Anaerobic reduction of nitroimidazoles by reduced flavin mononucleotide and by xanthine oxidase

Clarke, Eric D.; Wardman, Peter; Goulding, K. H.

doi:10.1016/0006-2952(80)90087-8

Cited by 72 publications

(45 citation statements)

References 16 publications

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“…First, Mtz and H 2 O 2 may interact with different types of biomolecules. For example, H 2 O 2 is known to oxidize thiol groups in proteins such as thioredoxin (63), whereas reactive Mtz intermediates might have greater affinity for reduced cofactors (68) or nucleic acids (10). Although the importance of DNA damage in the mechanism of Mtz cytotoxicity is contested (10,12), the increased transcription of genes encoding a pseudouridine synthase (acting to stabilize structural RNAs) (69) and several DNA repair enzymes specifically following Mtz exposure in this study suggests selective sensitivity of nucleic acids to this drug.…”

Section: Discussionmentioning

confidence: 99%

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Ansell

McConville

Baker

et al. 2016

Antimicrob Agents Chemother

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dUnderstanding how parasites respond to stress can help to identify essential biological processes. Giardia duodenalis is a parasitic protist that infects the human gastrointestinal tract and causes 200 to 300 million cases of diarrhea annually. Metronidazole, a major antigiardial drug, is thought to cause oxidative damage within the infective trophozoite form. However, treatment efficacy is suboptimal, due partly to metronidazole-resistant infections. To elucidate conserved and stress-specific responses, we calibrated sublethal metronidazole, hydrogen peroxide, and thermal stresses to exert approximately equal pressure on trophozoite growth and compared transcriptional responses after 24 h of exposure. We identified 252 genes that were differentially transcribed in response to all three stressors, including glycolytic and DNA repair enzymes, a mitogen-activated protein (MAP) kinase, high-cysteine membrane proteins, flavin adenine dinucleotide (FAD) synthetase, and histone modification enzymes. Transcriptional responses appeared to diverge according to physiological or xenobiotic stress. Downregulation of the antioxidant system and ␣-giardins was observed only under metronidazole-induced stress, whereas upregulation of GARP-like transcription factors and their subordinate genes was observed in response to hydrogen peroxide and thermal stressors. Limited evidence was found in support of stress-specific response elements upstream of differentially transcribed genes; however, antisense derepression and differential regulation of RNA interference machinery suggest multiple epigenetic mechanisms of transcriptional control. Giardia duodenalis (synonyms, Giardia lamblia and Giardia intestinalis) is a parasitic protist of the vertebrate gastrointestinal tract and the most common parasite of humans (1). The vegetative life cycle stage (trophozoite) infects around 1 billion people and causes 200 to 300 million cases of diarrheal disease (giardiasis) each year (1). Infection with G. duodenalis is also associated with the development of chronic diseases such as irritable bowel syndrome, chronic fatigue, and diabetes (2). At present, only two major drug classes are available to treat giardiasis: nitroimidazoles, primarily metronidazole (Mtz), and benzimidazoles, such as albendazole (3,4). Resistance to Mtz is documented in treatment-resistant clinical isolates (5-8), and resistant lines can be generated in vitro (reviewed in reference 9).The mechanism of action of Mtz is relatively poorly understood. This compound is thought to diffuse into G. duodenalis trophozoites as an inactive prodrug, whereupon it is enzymatically reduced (activated), yielding reactive intermediates. Mtz intermediates are thought to kill trophozoites by oxidizing proteins, lipids, and DNA (10, 11); however, the relative importance of damage to different biomolecules for Mtz-induced cytotoxicity is contested (10, 12). Resistance to Mtz involves changes in enzyme expression which limit drug activation. Nitroreductase-1, thioredoxin reductase, and pyruvat...

