Biliverdin reductase: A major physiologic cytoprotectant
- Departments of *Neuroscience, ‡Pharmacology and Molecular Sciences, and §Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and †Department of Medicine, Division of Gastroenterology, C-2104 Medical Center North, Vanderbilt University Medical Center, Nashville, TN 37232-2279
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Contributed by Solomon H. Snyder
Abstract
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.
Footnotes
Abbreviations
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BVR, biliverdin reductase
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GSH, glutathione
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H2DCF, carboxy-dichlorodihydrofluorescein diacetate
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HO, heme oxygenase
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RNAi, RNA interference
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ROS, reactive oxygen species
- Accepted October 16, 2002.
- Copyright © 2002, The National Academy of Sciences
