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.apoptosis ͉ biliverdin ͉ cell death ͉ heme oxygenase ͉ neuroprotection

Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV‐Positive and HIV‐Negative Individuals in VACS (Veterans Aging Cohort Study)

“…As such, it must be glucuronidated before being excreted in the bile. Alternatively, bilirubin can serve as a potent antioxidant by reducing reactive oxygen species and is subsequently oxidized back to biliverdin 34, 35. This pathway appears to affect oxidative stress–induced membrane lipid degradation more than its effect on water‐soluble proteins (in contrast to glutathione).…”

Physiological concentrations of unconjugated bilirubin prevent oxidative stress-induced hepatocanalicular dysfunction and cholestasis

“…Bilirubin, historically considered a waste product of heme catabolic pathway and even a potentially toxic compound, is nowadays regarded as a potent antioxidant agent (Sedlak et al 2009, Stocker et al 1987a, Vitek 2012. This study provides new insights into the hepatoprotective properties of UB by showing that the pigment, when present at physiological concentrations, can preserve the functional status of hepatocytes in terms of biliary secretory function under OS conditions, serving as a crucial antioxidant defense to keep the secretory machinery in operation after an oxidative challenge.…”

“…UB is highly lipophilic, and therefore it preferentially protects cell membranes, including the mitochondrial ones, from lipid peroxidation (Sedlak et al 2009); UB is even more efficient than α-tocopherol, which is regarded as the best exogenous antioxidant against lipid peroxidation (Stocker et al 1987a, Mancuso et al 2012. Low OS levels, like those developed under our experimental conditions, selectively impair mitochondrial function.…”

“…Previous in vitro studies demonstrated that bilirubin is an efficient antioxidant under physiological conditions (Stocker et al 1987a, Sedlak et al 2009). The antioxidant effects of bilirubin in vivo include scavenging of peroxyl radicals (Witting et al 1996), inhibition of membrane lipid peroxidation (Witting et al 1996), and scavenging of radical nitrogen species (Kaur et al 2003).…”

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

“…In addition, the bilirubin-mediated autoregulatory feedback loop appears to be finetuned since bilirubin is not only neurotoxic in the neonate but also a powerful antioxidant [81,82]. The latter property may have facilitated the occurrence of a frequent polymorphism of UGT1A1, termed UGT1A1*28, responsible for Gilbert's syndrome.…”