Biliverdin reductase:: A major physiologic cytoprotectant

Bilirubin, an abundant pigment that causes jaundice, has long lacked any clear physiologic role. It arises from enzymatic reduction by biliverclin reductase of biliverdin, a product of heme oxygenase activity. Bilirubin is a potent antioxidant that we show can protect cells from a 10,000-fold excess of H2O2. We report that bilirubin is a major physiologic antioxiclant cytoprotectant. Thus, cellular depletion of bilirubin by RNA interference markedly augments tissue levels of reactive oxygen species and causes apoptotic cell death. Depletion of glutathione, generally regarded as a physiologic antioxiclant cytoprotectant, elicits lesser increases in reactive oxygen species and cell death. The potent physiologic antioxiclant actions of bilirubin reflect an amplification cycle whereby bilirubin, acting as an antioxiclant, is itself oxidized to biliverclin and then recycled by biliverdin reductase back to bilirubin. This redox cycle may constitute the principal physiologic function of bilirubin.