Delineation of the toxicity of tacrine and its derivatives to the 3D primary human hepatocyte spheroid model

• Κύριος συγγραφέας: Σισμάνογλου, Δέσποινα-Χριστίνα
• Άλλοι συγγραφείς: Sismanoglou, Despoina-Christina
• Γλώσσα: English
• Έκδοση: 2022
• Θέματα: Tacrine; Hepatotoxicity; Primary human hepatocytes; Τακρίνη; Ηπατοτοξικότητα; Πρωτογενή ανθρώπινα ηπατοκύτταρα

Neurodegenerative disorders constitute a major health problem, with the Alzheimer’s disease being the most common one affecting millions of people worldwide. Tacrine, an inhibitor of the enzyme acetylcholinesterase, entered the market in 1993 and was used with the scope to alleviate the symptoms. Despite the beneficial effects in the cognitive functions, tacrine was withdrawn two decades after its release due to severe hepatotoxicity. The molecular mechanisms underlying tacrine’s toxicity are still under investigation. In the present study, we focus on tacrine and its metabolites so as to investigate which one is responsible for the hepatotoxicity. Our primary aim is to delineate whether the 7-hydroxytacrine (7-OH THA) metabolite constitutes the toxicity culprit leading to the quinonation of liver proteins. Secondly, we test two novel derivatives of tacrine with a substitution in the C7 position, the 7-MEOTA and 7-FEOTA, so as to investigate whether these compounds could serve as safer alternatives to tacrine. Furthermore, the involvement of the toxic metabolite quinone methide in the hepatotoxic mechanism was assessed. For this purpose, the organotypic 3D model of primary human hepatocytes is used with the aim to recapitulate the in vivo situation more precisely. We conclude that the 7-OH metabolite is not the culprit for the hepatotoxicity and 7-FEOTA was the most toxic compound.