The consequences of nitrofurantoin-induced oxidative stress in isolated rat hepatocytes: evaluation of pathobiochemical alterations

Klee, Sabine; Nürnberger, M.; Ungemach, F. R.

doi:10.1016/0009-2797(94)90089-2

Cited by 20 publications

(10 citation statements)

References 41 publications

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“…Most of the administered NF-type antibiotics are excreted within hours, but their protein-bound metabolites are highly stable and are excreted in 4-9 days [Leitner et al, 2001]. In vitro studies of 5-NF metabolism in hepatocytes showed that cytotoxicity was accompanied by lipid peroxidation [Klee et al, 1994].…”

Section: Discussionmentioning

confidence: 99%

Comparison of genomic damage caused by 5-nitrofurantoin in young and adult mice using the in vivo micronucleus assay

Fučić

Marković

Ferenčić

et al. 2005

Environ. Mol. Mutagen.

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The antibiotic 5-nitrofurantoin (5-NF) has been used widely for the treatment of urosepsis in children during the last 20 years. Recent experimentation suggests the need for reevaluating its genotoxic potential. Because of possible differences in the metabolism and clearance of 5-NF in young and adult animals, we conducted a study to determine whether micronuclei caused by 5-NF were age-related. The in vivo micronucleus (MN) assay was performed on 3- and 8-week-old mice given single intraperitoneal injections of 5, 10, and 50 mg/kg 5-NF. Blood samples from the tail vein were taken before injection (baseline) and at 48, 96, 168, and 336 hr (2 weeks) after the treatment. One thousand reticulocytes were analyzed for micronuclei from each animal. Compared to similar baseline values for young and adult mice, 5-NF caused a significant increase in MN frequency in both age groups. The mean MN frequency in the young animals was higher than in the adult animals for each dose and sampling time. MN frequencies remained significantly elevated in young animals even 2 weeks after exposure to 5-NF. The results of the study confirm the genotoxic potential of 5-NF in young and adult animals, and indicate that young animals are more sensitive to the genotoxic effects of 5-NF than adult mice and that the response in young mice persists for a significantly longer time. These findings may be related to poorly developed mechanisms of xenobiotic detoxification and renal elimination in young animals.

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Section: Discussionmentioning

confidence: 99%

Comparison of genomic damage caused by 5-nitrofurantoin in young and adult mice using the in vivo micronucleus assay

Fučić

Marković

Ferenčić

et al. 2005

Environ. Mol. Mutagen.

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“…Nitrofurantoin produces massive oxidant stress in hepatocytes [43,89,92] which is clearly due to nitroreductive metabolism of this drug. The parent compound is reduced to its nitroanion radical, and ROS are produced through subsequent redox cycling [16].…”

Section: Nitrofurantoinmentioning

confidence: 99%

“…Nitrofurantoin is a 5-nitrofuran-containing antibacterial agent that has been associated with pulmonary fibrosis and rare cases of hepatotoxicity [36,[83][84][85][86][87][88][89] (Fig. (5)).…”

Section: Nitrofurantoinmentioning

confidence: 99%

Bioactivation and Hepatotoxicity of Nitroaromatic Drugs

Boelsterli¹,

Ho²,

Zhou³

et al. 2006

CDM

165

116

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Certain drugs containing a nitroaromatic moiety (e.g., tolcapone, nimesulide, nilutamide, flutamide, nitrofurantoin) have been associated with organ-selective toxicity including rare cases of idiosyncratic liver injury. What they have in common is the potential for multistep nitroreductive bioactivation (6-electron transfer) that produces the potentially hazardous nitroanion radical, nitroso intermediate, and N-hydroxy derivative. These intermediates have been associated with increased oxidant stress and targeting of nucleophilic residues on proteins and nucleic acids. However, other mechanisms including the formation of oxidative metabolites and mitochondrial liability, as well as inherent toxicokinetic properties, also determine the drugs' overall potency. Therefore, structural modification not only of the nitro moiety but also of ring substituents can greatly reduce toxicity. Novel concepts have revealed that, besides the classical microsomal nitroreductases, cytosolic and mitochondrial enzymes including nitric oxide synthase can also bioactivate certain nitroarenes (nilutamide). Furthermore, animal models of silent mitochondrial dysfunction have demonstrated that a mitochondrial oxidant stress posed by certain nitroaromatic drugs (nimesulide) can produce significant mitochondrial injury if superimposed on a genetic mitochondrial abnormality. Finally, there may be mechanisms for all nitroaromatic drugs that do not involve bioactivation of the nitro group, e.g., AHR interactions with flutamide. Taken together, the focus of research on the hepatic toxicity of nitroarene-containing drugs has shifted over the past years from the identification of the reactive intermediates generated during the bioreductive pathway to the underlying biomechanisms of liver injury. Most likely one of the next paradigm shifts will include the identification of determinants of susceptibility to nitroaromatic drug-induced hepatotoxicity.

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“…Paradoxically, in some cases cell exposure to oxidative stress has a reverse effect of increasing GSH levels. In experiments involving rat hepatocytes exposed to the effect of N-nitrosodimethylamine (NDMA), butylated hydroxyanisole and nitrofurantoin, an increase in intracellular glutathione levels was seen [16,25,58]. The phenomenon of glutathione synthesis upregulation is caused by the stimulation of γ-GCS expression and it is most likely an adaptive mechanism of defence against the effects of reactive oxygen species.…”

Section: Glutathione As An Antioxidantmentioning

confidence: 99%

Role of Glutathione in the Multidrug Resistance in Cancer

Karwicka¹

2010

Advances in Cell Biology

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Summary: Multidrug resistance is the main problem in anticancer therapy. Cancer cells use many defense strategies in order to survive chemotherapy. Among known multidrug resistance mechanisms the most important are: drug detoxification inside the cell using II phase detoxifying enzymes and active transport of the drug to the extracellular environment. Cancer cells may be also less sensitive to proapoptotic signals and have different intracellular drug distribution, which makes them more resistant to anticancer drugs. Role of glutathione in multidrug resistance is the object of interest of many scientists, however, defining it's function in these processes still remains a challenge. In this paper, properties of glutathione and it's role in multidrug resistance in cancer cells were described.

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The consequences of nitrofurantoin-induced oxidative stress in isolated rat hepatocytes: evaluation of pathobiochemical alterations

Cited by 20 publications

References 41 publications

Comparison of genomic damage caused by 5-nitrofurantoin in young and adult mice using the in vivo micronucleus assay

Comparison of genomic damage caused by 5-nitrofurantoin in young and adult mice using the in vivo micronucleus assay

Bioactivation and Hepatotoxicity of Nitroaromatic Drugs

Role of Glutathione in the Multidrug Resistance in Cancer

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