Aerobic cytotoxicity of aromatic N-oxides: the role of NAD(P)H:quinone oxidoreductase (NQO1)
| Autor: | Audronė Marozienė, Mindaugas Lesanavičius, Aušra Nemeikaitė-Čėnienė, Jonas Šarlauskas, Violeta Jonušienė, Narimantas Čėnas, Lina Misevičienė |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cytochrome Protozoan Proteins Antioxidants lcsh:Chemistry Mice reductive activation NAD(P)H Dehydrogenase (Quinone) quinone oxidoreductase cytotoxicity oxidative stress tirapazamine [NAD(P)H] Enzyme Inhibitors Cytotoxicity lcsh:QH301-705.5 Spectroscopy Ferredoxin chemistry.chemical_classification tirapazamine biology Chemistry General Medicine Dicoumarol Aerobiosis Anti-Bacterial Agents Computer Science Applications Ferredoxin-NADP Reductase NAD(P)H:quinone oxidoreductase Oxidation-Reduction medicine.drug Dicumarol Cell Survival Stereochemistry Plasmodium falciparum Antiprotozoal Agents Quinone oxidoreductase Redox Article Catalysis Cyclic N-Oxides Inorganic Chemistry 03 medical and health sciences Oxidoreductase Cell Line Tumor medicine Animals Humans Physical and Theoretical Chemistry Molecular Biology Enzyme Assays NADPH-Ferrihemoprotein Reductase 030102 biochemistry & molecular biology Organic Chemistry HCT116 Cells Rats Kinetics 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 Hepatocytes biology.protein NAD+ kinase |
| Zdroj: | International journal of molecular sciences, Basel : MDPI, 2020, vol. 21, iss. 22, art. no. 8754, p. [1-13] International Journal of Molecular Sciences Volume 21 Issue 22 International Journal of Molecular Sciences, Vol 21, Iss 8754, p 8754 (2020) |
| ISSN: | 1422-0067 |
| Popis: | Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN&rarr O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN&rarr O aerobic cytotoxicity. We synthesized 9 representatives of ArN&rarr O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and Plasmodium falciparum ferredoxin:NADP+ oxidoreductase (PfFNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN&rarr O. The reactivity of ArN&rarr O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and PfFNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390/ijms20184602) shows that the cytotoxicity of ArN&rarr O (n = 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and PfFNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic N-oxides. |
| Databáze: | OpenAIRE |
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