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5Flavoenzyme-catalyzed single-electron reduction of nitroaromatic antiandrogens: implications for their cytotoxicity

Aušra Nemeikaitė-Čėnienė1, Audronė Marozienė2, Lina Misevičienė2

  • 1State Research Institute Center for Innovative Medicine, Vilnius, Lithuania.

Free Radical Research
|June 8, 2021
PubMed

Insights

Nitroaromatic antiandrogens like flutamide can be cytotoxic due to redox cycling. This study links their single-electron reduction potentials to cytotoxicity, suggesting oxidative stress is a primary mechanism.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Toxicology

Background:

  • The cytotoxicity of nitroaromatic antiandrogens, such as nilutamide and flutamide, is not fully understood.
  • Enzymatic redox cycling of flutamide and its metabolites is a key area of concern regarding their toxicity.

Purpose of the Study:

  • To investigate the single-electron reduction of nilutamide, flutamide, its metabolites, and a topical antiandrogen.
  • To correlate the reduction potentials with cytotoxicity and elucidate the mechanisms involved.

Main Methods:

  • Enzymatic reduction assays using NADPH:cytochrome P-450 reductase and adrenodoxin reductase/adrenodoxin.
  • Determination of steady-state bimolecular rate constants (kcat/Km) and single-electron reduction midpoint potentials (E1/7).
  • Cytotoxicity assays using murine hepatoma MH22a cells and quantum mechanical calculations.

Main Results:

  • Established single-electron reduction midpoint potentials (E1/7) for the studied compounds ranging from -0.377 to -0.413 V.
  • Correlated cytotoxicity with E1/7 values, indicating redox cycling and oxidative stress as major contributors.
  • Identified NAD(P)H:quinone oxidoreductase (NQO1) and cytochromes P-450 as minor factors in redox metabolism.

Conclusions:

  • Redox cycling and resultant oxidative stress are likely the primary mechanisms of cytotoxicity for nitroaromatic antiandrogens.
  • The single-electron reduction potential is a critical parameter for understanding the toxicity of these compounds.
  • Further research into the specific roles of NQO1 and cytochromes P-450 may refine understanding of antiandrogen toxicity.
Keywords:
Nilutamideflavoenzymesflutamideprooxidant cytotoxicityredox cycling

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