Bilirubin Links Heme Metabolism to Neuroprotection by Scavenging Superoxide

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Cell Chem Biol. 2019 Oct 17;26(10):1450-1460.e7. doi: 10.1016/j.chembiol.2019.07.006. Epub 2019 Jul 25.

Bilirubin Links Heme Metabolism to Neuroprotection by Scavenging Superoxide

C Vasavda;R Kothari;AP Malla;R Tokhunts;A Lin;M Ji;C Ricco;R Xu;HG Saavedra;JI Sbodio;AM Snowman;L Albacarys;L Hester;TW Sedlak;BD Paul;SH Snyder

The Solomon H. Snyder Department of Neuroscience, Department of Molecular Biology and Genetics, Department of Neurosurgery, Department of Biophysics and Biophysical Chemistry, Department of Psychiatry and Behavioral Sciences, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. Duke University School of Medicine, Durham, NC, USA.

Service type: Knockout mice


Bilirubin is one of the most frequently measured metabolites in medicine, yet its physiologic roles remain unclear. Bilirubin can act as an antioxidant in vitro, but whether its redox activity is physiologically relevant is unclear because many other antioxidants are far more abundant in vivo. Here, we report that depleting endogenous bilirubin renders mice hypersensitive to oxidative stress. We find that mice lacking bilirubin are particularly vulnerable to superoxide (O2⋅-) over other tested reactive oxidants and electrophiles. Whereas major antioxidants such as glutathione and cysteine exhibit little to no reactivity toward O2⋅-, bilirubin readily scavenges O2⋅-. We find that bilirubin's redox activity is particularly important in the brain, where it prevents excitotoxicity and neuronal death by scavenging O2⋅- during NMDA neurotransmission. Bilirubin's unique redox activity toward O2⋅- may underlie a prominent physiologic role despite being significantly less abundant than other endogenous and exogenous antioxidants.

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