Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo,Chemical Research in Toxicology

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Identification of an Epoxide Metabolite of Amitriptyline In Vitro and In Vivo
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2024-05-18 , DOI: 10.1021/acs.chemrestox.4c00008
Ximei Li ₁ , Lihua Xin ₂ , Lan Yang ₂ , Yi Yang ₂ , Wei Li ₂ , Mingyu Zhang ₂ , Yufen Liao ₁ , Chen Sun ₂ , Weiwei Li ₁ , Ying Peng ₂ , Jiang Zheng _{1,

2}

Affiliation

Amitriptyline (ATL), a tricyclic antidepressant, has been reported to cause various adverse effects, particularly hepatotoxicity. The mechanisms of ATL-induced hepatotoxicity remain unknown. The study was performed to identify the olefin epoxidation metabolite of ATL and determine the possible toxicity mechanism. Two glutathione (GSH) conjugates (M1 and M2) and two N-acetylcysteine (NAC) conjugates (M3 and M4) were detected in rat liver microsomal incubations supplemented with GSH and NAC, respectively. Moreover, M1/M2 and M3/M4 were respectively found in ATL-treated rat primary hepatocytes and in bile and urine of rats given ATL. Recombinant P450 enzyme incubations demonstrated that CYP3A4 was the primary enzyme involved in the olefin epoxidation of ATL. Treatment of hepatocytes with ATL resulted in significant cell death. Inhibition of CYP3A attenuated the susceptibility to the observed cytotoxicity of ATL. The metabolic activation of ATL most likely participates in the cytotoxicity of ATL.

中文翻译：

阿米替林环氧化物代谢物的体外和体内鉴定

阿米替林 (ATL) 是一种三环类抗抑郁药，据报道会引起各种不良反应，特别是肝毒性。 ATL 引起的肝毒性的机制仍不清楚。该研究旨在鉴定 ATL 的烯烃环氧化代谢物并确定可能的毒性机制。在补充有 GSH 和 NAC 的大鼠肝微粒体培养物中分别检测到两种谷胱甘肽 (GSH) 缀合物（M1 和 M2）和两种N-乙酰半胱氨酸 (NAC) 缀合物（M3 和 M4）。此外，在ATL处理的大鼠原代肝细胞以及给予ATL的大鼠的胆汁和尿液中分别发现了M1/M2和M3/M4。重组 P450 酶孵育证明 CYP3A4 是参与 ATL 烯烃环氧化的主要酶。用 ATL 处理肝细胞导致显着的细胞死亡。 CYP3A 的抑制减弱了对观察到的 ATL 细胞毒性的敏感性。 ATL 的代谢激活很可能参与了 ATL 的细胞毒性。

更新日期：2024-05-18

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