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A General Method for Detecting Nitrosamide Formation in the In Vitro Metabolism of Nitrosamines by Cytochrome P450s
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CYP1A1 and Cnr nitroreductase bioactivated niclosamide in vitro

Evelyn Beristain-Castillo1, Mariano Martínez-Vázquez, Rafael Camacho-Carranza

  • 1Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas and.

Mutagenesis
|August 20, 2013
PubMed

Insights

Niclosamide

Area of Science:

  • Biochemistry
  • Toxicology
  • Drug Metabolism

Background:

  • Niclosamide exhibits genotoxic effects, including mutations and chromosomal damage.
  • Cytochrome P450 enzymes are potential mediators in niclosamide's bioactivation.
  • Identifying specific cytochrome P450 subfamilies is crucial for understanding niclosamide's toxicity.

Purpose of the Study:

  • To investigate the role of specific cytochrome P450 subfamilies in niclosamide bioactivation.
  • To determine the involvement of CYP1A1 and CYP2E1 in niclosamide's genotoxic effects.
  • To elucidate the contribution of nitroreduction to niclosamide's bioactivation pathway.

Main Methods:

  • Utilized rat liver microsomal fractions induced with phenobarbital/β-naphthoflavone (PB/β-NF), benzo[a]pyrene (BaP), or cyclohexanol.
  • Employed CYP1A and CYP2E inhibitors (α-NF and diethyldithiocarbamate) to assess enzyme involvement.
  • Incubated niclosamide with CYP1A1 Supersomes™ and tested nitroreductase-deficient bacterial strains.

Main Results:

  • PB/β-NF and BaP-induced rat liver-S9 fractions enhanced niclosamide-induced revertants.
  • The CYP1A1 inhibitor α-NF reduced the number of revertants.
  • CYP1A1 Supersomes™ incubation increased niclosamide-induced revertants, and nitroreduction was also implicated.

Conclusions:

  • Cytochrome P450 1A1 (CYP1A1) plays a key role in the bioactivation of niclosamide.
  • Nitroreduction is also essential for niclosamide's bioactivation.
  • A metabolite formed by CYP1A1 action and nitroreduction contributes significantly to niclosamide's genotoxicity.

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