Interaction of bilirubin and biliverdin with reactive nitrogen species

Abstract

Bilirubin (BR) and biliverdin (BV), two metabolites produced during haem degradation by haem oxygenase, possess strong antioxidant activities toward peroxyl radical, hydroxyl radical and hydrogen peroxide. Considering the importance attributed to nitric oxide (NO) and its congeners in the control of physiological and pathophysiological processes, we examined the interaction of BR and BV with NO and NO-related species in vitro. Exposure of BR and BV to agents that release NO or nitroxyl resulted in a concentration-and time-dependent loss of BR and BV, as assessed by high performance liquid chromatography. Peroxynitrite, a strong oxidant derived from the reaction of NO with superoxide anion, also showed high reactivity toward BR and BV. The extent of BR and BV consumption largely depended on the NO species being analysed and on the half-lives of the pharmacological compounds considered. Of major importance, BR and BV decomposition occurred also in the presence of pure NO under anaerobic conditions, con¢rming the ability of bile pigments to scavenge the gaseous free radical. Increasing concentrations of thiols prevented BR consumption by nitroxyl, indicating that bile pigments and thiol groups can compete and/or synergise the cellular defence against NO-related species. In view of the high inducibility of haem oxygenase-1 by NO-releasing agents in di¡erent cell types, the present ¢ndings highlight novel anti-nitrosative characteristics of BR and BV suggesting a potential function for bile pigments against the damaging e¡ects of uncontrolled NO production. ß

Resistance to Nitric Oxide-induced Necrosis in Heme Oxygenase-1 Overexpressing Pulmonary Epithelial Cells Associated with Decreased Lipid Peroxidation

“…The results indicate that HO-1 mediates protection against NO-induced lipid peroxidation via the endogenous production of biliverdin/bilirubin. This finding is in accord with in vitro studies showing that biliverdin and bilirubin are able to quench the toxic RNS species NO and ONOO Ϫ (37,38). The exogenously added bilirubin seems to enter the cells, as 1-h pretreatment with bilirubin was sufficient to impart resistance to secondary NO and H 2 O 2 challenges (supplemental Fig.…”

“…S9). Given the ability of bilirubin to redox cycle (36) and the efficiency of NO/ONOO Ϫ scavenging by bilirubin (37,38), a relatively small fold-increase in cellular bilirubin levels may greatly enhance cellular survival of an NO challenge.…”

“…The selective protection by HO-1 against NO-induced lipid peroxidation is attributed to its production of biliverdin/bilirubin, which can quench both NO and ONOO Ϫ (37,38). The ability of HO-1 to prevent cellular toxicity by decreasing NOinduced lipid peroxidation suggests possible therapeutic approaches for diseases associated with NO-dependent lipid peroxidation, such as atherosclerosis (47), glaucoma (48), gastric cancer (49), and macular degeneration (50).…”

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

“…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). Albumin-bound bilirubin, in its unconjugated form, bears an extended system of conjugated double bonds and a pair of reactive hydrogen atoms which are most likely involved in bilirubin antioxidant action, by hydrogen donation to a radical species (Stocker 2004).…”

Curcumin reduces cold storage-induced damage in human cardiac myoblasts

“…This last aspect is of special interest for transplantation procedures as organs are usually kept at 4 o C in storage solutions before the actual transplant surgery. HO-1 and its products biliverdin, bilirubin and carbon monoxide exert beneficial effects that include protection against ischemia-reperfusion damage (Clark et al, 2000bForesti et al, 2001;Sandouka et al, 2006), mitigation of oxidative and nitrosative stress Kaur et al, 2003;Taille et al, 2005) and prolongation of graft survival of liver, heart and kidney allografts in experimental animal models of transplantation (Soares et al, 2001;Clark et al, 2003;Motterlini et al, 2005;Nakao et al, 2005). Because of its antioxidant and anti-inflammatory characteristics, the HO-1 pathway is potentially an excellent candidate to be exploited for amelioration of organ transplantation outcomes and survival Curcumin reduces cold storage-induced damage in human cardiac myoblasts Sandouka et al, 2006).…”