TY - GEN A1 - Ackermann, G. A1 - Peil, M. A1 - Quarz, C. A1 - Schmidt, A. A1 - Halaczkiewicz, M. A1 - Thomas, A. D. A1 - Stegmüller, S. A1 - Richling, E. A1 - Manolikakes, G. A1 - Christmann, M. A1 - Küpper, Jan-Heiner A1 - Schrenk, D. A1 - Fahrer, J. T1 - Molecular dosimetry of estragole and 1′-hydroxyestragole-induced DNA adduct formation, clastogenicity and cytotoxicity in human liver cell models T2 - Archives of toxicology N2 - The phenylpropene estragole (ES) is found in essential oils of herbs and spices, such as bitter fennel and basil. Humans are exposed to ES through the diet and phytomedicines. After its absorption, ES undergoes metabolic activation by CYP1A2 and SULT1A1 in the liver, which can give rise to DNA adducts and hepatocarcinogenesis. Until now, quantitative genotoxicity data for ES in human liver cells are scarce, correlating DNA adduct levels with critical effects such as clastogenicity. Here, we used human HepG2 and HepG2-CYP1A2 cells as well as primary human hepatocytes (PHH) to study the genotoxic, clastogenic and cytotoxic potential of ES and its crucial metabolite 1′-hydroxyestragole (1′OH-ES). In addition, primary rat hepatocytes (PRH) were used for selected endpoints. Treatment of HepG2-CYP1A2 cells with ES (0–2 mM) led to the concentration-dependent formation of E3′- N 2 -dG adducts. Apart from a moderate γH2AX induction, neither p53 accumulation nor cytotoxicity was observed. However, clastogenicity was demonstrated at ES concentrations ≥ 1 mM. Incubation of HepG2 cells with 1′OH-ES (0—35 µM) led to 10–50-fold higher E3′- N 2 -dG adduct levels compared to equimolar ES concentrations. Furthermore, 1′OH-ES caused γH2AX formation, p53 accumulation and cytotoxicity, which was confirmed in PHH. In agreement, 1′OH-ES induced clastogenicity at concentrations ≥ 25 µM. Molecular dosimetry revealed that a certain E3′- N 2 -dG adduct level is required to trigger clastogenicity and cytotoxicity. This was confirmed by Benchmark Concentration (BMC) modelling, showing that the BMC for clastogenicity is 12–17-fold higher than the respective BMC for DNA adduct formation. Our data indicate that a threshold level of DNA adducts is required, both in rat and human liver cells, to trigger markers of clastogenicity. These levels are unlikely to be reached in humans following chronic ES exposure through phytomedicines or the diet. KW - Plant toxin KW - Phenylpropanoids KW - Estragole KW - Human hepatocytes KW - Liver damage KW - Cytotoxicity KW - Genotoxicity KW - Clastogenicity KW - Concentration–response modelling Y1 - 2025 U6 - https://doi.org/10.1007/s00204-025-04084-2 SN - 0340-5761 SN - 1432-0738 VL - 99 IS - 9 SP - 3769 EP - 3785 PB - Springer CY - Berlin ; Heidelberg ER -