Evaluation of cytochromes and arylhydrocarbon receptor ligands effect on aflatoxin _G1 genotoxic markers

Introduction. Aflatoxins are highly toxic metabolites produced by Aspergillus fungi, with strong carcinogenic and immunosuppressive properties. Their genotoxicity arises from the formation of reactive epoxides during metabolic activation by CYP1A2 and CYP3A4 cytochrome enzymes. The aryl hydrocarbon receptor (AhR) plays a critical role in regulating aflatoxin metabolism and cellular response to toxicity.

This study investigates the genotoxic effects of aflatoxin G₁ (AFG₁) with a focus on its interaction with CYP450 enzymes and AhR, and its impact on DNA repair and apoptosis in human hepatoma HepaRG cells.

Material and methods. Cellular toxicity of AFG₁ was assessed using xCELLigence RTCA impedance analysis, which revealed an LC₅₀ value of 9.79 µM. DNA repair activity was analyzed using the Luminex xMAP multiplex technology. The study also evaluated the effects of AhR agonists (FICZ, ITE), an antagonist (CH223191), and CYP inhibitors (α-naphthoflavone for CYP1A2, ketoconazole for CYP3A4) on AFG₁-induced genotoxicity.

Results. AhR ligands exhibited moderate cytoprotective effects, increasing cell viability under AFG₁ exposure. In contrast, CYP inhibitors more effectively reduced activation of DNA repair proteins. The protective role of AhR ligands may involve competitive binding with AFG₁ and modulation of downstream signaling.

Limitations. The study was conducted using a cell culture model; extrapolation of the findings to the whole organism requires consideration of toxicodynamic and toxicokinetic data.

Conclusion. These findings highlight the pivotal role of CYP enzymes and AhR in shaping the genotoxic profile of AFG₁.

Compliance with ethical standards. The study does not require approval from a biomedical ethics committee or any other related documentation.

Authors’ contribution:
Perevoznikov I.E. – collection and processing of material, statistical processing, writing a text;
Rogovskaya N.Yu. – collection and processing of material;
Malygina D.A. – collection and processing of material;
Beltyukov P.P. – the concept and design of the study, editing;
Babakov V.N. – the concept and design of the study, editing.
All authors are responsible for the integrity of all parts of the manuscript and approval of the manuscript final version.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study had no sponsorship.

Received: August 21, 2025 / Accepted: October 2, 2025 / Published: November 19, 2025

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