Nitroreductive metabolic activation of some carcinogenic nitro heterocyclic food contaminants in rat mammary tissue cellular fractions

Bartel, Laura C.; Mecca, María Montalto de; Castro, J.A.

doi:10.1016/j.fct.2008.09.069

Cited by 24 publications

(15 citation statements)

References 23 publications

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“…However, enzymatic nitroreduction of nitrofurans has also been found in animal tissues, implying that toxic and mutagenic effects could also occur in mammalian cells [ 36 ]. A number of literatures demonstrated that some nitrofuran antibiotics such as nitrofurantoin and nitrofurazone showed mutagenic or carcinogenic effects on mammalian cells and tissues [ 36 , 37 ]. A prodrug strategy might give some clue to resolve this problem.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Antibacterial Evaluation of New N-acylhydrazone Derivatives from Dehydroabietic Acid

et al. 2012

Molecules

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A series of new N-acylhydrazone derivatives were synthesized in good yields through the reactions of dehydroabietic acid hydrazide with a variety of substituted arylaldehydes. The structures of the synthesized compounds were confirmed by IR, 1H- and 13C-NMR, ESI-MS, elemental analysis and single crystal X-ray diffraction. From the crystal structure of compound 4l, the C=N double bonds of these N-acylhydrazones showed (E)-configuration, while the NMR data of compounds 4a–q indicated the existence of two rotamers for each compound in solution. The target compounds were evaluated for their antibacterial activities against four microbial strains. The result suggested that several compounds exhibited pronounced antibacterial activities. Particularly, compound 4p exhibited good antibacterial activity against Staphylococcus aureus and Bacillus subtilis comparable to positive control. The possible antibacterial metabolism and the strategy for further optimization of this compound were also discussed.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Antibacterial Evaluation of New N-acylhydrazone Derivatives from Dehydroabietic Acid

et al. 2012

Molecules

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“…Nitroreductases usually catalyze the reduction of nitrocompounds that are cytotoxic and mutagenic (2,38). Despite their toxicity, some bacteria have been found to harbor enzymes for the metabolism of nitroaromatics, and they have been considered of great potential application in environmental bioremediation, biocatalysis, and as chemotherapeutic agents following the bioactivation of prodrugs (4,45,47,52,54,55,57).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Nitroreductase with Selective Nitroreduction Properties in the Food and Intestinal Lactic Acid Bacterium Lactobacillus plantarum WCFS1

Guillén

Curiel²,

Landete³

et al. 2009

J. Agric. Food Chem.

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Nitroreductases reduce nitroaromatic compounds and other oxidants in living organisms, having interesting implications in environmental and human health. A putative nitrobenzoate reductase encoding gene (lp_0050) was recently annotated in the completed DNA sequence of lactic acid bacterium Lactobacillus plantarum WCFS1 strain. In this research, this L. plantarum gene was cloned and expressed, and the corresponding protein (PnbA) was biochemically characterized. This L. plantarum PnbA reductase is a 216 amino acid residue FMN-flavoprotein, which exhibits 23% identity with Pseudomonas putida and Ralstonia eutropha nitroreductases and <11% identity with those from enterobacteria such as E. cloacae . This reductase also showed 32-43% identity (65-72% similarity) to predicted PnbA proteins from other lactic acid bacteria. It utilized a wide range of electron acceptors including dichlorophenolindophenol (DCPIP), nitroblue tetrazolium (NBT), ferricyanide, and quinones (menadione, benzoquinone), but not pyridinium cations (paraquat and N-methyl-beta-carbolines), and it was inhibited by dicoumarol and diphenyliodonium. HPLC-MS and spectroscopic data showed that it specifically catalyzed the reduction of the 4-nitroaromatic group to the corresponding hydroxylamine in the presence of NAD(P)H. Kinetics parameters (V(max) and K(m)) showed a higher efficiency for the reduction of 2,4-dinitrobenzoate than for the reduction of 4-nitrobenzoate. It was chemoselective for the reduction of 4-nitrobenzoates, being unable to reduce other nitroaromatics. Then, L. plantarum PnbA reductase might be more specific than other microbial nitroreductases that reduce a wider range of nitroaromatic compounds. The physiological and functional role of nitroreductases remain unknown; however, their presence in lactic acid bacteria widely occurring in foods and the human intestinal tract should be of further interest.

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“…Nitro reduction causes oxidative stress in most nitro compounds, including nitrofurans 8 , 9 , 10 . Nitroreductase induces a one-electron reduction of the nitro group, yielding nitro anion radicals, and the chemical instability increases various ROS, such as superoxide anions and hydroxyl radicals, via its electron-donating ability 28 .…”

Section: Discussionmentioning

confidence: 99%

“…1 ) and 1-aminohydantoin and is a renal carcinogen in rats 7 . The formation of reactive oxygen species (ROS) or intermediates resulting from the reduction of the nitro group of NFT is thought to exert antibacterial activity 8 , 9 , 10 . Accordingly, we hypothesized that oxidative stress is involved in NFT-induced renal carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Role of oxidative stress in the chemical structure-related genotoxicity of nitrofurantoin in <i>Nrf2</i>-deficient <i>gpt</i> delta mice

et al. 2018

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Despite its antimicrobial activity, nitrofurantoin (NFT) is a renal carcinogen in rats. Oxidative stress induced by reduction of the nitro group of NFT may contribute to its genotoxicity. This is supported by our recent results indicating that the structure of the nitrofuran plays a key role in NFT-induced genotoxicity, and oxidative DNA damage is involved in renal carcinogenesis. Nuclear factor erythroid 2-related factor 2 (NRF2) regulates cellular responses to oxidative stress. To clarify the role of oxidative stress in the chemical structure-related genotoxic mechanism of NFT, we performed reporter gene mutation assays for NFT and 5-nitro-2-furaldehyde (NFA) using Nrf2-proficient and Nrf2-deficient gpt delta mice. NFT administration for 13 weeks resulted in a significant increase in 8-hydroxydeoxyguanosine (8-OHdG; a marker of oxidative stress) and gpt mutant frequency only in the kidneys of Nrf2−/− mice. The mutation spectrum, characterized by increased substitutions at guanine bases, suggested that oxidative stress is involved in NFT-induced genotoxicity. However, NFA did not increase the mutation frequency in the kidneys, despite the increased 8-OHdG in NFA-treated Nrf2−/− mice. Thus, it is unlikely that oxidative stress is involved in the genotoxic mechanism of NFA. These results imply that nitro reduction plays a key role in the genotoxicity of NFT, but the lack of a role of oxidative stress in the genotoxicity of NFA indicates a potential role of side chain interactions in oxidative stress caused by nitro reduction. These findings provide a basis for the development of safe nitrofurans.

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Nitroreductive metabolic activation of some carcinogenic nitro heterocyclic food contaminants in rat mammary tissue cellular fractions

Cited by 24 publications

References 23 publications

Synthesis and Antibacterial Evaluation of New N-acylhydrazone Derivatives from Dehydroabietic Acid

Synthesis and Antibacterial Evaluation of New N-acylhydrazone Derivatives from Dehydroabietic Acid

Characterization of a Nitroreductase with Selective Nitroreduction Properties in the Food and Intestinal Lactic Acid Bacterium Lactobacillus plantarum WCFS1

Role of oxidative stress in the chemical structure-related genotoxicity of nitrofurantoin in <i>Nrf2</i>-deficient <i>gpt</i> delta mice

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