Oxygen radicals inhibit human plasma acetylhydrolase, the enzyme that catabolizes platelet-activating factor

Giuseppe Ambrosio, Alfonso Oriente, Claudio Napoli, Giuseppe Palumbo, Paola Chiariello, Gianni Marone, Mario Condorelli, Massimo Chiariello, Massimo Triggiani

Research output: Contribution to journalArticlepeer-review

Abstract

Platelet-activating factor (PAF) can exert profound inflammatory effects at very low concentrations. In plasma, PAF is hydrolyzed to lyso-PAF by acetylhydrolase, an enzyme that circulates bound to LDL. Previous studies suggest that oxygen radicals may act synergistically with PAF to potentiate tissue injury. However, mechanisms underlying this interaction have not been elucidated. In this study we investigated whether oxygen radicals may inactivate PAF acetylhydrolase. PAF acetylhydrolase activity was measured in human plasma and purified LDL before and after exposure to radicals (10-20 nmol/min per ml) generated by xanthine/xanthine oxidase. Oxygen radicals induced > 50% loss of PAF acetylhydrolase activity within 60 s and almost complete inactivation by 10 min. This phenomenon was irreversible and independent of oxidative modification of LDL. Inactivation occurred without changes in the affinity constant of the enzyme (K(m) was 17.9 μM under control conditions and 15.1 μM after exposure to oxygen radicals). Inactivation was prevented by the scavengers superoxide dismutase or dimethylthiourea or by the iron chelator deferoxamine. Thus, superoxide- mediated, iron-catalyzed formation of hydroxyl radicals can rapidly and irreversibly inactivate PAF acetylhydrolase. Since concomitant production of PAF and oxygen radicals can occur in various forms of tissue injury, inactivation of acetylhydrolase might represent one mechanism by which oxygen radicals may potentiate and prolong the proinflammatory effects of PAF.

Original languageEnglish
Pages (from-to)2408-2416
Number of pages9
JournalJournal of Clinical Investigation
Volume93
Issue number6
Publication statusPublished - Jun 1994

Keywords

  • acetylhydrolase
  • inflammation
  • neutrophils
  • oxygen radicals
  • platelet-activating factor

ASJC Scopus subject areas

  • Medicine(all)

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