ABSTRACT
Dimethylthiourea (DMTU) is a small, highly diffusible molecule that effectively scavenges toxic oxygen metabolites in vitro and reduces oxidative injury in many biologic systems. Nonetheless, for unknown reasons, DMTU has occasionally failed to decrease damage in some systems where injury is presumed to be mediated by oxygen metabolites. We hypothesized that the inconsistent pattern of protection might partially reflect a direct toxicity of DMTU. Our results supported this premise. We found that rats treated with commonly used doses of highly purified DMTU had increased lung accumulation of intravenously injected iodine 125-labeled albumin (4 hours after DMTU treatment) and decreased blood glutathione levels (24 hours after DMTU treatment) when compared with saline-injected control rats. In contrast, rats treated with dimethylurea, a analog of DMTU, did not develop increased accumulation of labeled albumin in the lungs or decreased blood glutathione levels. We conclude that DMTU has intrinsically toxic effects in rats and that DMTU toxicity may at times obscure its protective action.
Subject(s)
Thiourea/analogs & derivatives , Animals , Body Weight/drug effects , Dose-Response Relationship, Drug , Glutathione/blood , Lung/drug effects , Lung/metabolism , Male , Methylurea Compounds/pharmacology , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Serum Albumin , Stomach/pathology , Thiourea/isolation & purification , Thiourea/toxicityABSTRACT
Pretreatment with a single dose of the oxygen metabolite scavenger 1,3-dimethyl-2-thiourea (DMTU) decreased hyperoxia-induced injury (as assessed by measurement of pleural effusions and increases in hematocrits and blood acid-soluble sulfhydryl levels) in rats that were exposed to hyperoxia for 48 hours. However, the degree of protection was not proportional to DMTU dose. An intermediate dose of DMTU (250 mg/kg) reduced injury more than a lower dose of 125 mg/kg and at least as effectively as the higher, widely used dose of 500 mg/kg DMTU. In contrast to its protective action with respect to hyperoxic injury, none of the doses of DMTU that were tested decreased the elevations in lung oxidized glutathione levels or oxidized glutathione/reduced glutathione ratios associated with hyperoxia exposure. These findings indicate that maximal protection from hyperoxic injury may be achieved with doses of DMTU that are lower than the doses used routinely. The failure of DMTU to decrease lung oxidized glutathione and lung oxidized glutathione/reduced glutathione ratio increases after hyperoxia exposure suggests that the mechanism by which DMTU confers protection requires careful evaluation.
Subject(s)
Antioxidants , Oxygen/toxicity , Thiourea/analogs & derivatives , Animals , Dose-Response Relationship, Drug , Glutathione/metabolism , Hematocrit , Lung/metabolism , Male , Pleural Effusion , Rats , Rats, Inbred Strains , Sulfhydryl Compounds/blood , Thiourea/administration & dosageABSTRACT
Blood acid-soluble sulfhydryl, but not glutathione (GSH), levels increased during the development of acute edematous lung injury in rats exposed to normobaric hyperoxia for 48 h or more. A relationship between increases in blood sulfhydryl levels, lung injury, and O2 metabolite generation during exposure to hyperoxia was suggested by two observations. First, increases in blood sulfhydryl levels occurred simultaneously with increases in lung oxidized glutathione (GSSG) levels and lung GSSG-to-GSH ratios (GSSG/GSH). Second, hyperoxia-induced increases in blood sulfhydryl levels, blood hematocrits, pleural effusion volumes, lung GSSG levels, and lung GSSG/GSH were decreased by pretreating rats with dimethylthiourea (DMTU), an O2 metabolite scavenger. Our findings indicate that exposure of rats to hyperoxia increases blood acid-soluble sulfhydryl levels in vivo and that increases in blood sulfhydryl levels may provide an accessible marker of increased oxidant exposure and/or oxidant-mediated lung injury.
