Metabolic activation and hepatic cytotoxicity of osthole mediated by cytochrome P450 enzymes

Siyu Liu; Guode Zhao; Yingyun Xu; Yang Wang; Zifang Ding; Weiwei Li; Ying Peng; Jiang Zheng

doi:10.1016/j.toxlet.2024.12.009

Metabolic activation and hepatic cytotoxicity of osthole mediated by cytochrome P450 enzymes

Toxicol Lett. 2025 Jan 8:S0378-4274(24)02077-0. doi: 10.1016/j.toxlet.2024.12.009. Online ahead of print.

Authors

Siyu Liu¹, Guode Zhao¹, Yingyun Xu¹, Yang Wang¹, Zifang Ding¹, Weiwei Li², Ying Peng³, Jiang Zheng⁴

Affiliations

¹ Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
² 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.
³ Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China. Electronic address: yingpeng1999@163.com.
⁴ 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; Key Laboratory of Environmental Pollution, Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou 550025, PR China. Electronic address: zhengneu@yahoo.com.

PMID: 39793773
DOI: 10.1016/j.toxlet.2024.12.009

Abstract

Osthole (OST), a coumarin derivative, is one of the major components of Cnidium monnieri (L.) Cussion. OST was reported to induce apoptosis in hepatocytes. Elevated serum ALT and AST were documented in Sprague-Dawley rats after administration of OST. In the present study, OST was found to be metabolized to a phenol metabolite which was further metabolically oxidized to the corresponding quinone methide intermediate. A glutathione conjugate derived from the reactive metabolite was detected in vitro and in vivo. The structures of the metabolites were verified by chemical analysis. CYP3A4 and CYP1A2 were the major enzymes to catalyze the oxidation reactions. Pre-treatment with 1-aminobenzotriazole or ketoconazole decreased the susceptibility of primary hepatocytes to the cytotoxicity of OST. The findings provided solid evidence that the metabolic activation of OST correlated with the cytotoxicity of OST.

Keywords: Osthole; cytochrome P450; hepatotoxicity; metabolic activity.