Metabolic Activation of Atomoxetine Mediated by Cytochrome P450 2D6,Chemical Research in Toxicology

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Metabolic Activation of Atomoxetine Mediated by Cytochrome P450 2D6
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-08-25 , DOI: 10.1021/acs.chemrestox.1c00216
Yutong You ₁ , Xu Wang ₁ , Kaiqi Ma ₁ , Jiaru Li ₁ , Ying Peng ₁ , Jiang Zheng _{1,

2,

3}

Affiliation

Atomoxetine (ATX) is a neurological drug widely used for the treatment of attention deficit-hyperactivity disorder. Liver injury has been documented in patients administered ATX. The mechanism of ATX’s toxic action is less clear. This study is aimed to characterize reactive metabolites of ATX in vitro and in vivo to assist our understanding of the mechanisms of ATX hepatotoxicity. A hydroxylated metabolite, along with an O-dealkylation metabolite, was found in ATX-supplemented rat liver microsome incubations. Additionally, two glutathione (GSH) conjugates and two N-acetylcysteine (NAC) conjugates were observed in rat liver microsome incubations containing ATX, NADPH, and GSH or NAC. The corresponding GSH conjugates and NAC conjugates were found in bile and urine of ATX-treated rats, respectively. Recombinant P450 enzyme incubation study demonstrated that CYP2D6 dominated the metabolic activation of ATX. The insights gained from this study may be of assistance to illuminate the mechanisms of ATX-induced hepatotoxicity.

中文翻译：

细胞色素 P450 2D6 介导的托莫西汀代谢激活

阿托莫西汀（ATX）是一种广泛用于治疗注意力缺陷多动障碍的神经药物。服用 ATX 的患者已有肝损伤记录。 ATX 的毒性作用机制尚不清楚。本研究旨在表征 ATX 的体外和体内反应代谢物，以帮助我们了解 ATX 肝毒性的机制。在补充 ATX 的大鼠肝微粒体培养物中发现了羟基化代谢物以及O-脱烷基化代谢物。此外，在含有 ATX、NADPH 和 GSH 或 NAC 的大鼠肝微粒体培养物中观察到两种谷胱甘肽 (GSH) 缀合物和两种N-乙酰半胱氨酸 (NAC) 缀合物。在 ATX 处理的大鼠的胆汁和尿液中分别发现了相应的 GSH 结合物和 NAC 结合物。重组P450酶孵育研究表明CYP2D6主导ATX的代谢激活。从这项研究中获得的见解可能有助于阐明 ATX 诱导的肝毒性的机制。

更新日期：2021-09-20

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