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 biliverdin 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 antioxidant 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 antioxidant cytoprotectant, elicits lesser increases in reactive oxygen species and cell death. The potent physiologic antioxidant actions of bilirubin reflect an amplification cycle whereby bilirubin, acting as an antioxidant, is itself oxidized to biliverdin and then recycled by biliverdin reductase back to bilirubin. This redox cycle may constitute the principal physiologic function of bilirubin.
Baranano
David E
DE
Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Rao
Mahil
M
Ferris
Christopher D
CD
Snyder
Solomon H
SH
D000975:Antioxidants / Q000378:metabolism*; D001663:Bilirubin / Q000096:biosynthesis / Q000502:physiology*; D001664:Biliverdine / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000502:physiology*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D006419:Heme Oxygenase (Decyclizing); D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D005978:Glutathione; D001664:Biliverdine; D001663:Bilirubin