Potentiation of oxidant-induced toxicity in hamster lung slices by dimethylthiourea.
Dimethylthiourea (DMTU) is an effective scavenger of reactive oxygen metabolites. This property has been successfully exploited, experimentally, in the protection of cells and tissues against oxidative damage. In this study, however, we have observed that levels of nonprotein sulfhydryls (NPSH) in hamster lung slices were markedly decreased by incubation with 10 or 40 mM DMTU. These changes were associated with morphological signs of injury, increased levels of oxidised glutathione (GSSG), and an increased activity of the pentose phosphate pathway (PPP), suggesting that the loss of NPSH was due to their oxidation. Incubation with 40 mM, but not 10 mM DMTU, also resulted in a decreased ability to oxidise [6-14C]glucose or to synthesise proteins, suggesting that at the high concentration, DMTU may cause functional impairment of the tissue. Furthermore, the ability of the slices to accumulate putrescine decreased after incubation with the oxidative toxins paraquat (PQ), tert-butyl hydroperoxide (t-BOOH) or hydrogen peroxide (H2O2) and was further decreased by co-incubation with DMTU. Putrescine uptake, a function specific to the alveolar type I and II epithelial cells, was not affected by incubation with DMTU alone. DMTU did not exacerbate the effect of the nonoxidative toxin iodoacetamide (IAA) on putrescine uptake but it did affect markers of general cell damage or dysfunction. We suggest, therefore, that the toxicity of oxidants toward lung tissue is potentiated in alveolar epithelial cells by DMTU.
Laboratory of Lung Toxicology (Pneumology and Occupational Medicine), Katholieke Universiteit Leuven, Belgium.
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CP
Lewis
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Dinsdale
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Nemery
D000818:Animals; D006224:Cricetinae; D004357:Drug Synergism; D005260:Female; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000633:toxicity; D007460:Iodoacetamide / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D008854:Microscopy, Electron; D016877:Oxidants / Q000633:toxicity*; D010084:Oxidation-Reduction; D010269:Paraquat / Q000633:toxicity; D010545:Peroxides / Q000633:toxicity; D011700:Putrescine / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D020122:tert-Butylhydroperoxide
D005609:Free Radicals; D016877:Oxidants; D010545:Peroxides; C038983:1,3-dimethylthiourea; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; D013890:Thiourea; D010269:Paraquat; D011700:Putrescine; D007460:Iodoacetamide