title: Bilirubin and glutathione have complementary antioxidant and cytoprotective roles.
abstract: Glutathione (GSH) and bilirubin are prominent endogenous antioxidant cytoprotectants. Despite tissue levels that are thousands of times lower than GSH, bilirubin is effective because of the biosynthetic cycle wherein it is generated from biliverdin by biliverdin reductase (BVR). When bilirubin acts as an antioxidant, it is oxidized to biliverdin, which is immediately reduced by BVR to bilirubin. Why does the body employ both of these 2 distinct antioxidant systems? We show that the water-soluble GSH primarily protects water soluble proteins, whereas the lipophilic bilirubin protects lipids from oxidation. Mice with deletion of heme oxygenase-2, which generates biliverdin, display greater lipid than protein oxidation, while the reverse holds for GSH depletion. RNA interference depletion of BVR increases oxidation of lipids more than protein. Depletion of BVR or GSH augments cell death in an oxidant-specific fashion.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Sedlak
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Saleh
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Higginson
authors.forename: Bindu D
authors.initials: BD
authors.lastname: Paul
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Juluri
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D000975:Antioxidants; D001663:Bilirubin / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D001664:Biliverdine / Q000378:metabolism; D019610:Cytoprotection; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency / Q000378:metabolism; D011506:Proteins / Q000378:metabolism
chemical_list: D000975:Antioxidants; D011506:Proteins; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D005978:Glutathione; D001664:Biliverdine; D001663:Bilirubin