建立 UGT1A1 敲除人 iPS 衍生的肝类器官，用于 UGT1A1 特异性动力学和毒性评估,Molecular Therapy - Methods & Clinical Development

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建立 UGT1A1 敲除人 iPS 衍生的肝类器官，用于 UGT1A1 特异性动力学和毒性评估
Molecular Therapy - Methods & Clinical Development ( IF 4.6 ) Pub Date : 2023-08-11 , DOI: 10.1016/j.omtm.2023.08.003
Tomohiro Shintani ₁ , Chiharu Imamura ₂ , Yukiko Ueyama-Toba _{1,

2,

3,

4} , Jumpei Inui ₁ , Akira Watanabe ₂ , Hiroyuki Mizuguchi _{1,

2,

3,

4,

5,

6}

Affiliation

尿苷二磷酸葡萄糖醛酸基转移酶（UGT）在肝脏中高表达，参与许多药物的代谢。特别是，UGT1A1 具有基因多态性，会导致活性降低，从而导致药物引起的肝毒性。因此，需要一种能够准确预测涉及UGT1A1的药物动力学的评估系统。然而，由于缺乏UGT1A1选择性抑制剂，因此不存在这样的评估系统。在这里，利用人类诱导多能干（iPS）细胞、基因组编辑技术和类器官技术，我们生成了 UGT1A1 敲除的人 iPS 肝细胞来源的肝脏类器官（UGT1A1-KO i-HO）作为 UGT1A1 特异性动力学和毒性的模型评估。 i-HOs 显示出比人 iPS 细胞来源的肝细胞样细胞 (iPS-HLC) 更高的包括 UGT1A1 在内的许多药物代谢酶的基因表达，表明肝类器官技术可改善肝功能。野生型 (WT) i-HO 显示出与原代人（冷冻保存）肝细胞相似的 UGT1A1 活性水平，而 UGT1A1-KO i-HO 完全丧失了活性。此外，为了评估该模型是否可用于预测药物引起的肝毒性，将 UGT1A1-KO i-HO 暴露于抗癌药物伊立替康的活性代谢物 SN-38 和对乙酰氨基酚，并证实这些细胞可以预测 UGT1A1 -介导的毒性。因此，我们成功地生成了能够评估 UGT1A1 特异性动力学和毒性的模型细胞。

"点击查看英文标题和摘要"

Establishment of UGT1A1-knockout human iPS-derived hepatic organoids for UGT1A1-specific kinetics and toxicity evaluation

Uridine diphosphate glucuronosyltransferases (UGTs) are highly expressed in the liver and are involved in the metabolism of many drugs. In particular, UGT1A1 has a genetic polymorphism that causes decreased activity, leading to drug-induced hepatotoxicity. Therefore, an evaluation system that accurately predicts the kinetics of drugs involving UGT1A1 is required. However, there is no such evaluation system because of the absence of the UGT1A1-selective inhibitor. Here, using human induced pluripotent stem (iPS) cells, genome editing technology, and organoid technology, we generated UGT1A1-knockout human iPS hepatocyte-derived liver organoids (UGT1A1-KO i-HOs) as a model for UGT1A1-specific kinetics and toxicity evaluation. i-HOs showed higher gene expression of many drug-metabolizing enzymes including UGT1A1 than human iPS cell-derived hepatocyte-like cells (iPS-HLCs), suggesting that hepatic organoid technology improves liver functions. Wild-type (WT) i-HOs showed similar levels of UGT1A1 activity to primary human (cryopreserved) hepatocytes, while UGT1A1-KO i-HOs completely lost the activity. Additionally, to evaluate whether this model can be used to predict drug-induced hepatotoxicity, UGT1A1-KO i-HOs were exposed to SN-38, the active metabolite of irinotecan, an anticancer drug, and acetaminophen and confirmed that these cells could predict UGT1A1-mediated toxicity. Thus, we succeeded in generating model cells that enable evaluation of UGT1A1-specific kinetics and toxicity.

更新日期：2023-08-11

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