他克林第一阶段生物转化和相关肝毒性：避免醌甲基化物形成的可能方法,ACS Chemical Biology

当前位置： X-MOL 学术 › ACS Chem. Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

他克林第一阶段生物转化和相关肝毒性：避免醌甲基化物形成的可能方法
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2023-08-25 , DOI: 10.1021/acschembio.3c00219
Martin Novak _{1,

2} , Marie Vajrychova ₂ , Stefania Koutsilieri ₃ , Despoina-Christina Sismanoglou ₃ , Tereza Kobrlova ₂ , Lukas Prchal ₂ , Barbora Svobodova ₂ , Jan Korabecny ₂ , Tomas Zarybnicky ₄ , Lucie Raisova-Stuchlikova ₄ , Lenka Skalova ₄ , Volker M Lauschke _{3,

5,

6} , Radim Kučera ₁ , Ondrej Soukup ₂

Affiliation

他克林作为抗阿尔茨海默病药物于2013年退出临床使用，主要原因是药物引起的肝损伤。他克林相关肝毒性的罪魁祸首被认为是 7-OH-他克林代谢物，它可能是醌甲基化物 (Q _meth ) 的前体，可与细胞内 -SH 蛋白结合。在我们的研究中，使用了几种不同的动物和人类模型（肝微粒体、原代肝细胞和肝切片）来研究他克林及其7-取代类似物（7-甲氧基-、7-苯氧基-和7-苯氧基-）的生物转化和肝毒性。 -OH-他克林）。我们的目标是找到最合适的体外模型来研究他克林的肝毒性，并通过合理的结构修饰，开发出不易形成 Q _meth的他克林衍生物。我们的结果表明，没有一个测试的动物模型能够准确模拟人类他克林的生物转化；然而，小鼠模型似乎比大鼠模型更合适。总体而言，在原代人肝细胞 (PHH) 的三维 (3D) 球体培养物中，他克林代谢的模拟最为准确。在该系统中，他克林和7-甲氧基他克林被羟基化为7-OH-他克林，而如预期的那样，仅形成痕量的7-苯氧基他克林。然而，令人惊讶的是，我们的研究表明，即使在调整剂量以达到相同的细胞内浓度后，7-OH-他克林的肝毒性也最小（7-OH-他克林<他克林<7-甲氧基他克林<7-苯氧基他克林）。所有研究的他克林衍生物都证实了人肝微粒体孵育后Q_甲基半胱氨酸和 Q_甲基谷胱甘肽加合物的形成，但这些发现在与 3D PHH 球体孵育后并未得到证实。因此，所提供的数据对先前假设的毒性机制提出了质疑，并且结果为化学修饰以提高新型他克林衍生物的安全性开辟了新途径。

"点击查看英文标题和摘要"

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

Tacrine was withdrawn from clinical use as a drug against Alzheimer’s disease in 2013, mainly due to drug-induced liver injury.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 (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 < tacrine < 7-methoxytacrine < 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.

更新日期：2023-08-25

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南