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

IF 2.7 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro Pub Date : 2025-12-01 Epub Date: 2025-08-05 DOI:10.1016/j.tiv.2025.106126

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

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引用次数: 0

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.

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使用三维人肝细胞球体模型评估大麻二酚诱导的有丙戊酸和无丙戊酸肝损伤。

大麻二酚（CBD）和丙戊酸酯（VPA）是抗癫痫药物，通常共同用于治疗儿童Lennox-Gastaut综合征，Dravet综合征和结节性硬化症引起的癫痫发作。临床试验数据表明，CBD具有严重肝毒性的风险，当通过未知机制与VPA一起使用时，这种风险会大大增加。本研究的目的是通过体外肝模型研究cbd联合VPA诱导的肝损伤。三维人肝细胞球体是一个新兴的体外系统，允许研究长期毒性。来源于人原代肝细胞的球体分别用对照、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）处理。在暴露24小时、8天和15天后，对球体进行ATP消耗、尿素生成、CBD和VPA代谢物生成的分析。还进行了非靶向代谢组学分析。与对照组相比，暴露于每种药物治疗的球体中观察到延迟发作，剂量依赖性肝毒性。这项研究首次概述了CBD和VPA在体外的肝毒性药物相互作用，并证明了人类肝细胞球体在毒性研究中的实用性。未来的工作需要研究cbd诱导的VPA肝毒性的机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology in Vitro 医学-毒理学

CiteScore

6.50

自引率

3.10%

发文量

181

审稿时长

65 days

期刊介绍： Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.