Metabolomics reveals that sulfotransferase 1 may regulate colchicine-induced liver injury

Ruoyue Huang; Chunyan Wang; Zhanxuan E Wu; Qi Zhao; Jingyi Duan; Wen Huang; Yan Cheng; Beiwei Zhu; Fei Li

doi:10.1016/j.cbi.2023.110776

Metabolomics reveals that sulfotransferase 1 may regulate colchicine-induced liver injury

Chem Biol Interact. 2023 Oct 28:110776. doi: 10.1016/j.cbi.2023.110776. Online ahead of print.

Authors

Ruoyue Huang¹, Chunyan Wang¹, Zhanxuan E Wu¹, Qi Zhao¹, Jingyi Duan¹, Wen Huang¹, Yan Cheng², Beiwei Zhu³, Fei Li⁴

Affiliations

¹ Department of Gastroenterology & Hepatology, Laboratory of Metabolomics and Drug-induced Liver Injury, State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-related Molecular Network, And State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, China.
² Department of Gastroenterology & Hepatology, Laboratory of Metabolomics and Drug-induced Liver Injury, State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-related Molecular Network, And State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, China; Academician Workstation, Jiangxi University of Chinese Medicine, Nanchang, 330004, China.
³ School of Food Science and Technology, Dalian Polytechnic University, Dalian, 116034, China; National Engineering Research Center of Seafood, Dalian, 116034, China. Electronic address: [email protected].
⁴ Department of Gastroenterology & Hepatology, Laboratory of Metabolomics and Drug-induced Liver Injury, State Key Laboratory of Biotherapy, Frontiers Science Center for Disease-related Molecular Network, And State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].

PMID: 39492502
DOI: 10.1016/j.cbi.2023.110776

Abstract

Colchicine is widely used to treat gouty arthritis for years. Previous studies showed that colchicine overdose can cause liver damage, yet the mechanism underlying its hepatotoxicity remains unclear. In this study, hepatotoxicity of colchicine was investigated in vivo. Metabolomic analysis of colchicine metabolites and endogenous metabolites was performed using Ultra High Performance Liquid Chromatography (UHPLC) - mass spectrometry (MS). Seventeen metabolites of colchicine were identified, including 3 novel sulfated metabolites. Meanwhile, endogenous sulfated metabolites were found to be decreased by colchicine. Colchicine might regulate sulfotransferase 1 (SULT1) through perixisome proliferation-activated receptor ɑ (PPARα), and inhibition of SULT1 reduced the levels of sulfated metabolites of colchicine. Inhibition of SULT1 aggravated colchicine-induced liver injury, whereas activation of SULT1 attenuated its liver injury. The supplementation of endogenous sulfated metabolites indoxyl sulfate (IS) or p-cresol sulfate (PCS) alleviated colchicine-induced liver injury through modulation of the CASPASE-1-gasdermin D (GSDMD) pathway. These results indicated that colchicine might cause hepatotoxicity through inhibition of SULT1and decreased production of bioactive sulfated endogenous metabolites IS and PCS. Our results provided evidence for potential therapeutic targets and agents to prevent liver injury caused by colchicine. Targeting the SULT1 enzyme and administration of IS and PCS may be useful in alleviating colchicine hepatotoxicity.

Keywords: Colchicine; Liver injury; Mass spectrometry; Metabolomics analysis; Sulfotransferase.