The detoxification effect of cytochrome P450 3A4 on gelsemine-induced toxicity. (15th December 2021)

• Record Type: Journal Article
• Authors: You, Guoquan; Yang, Ruopeng; Wei, Yingjie; Hu, Wanyu; Gan, Lili; Xie, Cong; Zheng, Zhijie; Liu, Zhongqiu; Liao, Rongxin; Ye, Ling
• Is Part Of: Toxicology letters. Volume 353(2021)
• Page Start: 34
• Page End: 42
• Publication Date: 2021-12-15
• Subjects: ALT alanine aminotransferase -- AST aspartate aminotransferase -- CYPs cytochrome P450 enzymes -- DEX dexamethasone -- FVB Friend virus B -- GA gelsemine -- GSH glutathione -- GSH-PX glutathione peroxidase -- GSH-ST glutathione S-transferase -- HLMs human liver microsomes -- HRMS high resolution mass spectrometry -- IL-1β interleukin-1β -- KET ketoconazole -- MDA malondialdehyde -- MLMs mice liver microsomes -- NMR Nuclear Magnetic Resonance -- SOD superoxide dismutase -- hCYP3A4 CYP3A4-humanized -- UPLC-MS ultra-performance liquid chromatography-mass spectrometry -- WT wild-type; Gelsemine -- Toxicity -- CYP3A4 -- Metabolism -- CYP3A4-humanized mice; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2021.10.003
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: Gelsemine (GA) was mainly metabolized by CYP3A4/5. The major metabolite of GA was identified as 4-N-demethyl-GA. GA toxicity significantly increased when CYP3A4 was inhibited. GA toxicity significantly decreased in CYP3A4-humanized mice. Abstract: Gelsemine (GA), the principal alkaloid in Gelsemium elegans Benth, exhibits potent and specific antinociception in chronic pain without the induction of apparent tolerance. However, GA also exerts neurotoxicity and hepatotoxicity when overdosed, and potential detoxification pathways are urgently needed. Cytochrome P450 enzymes (CYPs) are important phase I enzymes involved in the detoxification of xenobiotic compounds. The study aimed to investigate the role of CYPs-mediated metabolism in GA-induced toxicity. Microsomes, chemical special inhibitors and human recombinant CYPs indicated that GA was mainly metabolized by CYP3A4/5. The major metabolite of GA was isolated and identified as 4-N-demethyl-GA by high-resolution mass spectrometry and nuclear magnetic resonance technology. The CYP3A4 inhibitor ketoconazole significantly inhibited the metabolism of GA. This drastically increased GA toxicity which is caused by increasing the level of malondialdehyde and decreasing the level of the superoxide dismutase in mice. In contrast, the CYP3A4 inducer dexamethasone significantly increased GA metabolism and markedly decreased GA toxicity in mice. Notably, in CYP3A4-humanized mice, the toxicity of GA was significantly reduced compared to normal mice. These findings demonstrated that CYP3A4-mediated metabolism is a robust detoxification pathway for GA-induced toxicity.