Inhibition of sulfur mustard-increased protease activity by niacinamide, N-acetyl-L-cysteine or dexamethasone.
The pathologic mechanisms underlying sulfur mustard-induced skin vesication remain undefined. Papirmeister et al. (1985) have postulated a biochemical mechanism for sulfur mustard-induced cutaneous injury involving DNA alkylation, metabolic disruption, and enhanced proteolytic activity. We have previously utilized a chromogenic peptide substrate assay to establish that human peripheral blood lymphocytes exposed to sulfur mustard exhibited enhanced proteolytic activity. In this study, compounds known to alter the biochemical events associated with sulfur mustard exposure or to reduce protease activity were tested for their ability to block the sulfur mustard-increased proteolysis. Treatment of cells with niacinamide, N-acetyl-L-cysteine, or dexamethasone resulted in a decrease of sulfur mustard-increased protease activity. Complete inhibition of sulfur mustard-increased proteolysis was achieved by using protease inhibitors (antipain, leupeptin, and 4-(2-aminoethyl)-benzenesulfonylfluoride). These data suggest that therapeutic intervention in the biochemical pathways that culminate in protease activation or direct inhibition of proteolysis might serve as an approach to the treatment of sulfur mustard-induced pathology.
Cowan
F M
FM
Biochemical Pharmacology Branch, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425.
Broomfield
C A
CA
Smith
W J
WJ
D000111:Acetylcysteine / Q000494:pharmacology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D006868:Hydrolysis; D009151:Mustard Gas / Q000633:toxicity*; D009536:Niacinamide / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D013379:Substrate Specificity
D011480:Protease Inhibitors; D009536:Niacinamide; D003907:Dexamethasone; D010450:Endopeptidases; D009151:Mustard Gas; D000111:Acetylcysteine