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 such as the hydroxyl radical by activated neutrophils has been proposed to play an important role in mediating toxin-induced liver injury. The antithyroid drug propylthiouracil protects against liver injury induced by many hepatotoxic agents and markedly reduces mortality in patients with alcoholic liver disease. However, the mechanism(s) by which propylthiouracil protects against liver injury is not well understood. The present studies investigate the effect of antithyroid drugs on proteolytic enzyme activity and on hydroxyl radical generation from activated neutrophils. In the presence of hydrogen peroxide and chloride, neutrophil myeloperoxidase, an enzyme from the same gene superfamily as thyroid peroxidase, generates hypochlorous acid which inactivates alpha-1-proteinase inhibitor (A1PI) present in serum. This inactivation allows neutrophil-released proteolytic enzymes to attack cells. In the present study myeloperoxidase activity was inhibited fully at therapeutic concentrations by antithyroid drugs (propylthiouracil and methimazole). Antithyroid drugs fully prevented hypochlorous acid formation, and prevented neutrophil-mediated inactivation of A1PI, with concomitant blockage of proteolytic activity. Conversely, generation of both superoxide 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 chloride, however. These studies indicate that antithyroid drugs are unlikely to prevent cell injury by inhibiting hydroxyl radical generation or by scavenging hydroxyl radicals, but are likely to exert their hepatoprotective anti-inflammatory action by inhibiting neutrophil myeloperoxidase, an enzyme akin to thyroid peroxidase.
Ross
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AD
Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Dey
I
I
Janes
N
N
Israel
Y
Y
D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology*; D002645:Chickens; D005260:Female; D017665:Hydroxyl Radical / Q000378:metabolism*; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology*; D011441:Propylthiouracil / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D013956:Antithyroid Agents; D009861:Onium Compounds; D011480:Protease Inhibitors; D017665:Hydroxyl Radical; C007517:diphenyleneiodonium; D011441:Propylthiouracil