STUDIES ON THE MECHANISM OF NITROFURANTOIN-MEDIATED RED-CELL TOXICITY

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Abstract
The mechanism of nitrofurantoin [an antibiotic]-mediated depletion of human red cell reduced glutathione (GSH) was investigated. Nitrofurantoin caused cellular depletion of GSH in vitro under aerobic and O2-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 O2-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 O2-depleted conditions. In the presence of O2, nitrofurantoin causes the release of superoxide from HbO2. The superoxide thus formed may deplete GSH via several mechanisms. In the absence of O2, nitrofurantoin is reduced to reactive metabolites via reactions which appear to require the participation of both an NADPH-dependent flavoprotein and Hb.

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