Metabolic activation and cytotoxicity of metaxalone mediated by cytochrome P450 enzymes and sulfotransferases

被引：0

作者：

Liu, He ^{[1
]}

Hu, Zixia ^{[1
]}

Han, Ningning ^{[1
]}

Yang, Yi ^{[1
]}

Zhao, Guode ^{[1
]}

Su, Mengdie ^{[1
]}

Zhang, Yue ^{[1
]}

Li, Weiwei ^{[2
]}

Peng, Ying ^{[1
]}

Zheng, Jiang ^{[1
,2
]}

机构：

[1] Shenyang Pharmaceut Univ, Wuya Coll Innovat, Shenyang 110016, Liaoning, Peoples R China

[2] Guizhou Med Univ, State Key Lab Funct & Applicat Med Plants, Key Lab Pharmaceut Guizhou Prov, Guiyang 550025, Guizhou, Peoples R China

来源：

CHEMICO-BIOLOGICAL INTERACTIONS | 2023年 / 382卷

关键词：

Metaxalone; Metabolic activation; Cytochrome P450 enzymes; Sulfotransferases; MUSCLE-RELAXANT; LIVER; SULFATION; RAT;

D O I：

10.1016/j.cbi.2023.110628

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. Pretreatment of primary hepatocytes with DCNP or MTS significantly decreased the susceptibility to the cytotoxicity of MTX.

引用

页数：9

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