Nitrofurantoin Produces Oxidative Stress and Loss of Glutathione and Protein Thiols in the Isolated Perfused Rat Liver

Hoener, Betty‐Ann; Noach, A.B.J.; Andrup, Mattias; Yen, Tsan-Shin

doi:10.1159/000138559

Cited by 35 publications

(14 citation statements)

References 12 publications

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“…These include inhibition of the bacterial enzymes involved in DNA and RNA synthesis and carbohydrate metabolism and other metabolic enzymes (15). The toxic side effects on eukaryotic cells were attributed to a rapid formation of glutathione-glutathione disulfides, mixed glutathione-protein disulfides, and protein-protein disulfides (17,29). Surprisingly, this oxidative protein damage has never been discussed to play a role in antimicrobial activity.…”

Section: Resultsmentioning

confidence: 99%

Proteomic Approach to Understanding Antibiotic Action

Bandow

Brötz

Leichert

et al. 2003

Antimicrob Agents Chemother

296

265

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We have used proteomic technology to elucidate the complex cellular responses of Bacillus subtilis to antimicrobial compounds belonging to classical and emerging antibiotic classes. We established on twodimensional gels a comprehensive database of cytoplasmic proteins with pIs covering a range of 4 to 7 that were synthesized during treatment with antibiotics or agents known to cause generalized cell damage. Although each antibiotic showed an individual protein expression profile, overlaps in the expression of marker proteins reflected similarities in molecular drug mechanisms, suggesting that novel compounds with unknown mechanisms of action may be classified. Indeed, one such substance, a structurally novel protein synthesis inhibitor (BAY 50-2369), could be classified as a peptidyltransferase inhibitor. These results suggest that this technique gives new insights into the bacterial response toward classical antibiotics and hints at modes of action of novel compounds. Such a method should prove useful in the process of antibiotic drug discovery.

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Section: Resultsmentioning

confidence: 99%

Proteomic Approach to Understanding Antibiotic Action

Bandow

Brötz

Leichert

et al. 2003

Antimicrob Agents Chemother

296

265

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“…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

161

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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“…For nitrofurantoin, oxidative stress occurs through reduction to its radical anion by NADPH-cytochrome P450 reductase, which generates superoxide anion radicals, and causes formation of hydrogen peroxide, leading to depletion of reduced glutathione and protein thiols, and lipid peroxidation in rat lungs (Suntres and Shek, 1992). Also, nitrofurantoin causes dose-dependent depletion of reduced glutathione and protein thiols as well as increased bile flow in the isolated perfused rat (Hoener et al, 1989), and time-and concentration-dependent enhancement of membrane damage due to hydroperoxides or diamide in rat liver mitochondria (Carbonera et al, 1988). As a result of basolateral active uptake, high intracellular concentrations of nitrofurantoin could cause oxidative stress, in the lactating mammary epithelial cells, depending on the activity of NADPH-cytochrome P450 reductase or other enzymes in the lactating mammary epithelium.…”

Section: Resultsmentioning

confidence: 99%