Bilirubin, the gold within.

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 addition, the conjugation of bilirubin is an energy requiring process, whereas biliverdin is water soluble and can be directly eliminated into bile. One of the most compelling theories is that evolution of the placenta created the need for complete conversion of biliverdin to bilirubin in mammals. Several studies have shown that bilirubin is able to traverse the placenta, either by diffusion or transport, whereas biliverdin cannot.3 Thus, the complete conversion of biliverdin to bilirubin would be a mechanism by which the developing fetus can get rid of heme metabolites.3 Arguing against this hypothesis is the recent discovery that humans homozygous for mutations that inactivate biliverdin reductase do not appear to present with physical problems.4 The absence of biliverdin reductase should prevent the conversion of biliverdin to bilirubin, and, indeed, during periods of obstruction of bile flow, plasma of these subjects became bright green. However, although the absence of biliverdin reductase gave rise to elevated biliverdin levels, plasma of these people also contained bilirubin,4 suggesting an alternative route of biliverdin conversion. Molecular biology offers another line of evidence for a beneficial role of bilirubin. Approximately 10% of the population has Gilbert syndrome, characterized by mildly elevated plasma bilirubin.5 In whites, Gilbert syndrome is caused by a TA nucleotide polymorphism in the promoter region of UGT1A1, the gene encoding bilirubin UDP glucuronyltransferase.6 Homozygotes for this UGT1A1*28 polymorphism have serum bilirubin levels in the high reference range but, combination with other factors, such as increased hemolysis, will elevate bilirubin levels further. The high frequency of the UGT1A1*28 polymorphism causing elevated bilirubin suggests a positive evolutionary selection for this allele. Compelling evidence that slightly elevated bilirubin levels confer an evolutionary advantage comes from studies in different ethnic groups. In Asians, mildly elevated bilirubin levels are also prevalent, but the molecular mechanism behind this elevation is different. Whereas in whites, Gilbert syndrome depends on the UGT1A1*28 polymorphism, in Asians a G A mutation in nucleotide 211 of the coding region of the UGT1A1 gene is the main cause of Gilbert syndrome.7 Two distinct molecular mechanisms causing the same phenotype suggest convergent evolution of the same trait and thus provide strong evidence for an evolutionary advantage of elevated bilirubin levels. However, it is also possible that elevated bilirubin levels are not beneficial, but that reduced glucuronidation by UGT1A1 of an as-yetunidentified compound provides a selective advantage. In this scenario, elevated bilirubin levels would just be an epiphenomenon. Glucuronidation by UGT1A1 is also important for the detoxification of hormones such as estradiol.8 Because it is easily imaginable that elimination speed of hormones affects fertility, the possibility that the evolutionary advantage of Gilbert syndrome polymorphisms have nothing to do with bilirubin cannot be completely discarded. On the other hand, several studies have reported an association between low serum bilirubin levels and increased The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, the Netherlands. Correspondence to Piter Bosma, PhD, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, S1-168, Meibergdreef 69, 1105 BK Amsterdam, the Netherlands. E-mail [email protected] (Circulation. 2012;126:2547-2549.) © 2012 American Heart Association, Inc.