title: High doses of 2,2'-dithienyl diselenide cause systemic toxicity in rats: an in vitro and in vivo study.
abstract: Organoselenium compounds have important pharmacological properties. However, these compounds can cause toxicity, typically related to oxidation of endogenous thiols. The aim of this study was to investigate whether 2,2'-dithienyl diselenide (DTDS) has potential toxicity in vitro and in vivo. Therefore, sulfhydryl-containing enzyme activities, δ-aminolevulinic acid dehydratase (δ-ALA-D) and Na(+) -K(+) -ATPase were used to predict DTDS toxicity in rat brain homogenate in vitro. In in vivo experiments, a DTDS administration (50 or 100 mg kg(-1) , p.o.) to rats was performed and toxicological parameters were determined. DTDS inhibited δ-ALA-D (IC50 2 µm) and Na(+) -K(+) -ATPase (IC50 17 µm) activities in vitro. The inhibitory effect of DTDS on δ-ALA-D and Na(+) -K(+) -ATPase activities was restored by dithiothreitol. DTDS (5-25 µm) elicited a thiol oxidase-like activity. In vivo, DTDS (50 and 100 mg kg(-1) ) caused systemic toxicity, evidenced by a decrease in water and food intakes and body weight gain, as well as the death of rats. DTDS at the dose of 100 mg kg(-1) increased plasma alanine and aspartate aminotransferase activities and decreased urea levels. At 50 and 100 mg kg(-1) , it increased lipid peroxidation levels. At the highest dose, DTDS inhibited δ-ALA-D activity. By contrast, Na(+) -K(+) -ATPase activity and antioxidant defense were not altered in the brains of rats exposed to DTDS. In conclusion, interaction with the cisteinyl residues seems to mediate the inhibitory effect of DTDS on sulfhydryl-containing enzymes in vitro. In addition, high oral doses of DTDS induce toxicity in rats.
authors.affiliation: Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, CEP 97105-900, RS, Brazil.
authors.forename: Pietro Maria
authors.initials: PM
authors.lastname: Chagas
authors.forename: Cristiani Folharini
authors.initials: CF
authors.lastname: Bortolatto
authors.forename: Ethel Antunes
authors.initials: EA
authors.lastname: Wilhelm
authors.forename: Cristina Wayne
authors.initials: CW
authors.lastname: Nogueira
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002374:Catalase / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology; D002712:Chlorides / Q000494:pharmacology; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D016566:Organoselenium Compounds / Q000633:toxicity*; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000378:metabolism; D000623:Porphobilinogen Synthase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013876:Thiophenes / Q000633:toxicity*; D015430:Weight Gain / Q000187:drug effects; D017967:Zinc Compounds / Q000494:pharmacology
chemical_list: C583912:2,2'-dithienyl diselenide; D000975:Antioxidants; D002712:Chlorides; D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; D013876:Thiophenes; D017967:Zinc Compounds; C016837:zinc chloride; D002374:Catalase; D013482:Superoxide Dismutase; D050862:Oxidoreductases Acting on Sulfur Group Donors; D000623:Porphobilinogen Synthase; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; D001205:Ascorbic Acid