Anti-oxidant properties of H2-receptor antagonists. Effects on myeloperoxidase-catalysed reactions and hydroxyl radical generation in a ferrous-hydrogen peroxide system

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dc.contributor.authorVan Zyl J.M.
dc.contributor.authorKriegler A.
dc.contributor.authorVan Der Walt B.J.
dc.date.accessioned2011-05-15T16:01:17Z
dc.date.available2011-05-15T16:01:17Z
dc.date.issued1993
dc.description.abstractUlcerogenesis of the gastroduodenal mucosa is caused by the digestive action of gastric juice and initially involves an inflammatory reaction with infiltration of phagocytes. The anti-inflammatory activity of many drugs have been attributed to the inhibition of the leukocyte enzyme, myeloperoxidase (MPO). In this study, the H2-antagonists in clinical use were found to be potent inhibitors of MPO-catalysed reactions (IC50 < 3 μM) under conditions resembling those in experiments with intact neutrophils. Since peak plasma concentrations of cimetidine, ranitidine and nizatidine are well within the micromolar range, after oral therapeutic dosing, our results may be of clinical relevance. The inhibitory actions of cimetidine and nizatidine were largely due to scavenging of hypochlorous acid (HOCl), a powerful chlorinating oxidant produced in the MPO-H2O2-Cl- system. In contrast to famotidine, ranitidine was also a potent scavenger of HOCl, while both drugs inhibited MPO reversibly by converting it to compound II, which is inactive in the oxidation of Cl-. The HOCl scavenging potencies of ranitidine and nizatidine were about three times higher than that of the anti-rheumatic drug, penicillamine, which had a potency similar to that of cimetidine. The rapid HOCl scavenging ability of penicillamine is thought to contribute to its anti-inflammatory effects. Using riboflavin as a probe, the H2-antagonists were found to be inhibitors of hydroxyl radical (·OH) generated in a Fe2+-H2O2 reaction mixture. Spectral analyses of the interaction of iron ions with the drugs and studies with chelators, suggest that the drugs were efficient chelators of Fe2+, in addition to their ·OH scavenging abilities. Since the gastrointestinal tract can contain potentially reactive iron, the simultaneous presence of H2-antagonists may help to suppress iron-driven steps in tissue damage.
dc.description.versionArticle
dc.identifier.citationBiochemical Pharmacology
dc.identifier.citation45
dc.identifier.citation12
dc.identifier.issn62952
dc.identifier.other10.1016/0006-2952(93)90218-L
dc.identifier.urihttp://hdl.handle.net/10019.1/11905
dc.subjectchelating agent
dc.subjectcimetidine
dc.subjectdeferoxamine
dc.subjectedetic acid
dc.subjectfamotidine
dc.subjecthistamine
dc.subjecthistamine h2 receptor antagonist
dc.subjecthydrogen peroxide
dc.subjecthydroxyl radical
dc.subjecthypochlorous acid
dc.subjectiron
dc.subjectleukocyte enzyme
dc.subjectmannitol
dc.subjectmyeloperoxidase
dc.subjectnizatidine
dc.subjectpenicillamine
dc.subjectphytic acid
dc.subjectranitidine
dc.subjectreduced nicotinamide adenine dinucleotide
dc.subjectscavenger
dc.subjectantioxidant activity
dc.subjectarticle
dc.subjectcatalysis
dc.subjectconcentration response
dc.subjectcontrolled study
dc.subjectdigestive system ulcer
dc.subjectfluorescence spectroscopy
dc.subjecthuman
dc.subjecthuman cell
dc.subjectpriority journal
dc.subjectAntioxidants
dc.subjectCimetidine
dc.subjectFamotidine
dc.subjectFerrous Compounds
dc.subjectHistamine H2 Antagonists
dc.subjectHydrogen Peroxide
dc.subjectHydroxides
dc.subjectHydroxyl Radical
dc.subjectHypochlorous Acid
dc.subjectIron Chelating Agents
dc.subjectNAD
dc.subjectNizatidine
dc.subjectPeroxidase
dc.subjectRanitidine
dc.titleAnti-oxidant properties of H2-receptor antagonists. Effects on myeloperoxidase-catalysed reactions and hydroxyl radical generation in a ferrous-hydrogen peroxide system
dc.typeArticle
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