Mitigation of nitrofurantoin-induced toxicity in the perfused rat lung.
1. Nitrofurantoin is an antimicrobial agent which produces pulmonary toxicity via the redox cycling of the nitro group and its radical anion. This futile cycling triggers a complex series of events known collectively as oxidative stress. 2. In the isolated perfused rat lung, nitrofurantoin induced a decrease in tissue levels of glutathione but not protein thiols by the end of the 180 min experiment. There was no decline in tissue levels of angiotensin converting enzyme (a marker of cell disruption). However, edema was extensive as monitored in real time by weight gain (2.71 +/- 0.56 g vs 0.63 +/- 0.53 g in control, P < 0.05, n = 4) and lung mechanical functioning. The edema was matched by an increase in lavage proteins (85 +/- 15 mg vs 16 +/- 9 mg in controls, P < 0.05, n = 4). Electron microscopic examination of tissue indicated that the endothelial cells were detached from the basement membrane which would account for the edema. 3. Co-infusion of penicillamine, N-acetylcysteine or N-(2-mercaptopropionyl)-glycine which can protect tissue from oxidative stress failed to mitigate NFT-induced edema. Allopurinol, an inhibitor of xanthine oxidase and a metal chelator, significantly decreased weight gain but did not prevent the loss of glutathione. These results suggested that allopurinol was not blocking metabolic activation of NFT by xanthine oxidase but scavenging metal cations which can initiate and/or propagate the oxidative stress cascade. 4. We concluded that, in the isolated perfused rat lung, the classic pathway of oxidative stress induced by NFT is interrupted at the stage of GSH loss. These experiments demonstrated that organ function was compromised more than the individual cells. They also suggested that allopurinol may prove beneficial in modulating NFT pulmonary toxicity.
Bernard
C E
CE
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco 94143, USA.
Magid
A A
AA
Yen
T S
TS
Hoener
B A
BA
D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D009582:Nitrofurantoin / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011654:Pulmonary Edema / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012129:Respiratory Function Tests; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014810:Vitamin E / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
D000892:Anti-Infective Agents, Urinary; D013438:Sulfhydryl Compounds; D014810:Vitamin E; D009582:Nitrofurantoin; D007703:Peptidyl-Dipeptidase A; D005978:Glutathione