Bilirubin: an endogenous product of heme degradation with both cytotoxic and cytoprotective properties.

Bilirubin is a linear tetrapyrrole that is formed during the process of heme degradation. Heme is released from a series of hemeproteins, including hemoglobin and cytochrome P450, and metabolized by heme oxygenase to form carbon monoxide, biliverdin, and free iron. Biliverdin is subsequently transformed to bilirubin by biliverdin reductase (Fig. 1). Bilirubin is a highly lipophilic molecule despite containing hydrophilic carboxyl groups, because the latter are unavailable for interaction with water as a result of intramolecular hydrogen bonding to the pyrrole nitrogen atoms. Bilirubin is found in blood bound to plasma albumin, which transports it to the liver, where it is conjugated to hydrophilic acceptors. The major conjugates are bilirubin glucuronides formed by UDP-glucuronosyltransferase 1 (UGT*01). These polar derivatives are thereafter excreted in the bile. The great interest in understanding the regulation of expression and enzymatic activity of heme oxygenase results from the wide array of biological effects displayed by the products of heme degradation (Maines, 1999; Shibahara et al., 2002). Carbon monoxide is a putative neural messenger and a major cardiovascular regulator but can also compete with O2 for binding to hemoglobin. The iron released from heme has been shown to be involved in cellular toxicity as a result of its capacity to induce the formation of reactive oxygen species (ROS). Biliverdin and bilirubin are potent antioxidants and protect cells from oxidative stress on the one hand, whereas bilirubin displays neurotoxicity on the other hand. This review provides a molecular insight into the complex cytotoxic and cytoprotective effects of bilirubin under both physiological and pathological conditions. Cytotoxic Effects of Bilirubin