Biliverdin reductase as a target in drug research and development: Facts and hypotheses

Biliverdin reductase-A (BVR) catalyzes the reduction of heme-derived biliverdin into bilirubin, this latter being a powerful endogenous free radical scavenger. Furthermore, BVR is also endowed with both serine/threonine/tyrosine kinase and scaffold activities, through which it interacts with the insulin receptor kinase, conventional and atypical protein kinase C isoforms, mitogen-activated protein kinases as well as the phosphatidylinositol-3 kinase/Akt system. By regulating this complex array of signal transduction pathways, BVR is involved in the pathogenesis of neurodegenerative, metabolic, cardiovascular and immune-inflammatory diseases as well as in cancer. In addition, both BVR and BVR-B, this latter being an alternate isozyme predominant during fetal development but sometimes detectable through adulthood, have been studied as peripheral biomarkers for an early detection of Alzheimer's disease, atherosclerosis and some types of cancer. However, despite these interesting lines of evidence, to date BVR has not been considered as an appealing drug target. Only limited evidence supports the neuroprotective effects of atorvastatin and ferulic acid through BVR regulation in the aged canine brain and human neuroblastoma cells, whereas interesting results have been reported regarding the use of BVR-based peptides in preclinical models of cardiac diseases and cancer.