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.