Unconjugated bilirubin functions intracellularly as a potent inhibitor of NADPH oxidase complexes, and albumin-bound bilirubin contributes significantly to the oxidant scavenging activity of plasma. So it is not surprising that serum levels of bilirubin have been found to correlate inversely with risk for vascular diseases and a host of other disorders. Nonetheless, recent Mendelian randomization analyses reveal that individuals who carry low expression alleles of the hepatic bilirubin conjugating enzyme UGT1A1, and hence have somewhat elevated levels of plasma bilirubin throughout life, are not at decreased risk for vascular disorders. This likely reflects the fact that, in most people, plasma levels of unconjugated, unbound bilirubin--the fraction of bilirubin capable of fluxing back into cells--are so low (near 1 nM) that they can exert only a trivial antioxidant influence on cells. In light of these findings, it is reasonable to propose that the inverse correlation of plasma bilirubin and disease risks noted in many studies often reflect the fact that elevated plasma bilirubin can serve as a marker for an increased propensity to generate bilirubin within cells. Consistent with this view, high expression alleles of the major enzymatic source of bilirubin, heme oxygenase-1 (HO-1), do associate with decreased vascular risk in the majority of studies that have addressed this issue, and increased plasma bilirubin has been reported in carriers of these alleles. Hence, the consistent reduction in vascular risk noted in people with Gilbert syndrome (traditionally defined as having serum bilirubin in excess of 20 μM) is likely attributable to an increased rate of bilirubin generation within tissues, rather than to the decreased hepatic UGT1A1 activity that characterizes this syndrome. However, there is good reason to suspect that, at some sufficiently high plasma bilirubin level--as in individuals with very intense Gilbert syndrome or in Gunn rats lacking UGT1A1 activity--the plasma bilirubin pool does indeed provide some antioxidant protection to cells. Strategies for boosting bilirubin production within cells via HO-1 induction, or for mimicking bilirubin's antioxidant activity with cyanobacterial phycobilins, may have important potential for health promotion.
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