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Section: Discussionmentioning

confidence: 99%

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Ansell

McConville

Baker

et al. 2016

Antimicrob Agents Chemother

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“…Again, in spite ofunfavorable thernodynamics, FMNH2 reduces many ArNO2 at readily measurable (and redox-controlled) rates (73), and FMN + NADH generates steady-state concentrations of ArNO2' which are detectable by ESR (7).…”

Section: Redox Properties Of Nitroaromatic Compoundsmentioning

confidence: 99%

“…The reduction of ArNO2 by flavins or thiols are catalyzed by trace quantities of Fe(II) (63,(73)(74)(75)(76). Oneelectron reduction by free thiols is thermodynamically much less favorable than by ascorbate, since E(RS/ RS-) must be much more positive than E(A/AH-) at pH-7, indeed higher than E(PZ+)/PZ) 0.8-0.9 V where PZ = common phenothiazines (77).…”

Section: Redox Properties Of Nitroaromatic Compoundsmentioning

confidence: 99%

Some Reactions and Properties of Nitro Radical-Anions Important in Biology and Medicine

Wardman¹

1985

Environmental Health Perspectives

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Nitroaromatic compounds, ArNO2 have widespread actual or potential use in medicine and cancer therapy. There is direct proof that free-radical metabolites are involved in many applications, and an appreciation of the conceptual basis for their therapeutic differential; however, an understanding of the detailed mechanisms involved is lacking. Redox properties control most biological responses of nitro compounds, and the characteristics of the one-electron couple: ArNO2/ArNO2 are detailed. The "futile metabolism" of nitroaryl compounds characteristic of most aerobic nitroreductase systems reflects competitioq between natural radical-decay pathways and a one-electron transfer reaction to yield superoxide ion, 02-Prototropic properties control the rate of radical decay, and redox properties control the rate Qf electron transfer to 02 or other acceptors. There are clear parallels in the chemistry of ArNO2 and°2-While nitro radicals have frequently been invoked as damaging species, they are very unreactive (except as simple reductants). It seems likely that reductive metabolism of nitroaryl compounds, although generally involving nitro radical-anions as obligate intermediates (and this is required for therapeutic selectivity towards anaerobes), results in biological damage via reductive metabolites of higher reduction order than the one-electron product.

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“…In addition to the microsomal enzyme components, xanthine oxidase (70,71) is also capable of catalyzing the reduction of metronidazole and other nitroimidazoles. N-(2-hydroxyethyl)oxamic acid and acetamide form in this system when metronidazole is reduced (70).…”

Section: Free-radical Metabolites Of Metronidazole and Other Nitroimimentioning

confidence: 99%

Mechanism of Toxicity of Nitro Compounds Used in the Chemotherapy of Trichomoniasis

Moreno¹,

Docampo²

1985

Environmental Health Perspectives

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The mechanism of the trichomonicidal activity of metronidazole and other 5-nitroimidazoles appears to depend on the ferredoxin-mediated reduction of their nitro group, with generation of a reactive metabolite or metabolites which interact with DNA leading to a subsequent inhibition of nucleic acid and protein synthesis. Redox cycling of these compounds under aerobic conditions appears to be a detoxification reaction by inhibiting net reduction of the drugs, thereby inhibiting their uptake. On the other hand, redox cycling of nitrofurans or other compounds with more positive reduction potential results in formation of high steady-state concentrations of oxygen-derived metabolites that might be of toxicological significance. It seems likely that reduced metabolites of nitroimidazoles (perhaps through covalent binding to tissue macromolecules and/or thiols depletion) are also involved in the nitroimidazoles' toxic effects to animal tissues and in their mutagenic and carcinogenic action.

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Anaerobic reduction of nitroimidazoles by reduced flavin mononucleotide and by xanthine oxidase

Cited by 72 publications

References 16 publications

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Some Reactions and Properties of Nitro Radical-Anions Important in Biology and Medicine

Mechanism of Toxicity of Nitro Compounds Used in the Chemotherapy of Trichomoniasis

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