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Streeter, Anthony J.; Hoener, Betty‐Ann

doi:10.1023/a:1015988401601

Cited by 27 publications

(12 citation statements)

References 9 publications

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“…Prokaryotes selected for resistance to nitrofurazone invariably acquire mutations in their type I nitroreductase genes. Following activation, the precise antimicrobial action of these prodrugs is largely unknown, but it is believed to rely on production of toxic intermediate metabolites that ultimately trigger DNA damage and cell death (12, 13). In contrast, nitrofuran reduction in eukaryotic cells is generally mediated by enzymes with a type II activity, leading to nitro anion radical formation.…”

Section: Discussionmentioning

confidence: 99%

“…However, in many cases these are reported to be biologically inactive. Instead, prodrug toxicity is believed to occur via formation of protein and nucleic acid adducts with reactive intermediates such as the hydroxylamine or nitrenium ions (12, 13, 47). Here, we demonstrated that the nitrile product generated from nifurtimox is toxic to bloodstream-form trypanosomes, displaying an IC 50 value comparable with that of the parent compound (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Nifurtimox Activation by Trypanosomal Type I Nitroreductases Generates Cytotoxic Nitrile Metabolites

Hall

Bot

Wilkinson

2011

Journal of Biological Chemistry

208

203

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The prodrug nifurtimox has been used for more than 40 years to treat Chagas disease and forms part of a recently approved combinational therapy that targets West African trypanosomiasis. Despite this, its mode of action is poorly understood. Detection of reactive oxygen and nitrogen intermediates in nifurtimox-treated extracts led to the proposal that this drug induces oxidative stress in the target cell. Here, we outline an alternative mechanism involving reductive activation by a eukaryotic type I nitroreductase. Several enzymes proposed to metabolize nifurtimox, including prostaglandin F2α synthase and cytochrome P450 reductase, were overexpressed in bloodstream-form Trypanosoma brucei. Only cells with elevated levels of the nitroreductase displayed altered susceptibility to this nitrofuran, implying a key role in drug action. Reduction of nifurtimox by this enzyme was shown to be insensitive to oxygen and yields a product characterized by LC/MS as an unsaturated open-chain nitrile. This metabolite was shown to inhibit both parasite and mammalian cell growth at equivalent concentrations, in marked contrast to the parental prodrug. These experiments indicate that the basis for the selectivity of nifurtimox against T. brucei lies in the expression of a parasite-encoded type I nitroreductase.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nifurtimox Activation by Trypanosomal Type I Nitroreductases Generates Cytotoxic Nitrile Metabolites

Hall

Bot

Wilkinson

2011

Journal of Biological Chemistry

208

203

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“…However, the nitroso and hydroxylamine intermediates can react with biomolecules to exert toxic and mutagenic effects [15,73]. In addition, there is evidence to suggest that hydroxylamines are converted to reactive nitrenium ions, which can react with DNA [73].…”

Section: Figurementioning

confidence: 99%

Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects

Patterson

Wyllie

2014

Trends in Parasitology

271

217

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“…The new concept involving NOS can, however, provide an explanation for the greater reactivity of nilutamide and other nitroarenes towards biological nucleophiles via NOScatalyzed subsequent production of hydroxylamines [26]. For example, the hydroxylamine can be further oxidized to the nitroso (which is an electrophile) or undergo acetylation to the N-acetoxy derivative, forming a highly reactive nitrenium ion that alkylates proteins or DNA [96].…”

Section: Nilutamidementioning

confidence: 99%

Bioactivation and Hepatotoxicity of Nitroaromatic Drugs

Boelsterli¹,

Ho²,

Zhou³

et al. 2006

CDM

164

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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Cited by 27 publications

References 9 publications

Nifurtimox Activation by Trypanosomal Type I Nitroreductases Generates Cytotoxic Nitrile Metabolites

Nifurtimox Activation by Trypanosomal Type I Nitroreductases Generates Cytotoxic Nitrile Metabolites

Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects

Bioactivation and Hepatotoxicity of Nitroaromatic Drugs

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