaped pocket in sub-domain IB. We also determined the co-crystal structure of HSA complexed with fusidic acid, an antibiotic that competitively displaces bilirubin from the protein, and showed that it binds to the same pocket. These results provide the first crystal structure of a natural bilirubin pigment bound to serum albumin, challenge some of the present conceptions about HSA–bilirubin interactions, and provide a sound structural framework for finally resolving the long-standing question of where 4Z,15Z-bilirubin-IXα binds to the protein.

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Blue light converts bilirubin in the skin of jaundiced rats to metastable geometric isomers that are transported in blood and excreted in bile. The same reaction probably occurs in jaundiced babies exposed to light, particularly during treatment with phototherapy. Excretion of unisomerized bilirubin is prevented by intramolecular hydrogen bonding, and the pigment has to be metabolized to more polar derivatives to be excreted efficiently.

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