PHENIDONE AND HYDROXYUREA REDUCE SULFUR MUSTARD-INCREASED PROTEOLYSISIN HAIRLESS GUINEA-PIG SKIN

Increased proteolytic activity at the dermal-epidermal junction is pos tulated as being involved in sulfur-mustard-induced cutaneous injury. Homogenates of skin punch biopsy specimens from the skin of hairless g uinea pig at 6, 9, 12, and 24 h after a 7 min vapor cup exposure to su lfur mustard (HD) demonstrated enhanced proteolytic activity. Homogena tes from the biopsy specimens of exposed animals produced from 3 to 10 times the hydrolysis of the chromogenic peptide substrate Chromzym TH (tosyl-gly-pro-arg-p-nitranilide) and human elastase substrate N-meth oxysuccinyl-ala-ala-pro-val-p-nitranilide than did the homogenates fro m control samples. In this study HD-increased proteolysis of the TH su bstrate by extracts of hairless guinea pig skin biopsies was nearly el iminated by systemic treatment with hydroxyurea and greatly reduced by topical application of the anti-inflammatory compound phenidone. Comp ounds that reduce HD-increased proteolytic activity, such as phenidone and hydroxyurea, can serve as probes to examine the role of proteolys is in HD-induced pathology. HD-increased proteolysis provides a bioche mical correlate for investigating cutaneous exposure to HD. Increased proteolysis may therefore serve as a biomarker for HD-induced patholog y that might be used as an index of efficacy for potential treatment c ompounds.