Free radical-mediated lung response to the monofunctional sulfur mustard butyl 2-chloroethyl sulfide after subcutaneous injection.
Vesicant-induced pathogenesis is initiated by rapid alkylation and cross-linking of DNA purine bases causing strand breaks leading subsequently to NAD depletion and cell death. We postulated that vesicants may also be associated with free radical-mediated oxidative stress distal to the site of exposure. To test this postulate in the lung, we injected 3 groups (n = 8) of 5-month-old, male, athymic, nude mice, weighing 30-35 g with a single subcutaneous (s.c.) injection (5 microliters/mouse) of butyl 2-chloroethyl sulfide (BCS), a monofunctional sulfur mustard analog. After 1, 24 and 48 h, we euthanized the treated mice along with 2 untreated control mice at each time point. We then pooled the control mice in one group (n = 6) and analyzed the lungs for biochemical indices of oxidative stress. We found that total lung weight was not altered after treatment, but wet/dry weight ratio decreased 18% (P less than 0.05) and hemoglobin content increased 50% and 36% at 1 and 24 h, respectively. The activity of glucose-6-phosphate dehydrogenase increased significantly, 40% at 1 and 24 h and 84% at 48 h and that of glutathione S-transferases was 60%, P less than 0.05 greater at all time points. Lipid peroxidation (estimated by the thiobarbituric acid test) and total protein content increased 3-fold and 2-fold, at 1 and 24 h, respectively. Total and oxidized glutathione contents were significantly elevated, 38% at 1 h and 64% at 24 h for the former and 45% at 24 h and 56% at 48 h for the latter. Because these changes are consistent with the cellular response to oxidative stress, we conclude that BCS injected subcutaneously, can cause changes in the lung possibly via a free radical-mediated mechanism.
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Letterman Army Institute of Research, Presidio of San Francisco, CA 94129.
Omaye
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Klain
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Korte
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D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007279:Injections, Subcutaneous; D015227:Lipid Peroxidation; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009151:Mustard Gas / Q000633:toxicity* / Q000031:analogs & derivatives; D009929:Organ Size / Q000187:drug effects
D005609:Free Radicals; C061448:2-chloroethyl butyl sulfide; D005954:Glucosephosphate Dehydrogenase; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D009151:Mustard Gas