Generation of bile pigments by haem oxygenase: a refined cellular strategy in response to stressful insults

The family of haem oxygenase enzymes is unique in nature for its role in haem degradation. Haem is cleaved at the α-meso position by haem oxygenase with the support of electrons donated by cytochrome P450 reductase, the first products of this reaction being CO, iron and biliverdin. Biliverdin is then converted to bilirubin by biliverdin reductase. If haem is viewed as a substrate for an anabolic pathway, it becomes evident that haem oxygenases do not break down haem for elimination from the body, but rather use haem to generate crucial molecules that can modulate cellular functions. The facts that biliverdin and bilirubin are potent antioxidants and that CO is both a vasoactive and signalling molecule sustain this idea. The existence of a constitutive haem oxygenase (HO-2), mainly present in the vasculature and nervous system, and an inducible haem oxygenase (HO-1), which is highly expressed during stress conditions in all tissues, also suggests that cells have evolved a fine control of this enzymic pathway to ultimately regulate haem consumption and to ensure production of CO, biliverdin/bilirubin and iron during physiological and pathophysiological situations. This review will focus primarily on the biological actions of biliverdin and bilirubin derived from the haem oxygenase/biliverdin reductase systems and their potential roles in counteracting oxidative and nitrosative stress.