Failure of desferrioxamine to modify the toxicity of paraquat in rats.
The feasibility of using desferrioxamine (DF), an iron chelator, as a therapeutic agent against paraquat (PQ++) toxicity in male Sprague-Dawley rats was explored, based on the rationale of limiting toxic hydroxyl radical production from hydrogen peroxide by removing redox-active iron. Body weights, mortality, and lung histopathology were followed for periods up to 14 days after intraperitoneal injection of PQ++ (20 or 25 mg/kg body weight) with or without concurrent daily subcutaneous injections of DF (300 mg/day). Animals receiving PQ++ showed the expected typical patterns of mortality and of lung histopathology, namely: marked edema, subpleural hemorrhage, acute inflammation, perivascular mononuclear cell infiltrates, sloughing of alveolar and bronchiolar lining cells, and diffuse interstitial fibrosis. Desferrioxamine alone was non-toxic. Surprisingly, results when both PQ++ and DF were administered indicated a failure of DF to ameliorate toxic effects of PQ++ in the lung, and even suggested an accentuation of PQ++-induced damage by DF. Mortality data showed that PQ++/DF animals died in greater numbers (20 mg PQ++/kg) or died earlier (25 mg PQ++/kg) than animals receiving DF alone. Qualitative histopathology in PQ++/DF animals was comparable to PQ++ animals in early stages, but damage was more severe in both incidence and severity of lesions in PQ++/DF animals, particularly at the 25 mg PQ++/kg dose level. After 14 days, surviving animals receiving PQ++ alone showed almost complete resolution of previous inflammation and other acute effects, whereas in the only surviving PQ++/DF animal initial fibrosis had persisted and become more generalized. Thus, chelation therapy with DF may not be straightforward in its effects on PQ++ toxicity.
D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D003676:Deferoxamine / Q000378:metabolism / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D006878:Hydroxides; D017665:Hydroxyl Radical; D007501:Iron / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D010269:Paraquat / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D002614:Chelating Agents; D006878:Hydroxides; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D007501:Iron; D003676:Deferoxamine; D010269:Paraquat