EFFECT OF ANTITHYROID DRUGS ON HYDROXYL RADICAL FORMATION AND ALPHA-1-PROTEINASE INHIBITOR INACTIVATION BY NEUTROPHILS - THERAPEUTIC IMPLICATIONS

The release of proteolytic enzymes and generation of strong oxidants s uch as the hydroxyl radical by activated neutrophils has been proposed to play an important role in mediating toxin-induced liver injury, Th e antithyroid drug propylthiouracil protects against liver injury indu ced by many hepatotoxic agents and markedly reduces mortality in patie nts with alcoholic liver disease. However, the mechanism(s) by which p ropylthiouracil protects against liver injury is not well understood. The present studies investigate the effect of antithyroid drugs on pro teolytic enzyme activity and on hydroxyl radical generation from activ ated neutrophils. In the presence of hydrogen peroxide and chloride, n eutrophil myeloperoxidase, an enzyme from the same gene superfamily as thyroid peroxidase, generates hypochlorous acid which inactivates alp ha-1-proteinase inhibitor (A1PI) present in serum, This inactivation a llows neutrophil-released proteolytic enzymes to attack cells. In the present study myeloperoxidase activity was inhibited fully at therapeu tic concentrations by antithyroid drugs (propylthiouracil and methimaz ole). Antithyroid drugs fully prevented hypochlorous acid formation, a nd prevented neutrophil-mediated inactivation of A1PI, with concomitan t blockage of proteolytic activity. Conversely, generation of both sup eroxide and hydroxyl radicals by activated neutrophils was unaffected by propylthiouracil. The production of these oxygen radicals was fully inhibited by the NADPH oxidase inhibitor diphenylene iodonium chlorid e, however. These studies indicate that antithyroid drugs are unlikely to prevent cell injury by inhibiting hydroxyl radical generation or b y scavenging hydroxyl radicals, but are likely to exert their hepatopr otective anti-inflammatory action by inhibiting neutrophil myeloperoxi dase, an enzyme akin to thyroid peroxidase.