Flavoenzyme-catalyzed single-electron reduction of nitroaromatic antiandrogens: implications for their cytotoxicity
| Autor: | Aušra Nemeikaitė-Čėnienė, A. V. Yantsevich, Jelena Tamulienė, Audronė Marozienė, Narimantas Čėnas, Lina Misevičienė |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
030102 biochemistry & molecular biology Therapeutic action Antiandrogens General Medicine Biochemistry Combinatorial chemistry Catalysis Flutamide 03 medical and health sciences chemistry.chemical_compound Single electron 030104 developmental biology chemistry Nilutamide medicine Cytotoxicity Redox cycling medicine.drug |
| DOI: | 10.6084/m9.figshare.14746224.v2 |
| Popis: | The therapeutic action of nitroaromatic antiandrogens nilutamide and flutamide may be complicated by their cytotoxicity, whose mechanisms are still incomprehensively understood. In particular this concerns the enzymatic redox cycling of flutamide and its metabolites, and its impact on their cytotoxicity. In this work, we examined the single-electron reduction of nilutamide, flutamide, its metabolites 2-hydroxyflutamide and 4-nitro-3-trifluorormethyl-phenylamine, and a topical antiandrogen (3-amino-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl)-phenyl) propanamide by NADPH:cytochrome P-450 reductase and adrenodoxin reductase/adrenodoxin. The obtained steady-state bimolecular rate constants of oxidant reduction (kcat/Km) enabled to establish single-electron reduction midpoint potentials (E17) of compounds, −0.377 – −0.413 V, which were in line with enthalpies of formation of their free radicals, obtained by quantum mechanical calculations. Using murine hepatoma MH22a cells, the obtained cytotoxicity vs. E17 correlation based on the data of model nitroaromatic compounds shows that redox cycling and oxidative stress could be the main factor of cytotoxicity of nitroaromatic antiandrogens. Other minor cytotoxicity factors could be their redox metabolism involving NAD(P)H:quinone oxidoreductase (NQO1) and cytochromes P-450. |
| Databáze: | OpenAIRE |
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