Mitigation of nitrofurantoin-induced toxicity in the perfused rat liver.
1. Nitrofurantoin is an antimicrobial agent which produces hepatotoxicity caused by 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. Our goal was to determine treatment strategies which could mitigate nitrofurantoin-induced toxicity in the isolated perfused rat liver. We co-infused various agents which blocked early or late events in the progression to toxicity. Tissue levels of glutathione and protein thiols were measured as indicators of the progression to toxicity and lactate dehydrogenase leakage into the perfusate was used as a marker of irreversible cell death. 3. Five treatments significantly (P < 0.05) decreased LDH leakage (reported as thousands of units accumulated in perfusate at 300 min, mean+/-standard error, n = 3-4) when compared to nitrofurantoin alone (274 +/- 37). These treatments were adenosine-2'-monophosphate (120 +/- 53), penicillamine (90 +/- 29), N-(2-mercaptopropionyl)-glycine (120 +/- 49) and bromosulfophthalein with (80 +/- 29) or without 5,5'-difluro-1,2-bis(O-aminophenoxy)ethane-N,N,N'N'-tetraace tic acid (101 +/- 46). Two other treatments, N-acetylcysteine (183 +/- 7) and dithiothreitol (166 +/- 59) delayed the onset of toxicity. Finally, calpeptin (319 +/- 34) which blocks activation of nonlysosomal proteases was ineffective. 4. We concluded that early intervention on the pathway to toxicity was most effective. The strategies detailed here may prove beneficial in treating hepatotoxicity seen following nitrofurantoin therapy.
Shen
W
W
Department of Pharmacy, School of Pharmacy, University of California, San Francisco 94143, USA.
Hoener
B
B
D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002614:Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology; D004229:Dithiothreitol / Q000378:metabolism; D004533:Egtazic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009582:Nitrofurantoin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010396:Penicillamine / Q000008:administration & dosage / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013448:Sulfobromophthalein / Q000008:administration & dosage / Q000494:pharmacology; D008625:Tiopronin / Q000008:administration & dosage / Q000494:pharmacology
D000892:Anti-Infective Agents, Urinary; D000931:Antidotes; D002614:Chelating Agents; D016166:Free Radical Scavengers; D005609:Free Radicals; D013438:Sulfhydryl Compounds; D013448:Sulfobromophthalein; D000249:Adenosine Monophosphate; D004533:Egtazic Acid; C039877:5,5'-difluoro-1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D009582:Nitrofurantoin; D008625:Tiopronin; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D010396:Penicillamine; D004229:Dithiothreitol; D000111:Acetylcysteine