Effects of Nitrofurantoin on the Glutathione Redox Status and Related Enzymes in the Isolated, Perfused Rabbit Lung

Nitrofurantoin (NF) is a urinary antimicrobial drug which causes pulmonary injury. We measured levels of total lung glutathione (TLG), a tripeptide central to cellular antioxidant defenses and xenobiotic detoxification, and enzyme activities related to maintenance and utilization of reduced glutathione (GSH) in isolated, New Zealand white rabbit lungs perfused with a Kreb's-Ringer's bicarbonate medium containing NF (420 microM). After 30 minutes there was no net difference in the level of TLG [GSH + GSSG(oxidized) + effluent GSH-GSSG] or total nonprotein sulfhydryls in NF-perfused or control lungs. However, there was a decrease in the GSH:GSSG redox ratio to 2% of control (P less than .0005) and an 87% increase in GSH-GSSG efflux (P less than .005). This increased oxidation of GSH indicates that toxicity of NF is likely oxidative in nature, possibly via redox cycling of NF in the presence of oxygen to generate activated oxygen species. Activities of glucose-6-phosphate and 6-phosphogluconate dehydrogenases, GSH reductase, and GSH S-transferase were not significantly different due to NF perfusion. GSH peroxidase activity decreased 34% (P less than .025) in NF-perfused lungs. Because all TLG, as well as total nonprotein thiol was accounted for in NF-perfused lungs, it would appear that no GSH-NF metabolite conjugation occurred. GSH metabolic conjugation in the perfused lung is easily detected when tissue-alkylating drugs or their metabolites are present.