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使用三维人肝细胞球体模型评估有无丙戊酸盐情况下大麻二酚诱导的肝损伤。

Evaluating cannabidiol-induced liver injury with and without valproate using a three-dimensional human hepatocyte spheroid model.

作者信息

Beers Jessica L, Harvey Shalon L, Lanphier Raeanne M, Rushing Blake R, McRitchie Susan L, Sumner Susan J, Jackson Klarissa D

机构信息

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America; Department of Pharmaceutics, University of Washington School of Pharmacy, Seattle, WA, United States of America.

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.

出版信息

Toxicol In Vitro. 2025 Dec;109:106126. doi: 10.1016/j.tiv.2025.106126. Epub 2025 Aug 5.

DOI:10.1016/j.tiv.2025.106126
PMID:40774642
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12412670/
Abstract

Cannabidiol (CBD) and valproate (VPA) are anti-epileptic medications commonly co-prescribed to treat seizures due to Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children. Clinical trial data have demonstrated that CBD carries a risk for severe hepatotoxicity that is greatly increased when prescribed with VPA through an unknown mechanism. The aim of this study was to investigate CBD-induced liver injury in combination with VPA using an in vitro liver model. Three-dimensional human hepatocyte spheroids are an emerging in vitro system that allows investigation of long-term toxicity. Spheroids derived from primary human hepatocytes were treated with vehicle control, 2-200 μM CBD, 0.5-20 mM VPA, CBD + VPA, and 0.1-10 mM acetaminophen (positive control). After 24 h, 8 days, and 15 days of exposure, spheroids were analyzed for ATP depletion, urea production, and CBD and VPA metabolite generation. Untargeted metabolomic analysis was also conducted. A delayed-onset, dose-dependent hepatotoxicity was observed in spheroids exposed to each drug treatment compared to vehicle control. This study is the first to recapitulate the hepatotoxic drug interaction of CBD and VPA in vitro and demonstrates the utility of human hepatocyte spheroids for toxicity studies. Future work is needed to examine mechanisms of CBD-induced hepatotoxicity with VPA.

摘要

大麻二酚（CBD）和丙戊酸盐（VPA）是常用于联合处方治疗儿童 Lennox-Gastaut 综合征、Dravet 综合征和结节性硬化症所致癫痫发作的抗癫痫药物。临床试验数据表明，CBD 存在严重肝毒性风险，与 VPA 联合使用时，这种风险会通过未知机制大幅增加。本研究的目的是使用体外肝脏模型研究 CBD 与 VPA 联合诱导的肝损伤。三维人肝细胞球体是一种新兴的体外系统，可用于研究长期毒性。将源自原代人肝细胞的球体用溶剂对照、2 - 200 μM CBD、0.5 - 20 mM VPA、CBD + VPA 和 0.1 - 10 mM 对乙酰氨基酚（阳性对照）进行处理。在暴露 24 小时、8 天和 15 天后，分析球体的 ATP 消耗、尿素生成以及 CBD 和 VPA 代谢产物的生成情况。还进行了非靶向代谢组学分析。与溶剂对照相比，在接受每种药物处理的球体中均观察到延迟发作的剂量依赖性肝毒性。本研究首次在体外再现了 CBD 和 VPA 的肝毒性药物相互作用，并证明了人肝细胞球体在毒性研究中的实用性。未来需要开展工作以研究 CBD 与 VPA 联合诱导肝毒性的机制。

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