The methylimidazolium ionic liquid M8OI (1-octyl-3-methylimidazolium chloride, also known as [C8mim]Cl) has been detected in the environment and may represent a hazard trigger for the autoimmune liver disease primary biliary cholangitis, based in part on studies using a rat liver progenitor cell. The effect of M8OI on an equivalent human liver progenitor (undifferentiated HepaRG cells; u-HepaRG) was therefore examined. u-HepaRG cells were less sensitive (>20-fold) to the toxic effects of M8OI. The relative insensitivity of u-HepaRG cells to M8OI was in part, associated with a detoxification by monooxygenation via CYP3A7 followed by further oxidation to a carboxylic acid. Expression of CYP3A7 - in contrast to the related adult hepatic CYP3A4 and CYP3A5 forms - was confirmed in u-HepaRG cells. However, blocking M8OI metabolism with ketoconazole only partly sensitized u-HepaRG cells. Despite similar proliferation rates, u-HepaRG cells consumed around 75% less oxygen than B-13 cells, reflective of reduced dependence on mitochondrial activity (Crabtree effect). Replacing glucose with galactose, resulted in an increase in u-HepaRG cell sensitivity to M8OI, near similar to that seen in B-13 cells. u-HepaRG cells therefore show reduced sensitivity to the toxic effects of M8OI through a combination of metabolic detoxification and their reduced reliance on mitochondrial function.

中文翻译：

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未分化的 HepaRG 细胞通过 CYP3A7 介导的氧化和减少对线粒体功能的依赖相结合，表现出对 M8OI 毒性作用的敏感性降低

甲基咪唑鎓离子液体 M8OI（1-辛基-3-甲基咪唑氯化物，也称为 [C8mim]Cl）已在环境中检测到，可能是自身免疫性肝病原发性胆汁性胆管炎的危险触发因素，部分基于以下研究：大鼠肝脏祖细胞。因此检查了 M8OI 对等效人肝脏祖细胞（未分化的 HepaRG 细胞；u-HepaRG）的影响。 u-HepaRG 细胞对 M8OI 的毒性作用不太敏感（>20 倍）。 u-HepaRG 细胞对 M8OI 的相对不敏感性部分与通过 CYP3A7 进行单氧合随后进一步氧化成羧酸的解毒有关。与相关的成人肝脏 CYP3A4 和 CYP3A5 形式相比，CYP3A7 的表达在 u-HepaRG 细胞中得到证实。然而，用酮康唑阻断 M8OI 代谢只能使 u-HepaRG 细胞部分敏感。尽管增殖率相似，但 u-HepaRG 细胞消耗的氧气比 B-13 细胞少约 75%，这反映出对线粒体活性的依赖性降低（克拉布特里效应）。用半乳糖代替葡萄糖，导致 u-HepaRG 细胞对 M8OI 的敏感性增加，与 B-13 细胞中观察到的情况几乎相似。因此，u-HepaRG 细胞通过代谢解毒和减少对线粒体功能的依赖，表现出对 M8OI 毒性作用的敏感性降低。