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

Abstract

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.

• Authors: He Liu, Zixia Hu, Ningning Han, Yi Yang, Guode Zhao, Mengdie Su, Yue Zhang, Weiwei Li, Ying Peng, Jiang Zheng
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 382 Pg. 110628 (Sep 01 2023) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 37442290 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier B.V. All rights reserved.

Chemical References

• 2,6-dichloro-4-nitrophenol
• metaxalone
• Sulfotransferases
• Cytochrome P-450 Enzyme System
• Glutathione

Topics

• Rats
• Animals
• Activation, Metabolic
• Sulfotransferases (metabolism)
• Cytochrome P-450 Enzyme System (metabolism)
• Microsomes, Liver (metabolism)
• Glutathione (metabolism)