SUPEROXIDE IS AN ANTAGONIST OF ANTIINFLAMMATORY DRUGS THAT INHIBIT HYPOCHLOROUS ACID PRODUCTION BY MYELOPEROXIDASE

Myeloperoxidase, the most abundant enzyme in neutrophils, catalyses th e conversion of hydrogen peroxide and chloride to hypochlorous acid. T his potent oxidant has the potential to cause considerable tissue dama ge in many inflammatory diseases. We have investigated the ability of dapsone, diclofenac, primaquine, sulfapyridine and benzocaine to inhib it hypochlorous acid production by stimulated human neutrophils. The d rugs were also tested against purified myeloperoxidase using xanthine oxidase to generate hydrogen peroxide and superoxide. The inhibitory e ffects of the drugs on hypochlorous acid production, either by cells s timulated with phorbol myristate acetate or by myeloperoxidase and xan thine oxidase, were significantly less than those determined with myel operoxidase and reagent hydrogen peroxide. Comparable potency was obse rved only when superoxide dismutase was present to remove superoxide. We also observed that with the xanthine oxidase system, inhibition of hypochlorous acid production by dapsone decreased markedly as the conc entration of myeloperoxidase increased. Dapsone was a poor inhibitor o f hypochlorous acid production by neutrophils stimulated with opsonize d zymosan, regardless of the presence of superoxide dismutase. With th is phagocytic stimulus, catalase inhibited hypochlorous acid formation by only 60%, which indicates that a substantial amount of the hypochl orous acid detected originated from within phagosomes. Thus, it is app arent that dapsone is unable to affect intraphagosomal conversion of h ydrogen peroxide to hypochlorous acid. All the drugs inhibit myelopero xidase reversibly by trapping it as its inactive redox intermediate, c ompound II. We propose that superoxide limits the potency of the drugs by reducing compound II back to the active enzyme. Furthermore, under conditions where the activity of myeloperoxidase exceeds that of the hydrogen peroxide-generating system, which is most likely to occur in phagosomes, partial inhibition of myeloperoxidase need not affect hypo chlorous acid production. We conclude that drugs that inhibit myeloper oxidase by converting it to compound II are unlikely to be effective a gainst hypochlorous acid-mediating tissue damage.