Bilirubin: its role in cytoprotection against oxidative stress

Abstract

Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, in the last 10 years, in vitro and in vivo studies, have demonstrated that bilirubin exhibits potent anti-oxidant properties preventing the oxidative damage triggered by a wide range of oxidant-related stimuli. Therefore, the idea of a beneficial and physiological role for bilirubin in cytoprotection against short and long-lasting oxidant-mediated cell injury is highlighted here.

Introduction

Heme oxygenase (HO)-1, the rate limiting enzyme in the heme degradation pathway, is the heat shock/stress inducible member of the heat shock protein (HSP) 32 family. Three isoforms of HO have been described in mammals: HO-1, the inducible enzyme [1], HO-2, the constitutive isoform [1] and the more recently identified HO-3 [2]. HO-1 can be induced in a wide range of animal tissues, particularly liver, following a number of stressful stimuli including its own substrate heme, various heme proteins, heavy metals, UVA radiation, hypoxia, hyperoxia, ischemia reperfusion and many others [3], [4], [5], [6].

Since its identification in the early 1970s [7], the HO system was considered as a molecule with an “unsavory reputation” [8] because it was responsible for the degradation of the heme moiety of hemoglobin (Hb) to toxic waste products, including bile pigments such as bilirubin. This metabolite has been regarded for many years as cytotoxic, mainly because of its association with neonate jaundice and its possibility of provoking disabling and irreversible brain damage at high concentrations. It is only since the early 1990s, that a physiological role for bilirubin as a potent anti-oxidant has emerged. Although anti-oxidant properties of bilirubin had actually been known for a long time [9], it was Stocker et al. [10] who first demonstrated, in vitro, that physiological concentrations of bilirubin efficiently protect against oxidation of lipid membranes. They also showed that scavenger and anti-oxidant activities of bilirubin surpassed those of α-tocopherol and vitamin C, regarded as the more potent anti-oxidants against lipid peroxidation known so far.

The role of HO-1 and its product bilirubin in protecting against oxidative stress, has been demonstrated in a number of in vitro and in vivo studies [5], [11], [12], [13], [14], [15], [16], [17]. Doré et al. [18] have also shown that increased bilirubin formation, due to activation of HO-2 protects against hydrogen peroxide-induced neurotoxicity. The first and yet only known human case of HO-1 deficiency [19] described a 6-year-old patient suffering from severe growth retardation, hemolytic anemia, low serum bilirubin and extensive endothelial damage and provided strong in vivo evidence for the essential part played by HO and bilirubin. The temporal association of plasma bilirubin and rapid-eye-movement (REM) sleep in populations, the correlation of biliary bilirubin secretion with REM sleep and the known responses of bilirubin to light, lead to the hypothesis that bilirubin might also play an evolutionary role in the regulation of REM sleep and in mediating some of light’s anti-depressant effects [20].

HO and bilirubin have therefore become relevant in all kinds of human pathophysiology. Obviously, concentration and localization of the bile pigment, as well as binding and transport proteins and excretion, are of importance and they all modulate the balance between the deleterious cytotoxic and the beneficial anti-oxidant effects of bilirubin. It has been demonstrated that intracellular bilirubin concentrations can be locally and temporarily increased by induction of HO-1 or rapid activation of HO-2, so to resist short and long-lasting oxidative stress. Therefore, tactful handling of HO-1 to enhance endogenous bilirubin concentrations might become a therapeutic strategy to prevent or counteract oxidative stress-mediated injury.