title: Studies on the mechanism of nitrofurantoin-mediated red cell toxicity.
abstract: The mechanism of nitrofurantoin-mediated depletion of red cell reduced glutathione (GSH) was investigated. Nitrofurantoin caused cellular depletion of GSH in vitro under aerobic and oxygen-depleted conditions, an effect which could be partially inhibited by coincubation with the hemeprotein ligand ethyl isocyanide, or completely prevented by coincubation with 2'-AMP, an inhibitor of NADPH-dependent reductase enzymes. Covalent binding of nitrofurantoin to red cell macromolecules appeared to be a minor process and was not substantially inhibited by either ethyl isocyanide or 2'-AMP. Covalent binding was only slightly greater under oxygen-depleted conditions. Nitrofurantoin increased the rate of superoxide formation in red cell lysate, an effect inhibited by ethyl isocyanide but not by 2'-AMP. These data suggest different mechanisms for nitrofurantoin-mediated depletion of GSH under aerobic and oxygen-depleted conditions. In the presence of oxygen, nitrofurantoin causes the release of superoxide from oxyhemoglobin. The superoxide thus formed may deplete GSH via several mechanisms. In the absence of oxygen, nitrofurantoin is reduced to reactive metabolites via reactions which appear to require the participation of both an NADPH-dependent flavoprotein and hemoglobin.
mesh_terms: D000249:Adenosine Monophosphate; D000328:Adult; D004912:Erythrocytes / Q000187:drug effects*; D005978:Glutathione / Q000097:blood; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009570:Nitriles / Q000494:pharmacology; D009582:Nitrofurantoin / Q000097:blood / Q000633:toxicity*; D010100:Oxygen / Q000502:physiology; D013481:Superoxides / Q000097:blood
chemical_list: D009570:Nitriles; D013481:Superoxides; D000249:Adenosine Monophosphate; C001187:ethyl isocyanide; D009582:Nitrofurantoin; D005978:Glutathione; D010100:Oxygen