Bilirubin scavenges chloramines and inhibits myeloperoxidase-induced protein/lipid oxidation in physiologically relevant hyperbilirubinemic serum

Abstract

Hypochlorous acid (HOCl), an oxidant produced by myeloperoxidase (MPO), induces protein and lipid oxidation, which is implicated in the pathogenesis of atherosclerosis. Individuals with mildly elevated bilirubin concentrations (i.e. Gilbert's syndrome; GS) are protected from atherosclerosis, cardiovascular disease (CVD) and related-mortality. We aimed to investigate Albumin-bound UCB efficiently and specifically (3.9-125 µM; P<0.05) scavenged taurine-, glycine-and N-α-acetyl-lysine-chloramines. These results were translated into Gunn rat and GS serum/plasma which showed significantly (P<0.01) reduced chloramine formation after MPO-induced oxidation. Protein carbonyl and MDA formation were also reduced after MPO oxidation in plasma supplemented with UCB (P<0.05; 25 µM and 50 µM, respectively).Significant inhibition of protein and lipid oxidation was demonstrated within the physiological range of UCB, providing a hypothetical link to protection from atherosclerosis in hyperbilirubinaemic individuals. These data demonstrate a novel and physiologically relevant mechanism whereby UCB could inhibit protein and lipid modification, by quenching chloramines, induced by MPO-induced HOCl.

Chronically elevated bilirubin protects from cardiac reperfusion injury in the male Gunn rat

“…Relative reductions in MDA and protein carbonyl content were similar (~30–40%), suggesting relatively broad antioxidant specificity of UCB. Bilirubin protects against lipid and protein oxidation in serum of GS individuals, supporting a conclusion that bilirubin protects from tissue injury via an antioxidant mechanism of action . The impact of bilirubin's effect is highlighted by the profound reduction in infarct size reported here, a cardio‐protective effect that correlates favourably with tissue bilirubin content.…”

Endogenously elevated bilirubin modulates kidney function and protects from circulating oxidative stress in a rat model of adenine-induced kidney failure

“…Previous studies have shown that the uraemic state is associated with low concentrations of GSH and reduced thiols (SH), which continue to decrease with the progression of kidney failure in dialysis patients 45 . Our findings, therefore, may indicate that bilirubin plays an important role in maintaining circulating thiol status providing an important pool of antioxidant capacity, which can protect proteins and lipids from oxidation by oxidants produced during inflammation, namely hypochlorous acid produced from myeloperoxidase (MPO) 46 . The importance of MPO-catalysed protein and lipid adduct formation has been considered an important mechanistic link between oxidation, atherosclerosis and kidney disease 47 , which bilirubin effectively inhibits 46 .…”

Association of total bilirubin and indirect bilirubin content with metabolic syndrome among Kazakhs in Xinjiang

“…Hypochlorous acid (HOCl), an oxidant produced by myeloperoxidase (MPO), can induce protein and lipid oxidation. An in vitro experimental study showed that the addition of exogenous UCB to the serum and plasma of humans and rats can protect proteins and lipids from MPO-induced oxidation and reduce the production of chloramine and its decomposition products induced by HOCl and MPO [33].…”