‘‘Iatrogenic Gilbert syndrome’’– A strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubin

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Summary

The catabolism of heme, generating biliverdin, carbon monoxide, and free iron, is mediated by heme oxygenase (HO). One form of this of this enzyme, heme oxygenase-1, is inducible by numerous agents which promote oxidative stress, and is now known to provide important antioxidant protection, as demonstrated in many rodent models of free radical-mediated pathogenesis, and suggested by epidemiology observing favorable health outcomes in individuals carrying high-expression alleles of the HO-1 gene. The antioxidant impact of HO-1 appears to be mediated by bilirubin, generated rapidly from biliverdin by ubiquitously expressed biliverdin reductase. Bilirubin efficiently scavenges a wide range of physiological oxidants by electron donation. In the process, it is often reconverted to biliverdin, but biliverdin reductase quickly regenerates bilirubin, thereby greatly boosting its antioxidant potential. There is also suggestive evidence that bilirubin inhibits the activity or activation of NADPH oxidase. Increased serum bilirubin is associated with reduced risk for atherogenic disease in epidemiological studies, and more limited data show an inverse correlation between serum bilirubin and cancer risk. Gilbert syndrome, a genetic variant characterized by moderate hyperbilirubinemia attributable to reduced hepatic expression of the UDP-glucuronosyltransferase which conjugates bilirubin, has been associated with a greatly reduced risk for ischemic heart disease and hypertension in a recent study. Feasible strategies for boosting serum bilirubin levels may include administration of HO-1 inducers, supplementation with bilirubin or biliverdin, and administration of drugs which decrease the efficiency of hepatic bilirubin conjugation. The well-tolerated uricosuric drug probenecid achieves non-competitive inhibition of hepatic glucuronidation reactions by inhibiting the transport of UDP-glucuronic acid into endoplasmic reticulum; probenecid therapy is included in the differential diagnosis of hyperbilirubinemia, and presumably could be used to induce an ‘‘iatrogenic Gilbert syndrome’’. Other drugs, such as rifampin, can raise serum bilirubin through competitive inhibition of hepatocyte bilirubin uptake – although unfortunately rifampin is not as safe as probenecid. Measures which can safely achieve moderate serum elevations of bilirubin may prove to have value in the prevention and/or treatment of a wide range of disorders in which oxidants play a prominent pathogenic role, including many vascular diseases, cancer, and inflammatory syndromes. Phycobilins, algal biliverdin metabolites that are good substrates for biliverdin reductase, may prove to have clinical antioxidant potential comparable to that of bilirubin.

Section snippets

Antioxidant role of heme oxygenase

Heme oxygenase has emerged in recent research as an antioxidant enzyme of great physiological importance [1], [2]. There are at least three isoforms of this enzyme in mammals; two of these are constitutively expressed, but heme oxygenase-1, the most important from the standpoint of antioxidant protection, is inducible. Heme oxygenase functions to cleave heme, converting it to carbon monoxide, free ferrous iron, and the linear tetrapyrrole biliverdin; the latter is rapidly reduced to bilirubin

Protective potential of HO-1 confirmed

The likelihood that HO-1 activity has an important impact on the pathogenesis of various diseases finds strong support in rodent studies as well as in epidemiology. Increasing tissue activity of HO-1, either by transgenic methods or by treatment with HO-1 inducers, has protected rodents from atherogenesis, thrombosis, renal, hepatic, or pulmonary injury, ischemia–reperfusion injury, and angiotensin II-mediated cardiac hypertrophy; in many of these studies, concurrent administration of HO-1

Prognostic significance of serum bilirubin

A related strain of epidemiological research has attempted to correlate serum bilirubin levels with endpoints related to atherosclerosis – coronary or carotid stenosis, ischemic heart disease, and cardiovascular death. The first such study, by Schwertner and colleagues, examined the prevalence of subclinical coronary stenosis (⩾50%) as a function of bilirubin level; a marked inverse association was noted. Relative risk in the four quartiles of serum bilirubin was found to be 1.0, 0.6, 0.4, and

Why is bilirubin such an important antioxidant?

Albumin-bound bilirubin makes a substantial contribution to plasma antioxidant activity [88]. Bilirubin is bound in such a way that the C-10 methylene group can readily donate electrons to plasma oxidants [10]; thus, it may help to protect LDL particles from plasma oxidants.

But how is it that intracellular bilirubin – in a concentration not exceeding 50 nM - can have an important impact on free radical damage? It is not likely that, in such low concentrations, bilirubin is an important direct

Strategies for harnessing Bilirubin’s health protective potential

How can the versatile antioxidant benefits of bilirubin be exploited in prevention and therapy? One evident approach is to administer agents which have HO-1 inductive activity in target tissues. Phase II inducers, such as sulforaphane, lipoic acid, green tea polyphenols, and various other bioavailable flavonoids have evident potential in this regard. The intriguing report that alanine has HO-1 inductive activity [19] should be followed up, and the extent to which the poorly understood

Biliverdin and phycobilins as antioxidant nutraceuticals

Since bilirubin undergoes enterohepatic circulation (free but not conjugated bilirubin is readily reabsorbed [115]), oral administration of bilirubin – or, preferably, of its precursor biliverdin, which is much more soluble and likely would be converted to bilirubin in the intestinal mucosa - has the potential to raise serum and tissue bilirubin levels. A handful of studies have in fact evaluated the impact of biliverdin supplementation in rodents. Back in 1993, Nakagami and colleagues reported

Slowing bilirubin conjugation

There is however a further strategy for exploiting the antioxidant benefits of bilirubin that should be more immediately applicable. Since the hyperbilirubinemia associated with Gilbert syndrome reflects underactivity of hepatic UGT1A1, it may be feasible to induce an ‘‘iatrogenic Gilbert syndrome’’ with drugs that diminish hepatic glucuronidation activity. In particular, the uricosuric agent probenecid has long been known to have this effect [149], [150], [151], [152] – presumably because this

Targeting NADPH oxidase for prevention and therapy

If indeed bilirubin – and possibly also the phycorubin homologues of bilirubin – can decrease the activation and/or activity of NADPH oxidase in many tissues, the ramifications for prevention and therapy may be of stunning breadth, as this enzyme complex appears to be a key mediator of inflammation and hyperplasia in a vast range of pathologies. Increased endothelial NADPH oxidase activity is largely responsible for the oxidant stress-mediated endothelial dysfunction associated with

Summing up

Accumulating evidence provides strong support for the thesis that bilirubin, owing to its versatile and potent antioxidant activity, and the ability of biliverdin reductase to rapidly recycle it, makes a crucially important contribution to the body’s antioxidant defenses. And, unlike antioxidant enzymes which may be of comparable importance in this regard, its tissue concentrations may be highly susceptible to modulation with practical, well tolerated strategies. Further rodent and clinical

Acknowledgements

I thank my friends Dr. Sheldon Hendler and David Rorvik for the insightful suggestion that phycobilins might mimic the antioxidant activity of bilirubin, as well as Dr. Toyoshi Inoguchi for generously sharing his pre-publication data on phycocyanobilin.

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