Nitrofurantoin produces oxidative stress and loss of glutathione and protein thiols in the isolated perfused rat liver.

The effects of 150, 600 or 1,200 nmol/ml of nitrofurantoin on glutathione (GSH), glutathione disulfide (GSSG), protein thiols (PSH) and cell integrity were studied in the isolated perfused rat liver. Nitrofurantoin produced a dose-dependent, up to 3-fold, increase in bile flow and a marked, up to 150-fold, increase in biliary excretion of GSSG. By the conclusion of the experiment, tissue levels of GSH had fallen to 81 +/- 14, 41 +/- 10 and 16 +/- 5% of control values at the three dose levels. Tissue levels of GSSG rose from 18.3 +/- 2.3 to 45.3 +/- 8.0 nmol/g and from 20.0 +/- 6.0 to 187 +/- 47 nmol/g within 15 min at the two higher doses, but fell to initial levels by the end of the experiment. Only at the 1,200-nmol/ml dose did the tissue levels of PSH decline, to 64 +/- 14% of initial values, by the end of the experiment. Lactate dehydrogenase and transaminases were found in the perfusate only after the GSH and PSH levels had fallen. After a 60-min exposure to 1,200 nmol/ml of NFT followed by blank perfusate for 3 h, massive engorgement of the liver was noted. Microscopic examination revealed extensive interstitial edema, nuclear pyknosis, cytoplasmic shrinkage and vacuolization, and mitochondrial dense deposits. We conclude that toxic doses of nitrofurantoin can produce cellular depletion of GSH and PSH which, if not the direct cause, at least signal the loss of cell viability.