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

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F23%3A10469174" target="_blank" >RIV/00179906:_____/23:10469174 - isvavai.cz</a>

  • Alternative codes found

    RIV/00216208:11160/23:10469174

  • Result on the web

    <a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=dage4Z_4L-" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=dage4Z_4L-</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1021/acschembio.3c00219" target="_blank" >10.1021/acschembio.3c00219</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

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

  • Original language description

    Tacrine was withdrawn from clinical use as a drug against Alzheimer&apos;s disease in 2013, mainly due to drug-induced liver injury.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 (Q(meth)), 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 Q(meth) 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 &lt; tacrine &lt; 7-methoxytacrine &lt; 7-phenoxytacrine) even after doses had been adjusted to achieve the same intracellular concentrations. The formation of Q(meth)-cysteine and Q(meth)-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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    30104 - Pharmacology and pharmacy

Result continuities

  • Project

    <a href="/en/project/GA23-07570S" target="_blank" >GA23-07570S: Biotransformation of tacrine implicating its hepatotoxicity</a><br>

  • Continuities

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Others

  • Publication year

    2023

  • Confidentiality

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Data specific for result type

  • Name of the periodical

    ACS chemical biology

  • ISSN

    1554-8929

  • e-ISSN

    1554-8937

  • Volume of the periodical

    18

  • Issue of the periodical within the volume

    9

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    10

  • Pages from-to

    1993-2002

  • UT code for WoS article

    001063643000001

  • EID of the result in the Scopus database

    2-s2.0-85170071727