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Special Issue "Bioreductive Activation/Detoxification of Prooxidant Xenobiotics and Drugs"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 July 2019).

Special Issue Editor

Prof. Dr. Narimantas K. Cenas
E-Mail Website
Guest Editor
Institute of Biochemistry of Vilnius University, Saulėtekio 7, LT-10257 Vilnius, Lithuania
Interests: flavoenzyme catalysis; quinones; nitroaromatics; aromatic N-oxides; polyphenolic antioxidants; mechanisms of cytotoxicity
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Special Issue Information

Dear Colleagues,

Quinones, nitroaromatic compounds, and aromatic N-oxides represent important groups of anticancer, antimicrobial, and antiparasitic agents used with variable success. Besides, nitroaromatics comprise an important group of industrial pollutants and are widely used as explosives. Importantly, the therapeutic activity and cytotoxicity or side-action of the above groups of compounds are most frequently attributed to their single- or two-electron reduction, performed mainly by flavoenzymes or low-potential FeS redox proteins. Depending on the reaction mechanism and the presence of reductively activated alkylating or leaving groups, bioreductive events may either confer cytotoxicity to the above compounds by means of oxidative stress or formation of alkylating products, or contribute to their detoxification. Interestingly, similar bioreductive events occur at the initial steps of nitroaromatic pollutants’ biodegradation.

The diversification of cancer chemotherapy and tumour imaging methods and the emergence of parasite strains resistant to classical drugs require the permanent synthesis of new representatives of these compounds and studies of their mechanisms of action. The same applies for the design of new methods of biodegradation of prooxidant pollutants.

The aim of this Special Issue is to provide an updated point of view about the enzymatic mechanisms of single- and two-electron reduction of quinones, nitroaromatic compounds, aromatic N-oxides, and other groups of prooxidant compounds, their possible enzymatic targets, their role(s) in compound cytotoxicity or therapeutic activity, and their biodegradation efficiency.

Prof. Dr. Narimantas K. Cenas
Guest Editor

Manuscript Submission Information

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Keywords

  • prooxidant xenobiotics and drugs
  • free radicals
  • oxidative stress
  • bioreductive activation and alkylation
  • biodegradation

Published Papers (1 paper)

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Research

Article
Kinetics of Flavoenzyme-Catalyzed Reduction of Tirapazamine Derivatives: Implications for Their Prooxidant Cytotoxicity
Int. J. Mol. Sci. 2019, 20(18), 4602; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184602 - 17 Sep 2019
Cited by 6 | Viewed by 1071
Abstract
Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the mechanism(s) of aerobic mammalian cell cytotoxicity of [...] Read more.
Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the mechanism(s) of aerobic mammalian cell cytotoxicity of ArN→O performing the parallel studies of their reactions with NADPH:cytochrome P-450 reductase (P-450R), adrenodoxin reductase/adrenodoxin (ADR/ADX), and NAD(P)H:quinone oxidoreductase (NQO1); we found that in P-450R and ADR/ADX-catalyzed single-electron reduction, the reactivity of ArN→O (n = 9) increased with their single-electron reduction midpoint potential (E17), and correlated with the reactivity of quinones. NQO1 reduced ArN→O at low rates with concomitant superoxide production. The cytotoxicity of ArN→O in murine hepatoma MH22a and human colon adenocarcinoma HCT-116 cells increased with their E17, being systematically higher than that of quinones. The cytotoxicity of both groups of compounds was prooxidant. Inhibitor of NQO1, dicoumarol, and inhibitors of cytochromes P-450 α-naphthoflavone, isoniazid and miconazole statistically significantly (p < 0.02) decreased the toxicity of ArN→O, and potentiated the cytotoxicity of quinones. One may conclude that in spite of similar enzymatic redox cycling rates, the cytotoxicity of ArN→O is higher than that of quinones. This is partly attributed to ArN→O activation by NQO1 and cytochromes P-450. A possible additional factor in the aerobic cytotoxicity of ArN→O is their reductive activation in oxygen-poor cell compartments, leading to the formation of DNA-damaging species similar to those forming under hypoxia. Full article
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