Turning catabolism into usefulness--a jaundiced view.
My interest in bilirubin, a product of heme catabolism in mammals, was sparked by 2 momentous and interrelated events in 1983. The first was the premature birth of my eldest daughter, Sophie. The second was her treatment with "blue light" therapy for jaundice, which was successful despite my initial fears of its potential harmful effects. However, it was not until I joined the Bruce Ames laboratory at the University of California, Berkeley, in early 1986 that I was presented with the opportunity to work with this golden bile pigment as a postdoctoral scientist. At that time, natural antioxidants were a major interest of Bruce Ames in the context of cancer prevention (1). His close colleague, Alex Glazer, who carried out fundamental work on phycobiliproteins in a photosynthetic antenna (2 ), put forward a general hypothesis that end products of degradative metabolic pathways may play important roles as protective agents and that in this context bilirubin is a likely candidate for such a role. I immediately volunteered to test this hypothesis.
Two other important factors played a crucial role in the discovery of bilirubin as an antioxidant of potential physiological importance. First, Yorihiro (Junkan) Yamamoto was also a postdoctoral scientist in the Ames laboratory. This was extremely fortuitous because Junkan introduced me to the use of azo initiators for the controlled peroxidation of unsaturated lipids. This experience provided me with the necessary technology and methodologies to quantitatively investigate the radical-scavenging properties of bilirubin.
Second, I contacted one of the inventors of the blue light therapy, Antony McDonagh, at the University of California, San Francisco. Being a keen lunchtime runner, Tony had just discovered that sunlight induced the isomerization of bilirubin, just as blue light did, suggesting that this "mutation" of bilirubin was a physiological process (3). We jointly set out to test whether photoisomerization altered the antioxidant property of the bile pigment. Although we eventually learned that different configurational bilirubin isomers have comparable antioxidant activities, collaborating with Tony afforded an insight into the chemistry and properties of bile pigments, without which a meaningful assessment of their antioxidant activity would not have been possible.
Crucial steps for the discovery were taking the test system from homogeneous solution to liposomes and lowering the oxygen tension to a physiologically relevant 2%. Under these conditions, bilirubin surpassed the lipid peroxidation--inhibiting activity of [alpha]-tocopherol, considered to be the most effective lipid-soluble antioxidant in humans. In view of these observations and the fact that the bile pigment associates stronglywith membranes, our work suggested that one beneficial role of the waste product bilirubin may be to act as a powerful biological chain-breaking antioxidant.
The scientific importance of the work is that it opened a now blossoming area of research on the beneficial effects of heme catabolism initiated byheme oxygenase (4). This research has extended to the direct product of heme oxygenase enzymatic activity, carbon monoxide (CO). Indeed, there is now growing interest in bile pigments and CO as therapeutics, with CO being investigated in a clinical trial to improve kidney function after transplantation, and bilirubin and its precursor biliverdin having been reported to protect against vascular diseases (5 ).
Arguably, the work has had an even more important impact at a personal level. I am forever grateful to Bruce Ames for the unique opportunity he gave me at that early stage in my career. I am also indebted to him and the other authors of the Science report for their ongoing friendship that is alive nearly 30 years later. And my daughter Sophie? She is now doing postdoctoral work at UC San Francisco and is lucky to count Tony and Bruce among her friends.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors' Disclosures or Potential Conflicts of Interest: No authors declared anypotential conflicts of interest.
(1.) Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 1981;78:6858-62.
(2.) Glazer AN. Light guides. Directional energy transfer in a photosynthetic antenna. J Biol Chem 1989; 264:1-4.
(3.) McDonagh AF. Sunlight-induced mutation of bilirubin in a long-distance runner. N Engl J Med 1986;314:121-2.
(4.) Stocker R, Perrella MA. Heme oxygenase-1. A novel drug target for atherosclerotic diseases? Circulation 2006;114:2178-89.
(5.) Ollinger R, Bilban M, Erat A, Froio A, McDaid J, Tyagi S, et al. Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation. Circulation 2005;112:1030-9.
Roland Stocker  *
 Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, University of Sydney, Sydney, Australia.
* Address correspondence to the author at: Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, Sydney Medical School, University of Sydney, Medical Foundation Bldg. K25, 92-94 Parramatta Rd., Camperdown NSW 2006, Australia. Fax 2-9036-3038; e-mail email@example.com.
Received May 16, 2011; accepted June 10, 2011.
Previously published online at DOI: 10.1373/clinchem.2011.164889
 This article has been cited more than 1600 times since publication.
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