Bilirubin, the Gold Within

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When heme-containing proteins such as hemoglobin and cytochrome P450 are degraded, their prosthetic groups cannot be metabolized and have to be excreted. Elimination of heme could be considered straightforward detoxification, but a large body of evidence shows that this pathway plays a role in various physiological processes as well. Article see p 2556 The first step in the catabolism of heme is cleavage of the porphyrin ring by heme oxygenase (HO); this reaction yields biliverdin, carbon monoxide, and iron. Two HO isoforms mediate this process, constitutively expressed HO-2 and inducible HO-1. Many cell types express HO, with high expression present in cells of the reticuloendothelial system involved in the degradation of erythrocytes.1 The first step in heme catabolism has attracted considerable interest because HO activity is involved in the regulation of processes such as arthrosclerosis, inflammation, and diabetes mellitus.1 This regulation is mediated by the products of HO action on heme, with the potent signaling molecule carbon monoxide likely playing a major role.1 The other product of HO action on heme is the green and water-soluble compound biliverdin. In mammals, levels of biliverdin are low because it is quickly converted to the hydrophobic yellow compound bilirubin by ubiquitously expressed biliverdin reductase. However, other animal species, such as fish,2 do not completely metabolize all biliverdin to bilirubin and excrete significant amounts of the green pigment. Because bilirubin is poorly water soluble, mammals require efficient conjugation with glucuronic acid by UDP glucuronyltransferase before bilirubin glucuronides can be excreted into bile. This aspect of heme metabolism has always puzzled scientists. Why is bilirubin the sole end product of heme degradation in mammals? Bilirubin is toxic, and the absence of bilirubin UDP glucuronyltransferase (UGT1A1) in patients with Crigler-Najjar syndrome causes high unconjugated bilirubin levels and subsequent severe brain damage. In …