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

被引：4

作者：

Liu, Siyu ^{[1
]}

Zhao, Guode ^{[1
]}

Xu, Yingyun ^{[1
]}

Wang, Yang ^{[1
]}

Ding, Zifang ^{[1
]}

Li, Weiwei ^{[2
]}

Peng, Ying ^{[1
]}

Zheng, Jiang ^{[1
,2
,3
]}

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

[3] Guizhou Med Univ, Key Lab Environm Pollut Monitoring & Dis Control, Minist Educ, Guiyang 550025, Guizhou, Peoples R China

来源：

TOXICOLOGY LETTERS | 2025年 / 404卷

关键词：

Osthole; Metabolic activity; Hepatotoxicity; Cytochrome P450; IN-VITRO; COUMARIN; IDENTIFICATION; MECHANISM; TOXICITY; KINETICS;

D O I：

10.1016/j.toxlet.2024.12.009

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 ;

摘要：

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.

引用

页码：1 / 8

页数：8

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