Inhibition of iron toxicity in rat and human hepatocyte cultures by the hydroxypyridin-4-ones CP20 and CP94.
The protective effect of the hydroxypyridin-4-ones (CP20 and CP94) was studied on iron-loaded rat and human hepatocytes; desferrioxamine B was used as a chelator reference. Iron load was achieved by addition of 5 up to 50 microM iron citrate to the culture medium. One day after iron treatment, an increase in lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and malondialdehyde extracellular concentrations was measured in rat and human hepatocyte cultures. This enzyme release and the increase in free extracellular malondialdehyde were observed with 5 microM iron and high levels were obtained with 50 microM. The bidentate chelators CP20 and CP94 (150 microM) appeared to be as effective as the hexadentate chelator desferrioxamine (50 microM) in the protection of rat and human hepatocytes against the toxic effect of iron load achieved by culturing the cells for 1 day in the presence of 50 microM iron citrate. In rat and human hepatocytes cultured for 1 day in the presence of 1 microM 55Fe-50 microM iron citrate plus CP20, CP94 or desferrioxamine B, a decrease of iron uptake by the cells was observed. When the hepatocytes were cultured for 1 day in the presence of 1 microM 55Fe-50 microM iron citrate and then for a further day in the presence of CP20, CP94 or desferrioxamine B but not iron, the chelators decreased the intracellular iron level, indicating their iron releasing effect from the loaded cells. The observed effects of the hydroxypyridin-4-ones CP20 and CP94 were as potent as the effect of desferrioxamine B. This study presents new data favoring the potential clinical interest of this new class of chelating agents in the treatment of human iron overload.
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002478:Cells, Cultured; D000077543:Deferiprone; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000633:toxicity*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007504:Iron Radioisotopes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008854:Microscopy, Electron; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007502:Iron Chelating Agents; D007504:Iron Radioisotopes; D011728:Pyridones; C068543:1,2-diethyl-3-hydroxypyridin-4-one; D000077543:Deferiprone; D008315:Malondialdehyde; D007501:Iron; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase