抗肿瘤药物巴司替尼可能诱发不同的肝脏病变，包括胆汁淤积和窦性梗阻综合征。然而，尚未有报道显示巴司替尼可导致患者肝脏脂肪变性。本研究旨在确定巴司替尼是否能够诱导原代人肝细胞（PHH）和分化的HepaRG细胞发生脂肪变性。检测了PHH和HepaRG细胞中的中性脂质。通过测量与脂质稳态相关的代谢通量、还原型谷胱甘肽（GSH）水平和涉及脂质代谢和内质网（ER）应激的基因表达，在HepaRG细胞中进行了机制研究。进行了两个先前转录组数据集的分析。巴司替尼诱导HepaRG细胞中的脂质积聚，但不会出现在六个不同批次的PHH中。在HepaRG细胞中，巴司替尼影响VLDL分泌，增加脂肪酸摄取，并引发ER应激。转录组数据分析和GSH水平的降低表明，巴司替尼诱导的脂肪变性可能与谷胱甘肽S转移酶（GST）同工酶A1的高表达有关，该酶负责生成肝毒性的硫鎓阳离子共轭物。与此一致，GST抑制剂依他克酸和化学分子伴侣牛磺胆酸酰基脱氧胆酸可以缓解HepaRG细胞中巴司替尼诱导的脂质积聚，支持硫鎓阳离子共轭物和ER应激在脂肪变性中的作用。尽管HepaRG细胞系是药物毒理学研究中的宝贵工具，但它可能不总是预测和机械研究药物诱导的肝脏损伤的合适模型。因此，我们建议在HepaRG细胞和PHH中进行毒理学研究，以避免对药物和其他异物的潜在肝毒性得出错误结论。© 2023 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.

The antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients.This study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells.Neutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out.Busulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan-induced steatosis might be linked to the high expression of glutathione S-transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan-induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis.While the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug-induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics.© 2023 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.