Why Bilirubin Functions as an Antioxidant
Bilirubin acts as a potent antioxidant because it is a reducing species that directly scavenges reactive oxygen species (ROS) and reactive nitrogen species (RNS), and its antioxidant capacity is amplified through a continuous redox cycle with biliverdin reductase. 1
Molecular Mechanism of Antioxidant Activity
Direct Free Radical Scavenging
Bilirubin functions as a chain-breaking antioxidant by donating electrons to neutralize free radicals, thereby interrupting lipid peroxidation cascades and preventing cellular damage. 2
The molecule's reducing properties allow it to scavenge both nitric oxide and reactive nitrogen species (including peroxynitrite), extending its protective role beyond oxygen-derived radicals. 3
Bilirubin demonstrates greater antioxidant potency than alpha-tocopherol (vitamin E) in preventing both lipid peroxidation and protein oxidation in brain tissue exposed to peroxyl radicals and peroxynitrite. 4
The Bilirubin-Biliverdin Redox Cycle
The amplification mechanism is critical: when bilirubin neutralizes an oxidant, it is itself oxidized to biliverdin, which is then rapidly reduced back to bilirubin by the enzyme biliverdin reductase, allowing the same bilirubin molecule to scavenge multiple oxidant species. 1
This recycling system constitutes the principal physiologic function of bilirubin and explains why relatively low concentrations can provide substantial antioxidant protection. 1
Experimental depletion of bilirubin through RNA interference targeting biliverdin reductase causes marked increases in cellular reactive oxygen species and triggers apoptotic cell death, demonstrating that bilirubin is a major physiologic cytoprotectant—more so than glutathione in some experimental systems. 1
Structural Features Enabling Antioxidant Activity
The terminal pyrrole nitrogens in bilirubin's structure provide copper-binding sites, and the absence of a double bond between pyrrole rings II and III creates an additional binding site that enhances its copper-reducing capacity. 5
These same structural features that enable bilirubin's prooxidant activity (in the presence of transition metals like copper) paradoxically also make it a more effective antioxidant than its precursor biliverdin. 5
Bilirubin can protect cells from a 10,000-fold excess of hydrogen peroxide, demonstrating extraordinary antioxidant potency at physiologic concentrations. 1
Clinical Relevance
The mild physiologic hyperbilirubinemia seen in breastfed neonates may be beneficial because bilirubin is a potent antioxidant, potentially protecting against oxidative stress during early development. 6
There is evidence that bilirubin in neonates may be beneficial for neurodevelopment, likely through its antioxidant and cytoprotective mechanisms. 6
Albumin's biological actions include binding bilirubin and providing antioxidant properties, suggesting that the bilirubin-albumin complex contributes to systemic antioxidant defense. 6
Comparative Antioxidant Efficacy
Both bilirubin and its precursor biliverdin inhibit lipid peroxidation with greater potency and efficacy than alpha-tocopherol across a concentration range of 1-200 μM. 4
Bilirubin shows preferential activity against peroxynitrite-induced damage compared to peroxyl radical-induced damage, suggesting specialized protection against reactive nitrogen species. 4
The antioxidant superiority of bilirubin over biliverdin reflects the structural differences between the two molecules, with bilirubin being both a more efficient copper reducer and a more effective radical scavenger. 5