Mechanism of protection of alveolar type II cells against paraquat-induced cytotoxicity by deferoxamine.
Paraquat toxicity has been associated with the generation of free radicals in alveolar epithelial cells in which paraquat specifically accumulates via a polyamine uptake system. In the present study we investigated whether deferoxamine (DF), an iron chelator that has antioxidant capacity and that also has a polyamine-like structure, could protect alveolar type II cells (ATTC) against injury by paraquat. Radiolabeled [3H]adenine ATTC were incubated in a medium containing 75 microM paraquat in the absence or presence of DF (500 microM). After 3 hr of incubation paraquat-mediated cytotoxicity of ATTC, as measured by [3H]adenine release, was significantly (P less than 0.005) decreased by addition of DF (26.6 +/- 2.6% vs 7.4 +/- 1.7%). Accumulation of radiolabeled [14C]paraquat at a concentration of 75 microM was also decreased (70%) by 500 microM DF from 94.8 +/- 2.1 to 28.9 +/- 6.7 nmoles paraquat/2.5 x 10(5) ATTC. This effect of DF was dose dependent and comparable with the protective effect of equimolar concentrations of putrescine. However, per cent uptake of paraquat at a concentration of 500 microM was not significantly inhibited by DF (1 mM), whereas paraquat-induced injury was still markedly reduced (36.2 +/- 2.5% vs 2.6 +/- 4.2%). This indicated that the protective effect of DF could not be explained by its competition with paraquat on uptake alone. In the same series of experiments using another iron chelator, pyridoxal benzoyl hydrazone (PBH), which has antioxidant properties similar to DF but does not show its polyamine-like structure, ATTC lysis was also prevented although paraquat uptake was not reduced. These in vitro data indicate that the mechanism of protection by DF against paraquat toxicity in lung epithelial type II cells is two-fold: inhibition of paraquat uptake through its compliance with the structural requirements necessary for transport, and inhibition of paraquat-induced iron-catalysed free radical generation.
van der Wal
N A
NA
Department of Internal Medicine, University Hospital Utrecht, The Netherlands.
van Oirschot
J F
JF
van Dijk
A
A
Verhoef
J
J
van Asbeck
B S
BS
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents; D003676:Deferoxamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals; D006835:Hydrazones / Q000494:pharmacology; D006878:Hydroxides; D017665:Hydroxyl Radical; D008297:Male; D010269:Paraquat / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011700:Putrescine / Q000494:pharmacology; D011730:Pyridoxal / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D002614:Chelating Agents; D005609:Free Radicals; D006835:Hydrazones; D006878:Hydroxides; D017665:Hydroxyl Radical; D011730:Pyridoxal; C064460:pyridoxal benzoyl hydrazone; D003676:Deferoxamine; D010269:Paraquat; D011700:Putrescine