Effect of iron chelators on paraquat toxicity in rats and alveolar type II cells.
There is general agreement that the lung damage seen in paraquat poisoning is due to the generation of free radicals in alveolar epithelial cells. We have recently shown that the iron chelator and antioxidant deferoxamine (DF) reduces the mortality caused by paraquat in vitamin-E-deficient rats. In the present study we investigated the effect of DF and the lipid soluble iron chelator compound 51 (CP51) of the hydroxypyridin-4-one family on paraquat poisoning in rats with a normal vitamin E status and on isolated alveolar type II cells (ATTC). Adult rats were intravenously injected with a lethal dose of paraquat (40 mg/kg) while concurrent treatment with a continuous intravenous infusion of DF or CP51 was started. Survival of rats receiving DF at 25 and 50 mg/kg/24 h was not significantly increased compared with PBS-treated control animals. CP51, however, significantly (p less than 0.01) reduced the mortality caused by paraquat. When rats were treated with 25 mg/kg/24 h, eight of 15 rats survived the study period of 35 days compared with three in the PBS-treated control group (n = 27). In ancillary in vitro studies radiolabeled [51Cr]ATTC were incubated in a medium containing 100 microM paraquat in the absence or presence of DF and CP51. Paraquat-induced ATTC lysis increased to approximately 25% after 7 h of incubation. At the highest tested concentration (500 microM) of chelator, injury decreased markedly (80%), whereas at the lowest tested concentration (50 microM) cytotoxicity was not prevented.(ABSTRACT TRUNCATED AT 250 WORDS)
Van der Wal
N A
NA
Department of Internal Medicine, University Hospital Utrecht, The Netherlands.
Smith
L L
LL
van Oirschot
J F
JF
van Asbeck
B S
BS
D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D003676:Deferoxamine / Q000494:pharmacology*; D016166:Free Radical Scavengers; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000378:metabolism; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D008168:Lung / Q000378:metabolism; D008297:Male; D010269:Paraquat / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains
D002614:Chelating Agents; D016166:Free Radical Scavengers; D005609:Free Radicals; D006878:Hydroxides; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D003676:Deferoxamine; D010269:Paraquat