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Tacrine First-Phase Biotransformation and Associated Hepatotoxicity: A Possible Way to Avoid Quinone Methide Formation

  • Martin Novak
    Martin Novak
    Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
    Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic
    More by Martin Novak
  • Marie Vajrychova
    Marie Vajrychova
    Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic
  • Stefania Koutsilieri
    Stefania Koutsilieri
    Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden
  • Despoina-Christina Sismanoglou
    Despoina-Christina Sismanoglou
    Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden
  • Tereza Kobrlova
    Tereza Kobrlova
    Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic
  • Lukas Prchal
    Lukas Prchal
    Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic
    More by Lukas Prchal
  • Barbora Svobodova
    Barbora Svobodova
    Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic
  • Jan Korabecny
    Jan Korabecny
    Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic
  • Tomas Zarybnicky
    Tomas Zarybnicky
    Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
  • Lucie Raisova-Stuchlikova
    Lucie Raisova-Stuchlikova
    Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
  • Lenka Skalova
    Lenka Skalova
    Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
  • Volker M. Lauschke
    Volker M. Lauschke
    Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden
    Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany
    University of Tübingen, 72074 Tübingen, Germany
  • Radim Kučera*
    Radim Kučera
    Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
    *Email: [email protected]. Tel:+420 495 067 446
  • , and 
  • Ondrej Soukup*
    Ondrej Soukup
    Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic
    *Email: [email protected]. Tel: +420 495 833 447
Cite this: ACS Chem. Biol. 2023, 18, 9, 1993–2002
Publication Date (Web):August 25, 2023
https://doi.org/10.1021/acschembio.3c00219
Copyright © 2023 American Chemical Society

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    Abstract

    Abstract Image

    Tacrine was withdrawn from clinical use as a drug against Alzheimer’s disease in 2013, mainly due to drug-induced liver injury. The culprit of tacrine-associated hepatotoxicity is believed to be the 7-OH-tacrine metabolite, a possible precursor of quinone methide (Qmeth), which binds to intracellular -SH proteins. In our study, several different animal and human models (liver microsomes, primary hepatocytes, and liver slices) were used to investigate the biotransformation and hepatotoxicity of tacrine and its 7-substituted analogues (7-methoxy-, 7-phenoxy-, and 7-OH-tacrine). Our goal was to find the most appropriate in vitro model for studying tacrine hepatotoxicity and, through rational structure modifications, to develop derivatives of tacrine that are less prone to Qmeth formation. Our results show that none of animal models tested accurately mimic human tacrine biotransformation; however, the murine model seems to be more suitable than the rat model. Tacrine metabolism was overall most accurately mimicked in three-dimensional (3D) spheroid cultures of primary human hepatocytes (PHHs). In this system, tacrine and 7-methoxytacrine were hydroxylated to 7-OH-tacrine, whereas 7-phenoxytacrine formed, as expected, only trace amounts. Surprisingly, however, our study showed that 7-OH-tacrine was the least hepatotoxic (7-OH-tacrine < tacrine < 7-methoxytacrine < 7-phenoxytacrine) even after doses had been adjusted to achieve the same intracellular concentrations. The formation of Qmeth–cysteine and Qmeth–glutathione adducts after human liver microsome incubation was confirmed by all of the studied tacrine derivatives, but these findings were not confirmed after incubation with 3D PHH spheroids. Therefore, the presented data call into question the suggested previously hypothesized mechanism of toxicity, and the results open new avenues for chemical modifications to improve the safety of novel tacrine derivatives.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschembio.3c00219.

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