Nitrofurantoin-mediated oxidative stress cytotoxicity in isolated rat hepatocytes.
Freshly isolated rat hepatocytes were used to study the mechanism(s) of toxicity of the antimicrobial drug nitrofurantoin. This 5-nitrofuran derivative stimulated hepatocyte oxygen uptake in the presence of the mitochondrial respiration inhibitors KCN or antimycin A. This could indicate the formation of O2- and H2O2, following intracellular nitrofurantoin reduction. Addition of nitrofurantoin to suspensions of isolated rat hepatocytes produced a dose- and time-dependent decrease of cell viability. H2O2 probably plays a significant role in the cytotoxic effects of nitrofurantoin as the catalase inhibitors azide or aminotriazole markedly enhanced cytotoxicity. The loss of cell viability was preceded by glutathione (GSH) depletion and a concomitant and nearly stoichiometric formation of oxidised glutathione (GSSG) that did not occur in hepatocytes lacking glutathione peroxidase activity isolated from rats fed a low-selenium diet. This indicates that H2O2 and the seleno-enzyme glutathione peroxidase are responsible for GSH oxidation. Furthermore, addition of nitrofurantoin to isolated rat hepatocytes produced a reversible inactivation of hepatocyte glutathione reductase activity and explains the maintenance of high GSSG levels. The compromised hepatocytes were also highly susceptible to H2O2. The hepatocyte toxicity of nitrofurantoin may, therefore, be attributed to oxidative stress caused by redox-cycling mediated oxygen activation.
Rossi
L
L
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Silva
J M
JM
McGirr
L G
LG
O'Brien
P J
PJ
D000818:Animals; D002374:Catalase / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D009582:Nitrofurantoin / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats
D009582:Nitrofurantoin; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione; D019803:Glutathione Disulfide