Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China.
Chem Biol Interact. 2023 Sep 1;382:110628. doi: 10.1016/j.cbi.2023.110628. Epub 2023 Jul 11.
Metaxalone (MTX) is a central nervous system (CNS) depressant used for the treatment of acute skeletal muscle pain. Several cases of fatal overdose deaths in the clinical use of MTX, along with the presence of ischemic hepatitis in deceased patients, have been documented. The present study aimed to investigate the metabolic activation of MTX and to define the possible correlation between the metabolic activation and cytotoxicity of MTX. An oxidative metabolite (M1) and a GSH conjugate (M2) were observed in S9 fraction incubations as well as in rat primary hepatocyte culture after exposure to MTX. M1 and M2 were also observed in bile of MTX-treated rats. CYP2A6 was found to dominate the oxidation of MTX. Both methoxsalen (MTS, a CYP2A6 inhibitor) and 2,6-dichloro-4-nitrophenol (DCNP, a sulfotransferase inhibitor) dramatically decreased the formation of M2. Pre-treatment of primary hepatocytes with DCNP or MTS significantly decreased the susceptibility to the cytotoxicity of MTX.
美他沙酮（MTX）是一种中枢神经系统（CNS）抑制剂，用于治疗急性骨骼肌疼痛。有几例 MTX 临床用药过量导致死亡的病例，以及死亡患者存在缺血性肝炎的病例都有记录。本研究旨在研究 MTX 的代谢激活，并确定 MTX 的代谢激活与细胞毒性之间可能存在的相关性。在 S9 级分孵育以及暴露于 MTX 后的大鼠原代肝细胞培养物中观察到氧化代谢物（M1）和 GSH 缀合物（M2）。在 MTX 处理的大鼠的胆汁中也观察到了 M1 和 M2。发现 CYP2A6 主导 MTX 的氧化。甲氧沙林（MTS，CYP2A6 抑制剂）和 2,6-二氯-4-硝基苯酚（DCNP，磺基转移酶抑制剂）均可显著减少 M2 的形成。用 DCNP 或 MTS 预处理原代肝细胞可显著降低对 MTX 细胞毒性的敏感性。
