The effects of the trivalent arsenical phenylarsine oxide (PAO) on the activity of NADPH oxidase in human neutrophils were studied. PAO caused a rapid dosedependent inhibition of superoxide generation which was maximal at a concentration of 1 µM, irrespective of the stimulating agent. This inhibitory effect was not due to impaired transduction of activation signals since neither degranulation nor phagocytosis were modified. When cytosolic and membrane fractions from resting neutrophils were combined to reconstitute the NADPH oxidase, Ogeneration was inhibited by PAO while translocation of the NADPH oxidase components to the plasma membrane fraction was not affected. The inhibition was completely and specifically reversed by 2,3-dimercaptopropanol, not by dithiothreitol or -mercaptoethanol, indicating that PAO binds covalently to spatially vicinal thiol groups. PAO inhibited the plasma membrane's capacity to initiate Ogeneration while it apparently did not affect the cytosol. When PAO was added subsequently to NADPH oxidase activation, no inhibition was observed, indicating that PAO cannot reach its target once the oxidase is functionally assembled. In conclusion, PAO is the first complete and reversible inhibitor of NADPH oxidase which could provide the basis for new therapeutical approaches in inflammatory diseases.

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