Tamargo-Rubio Isabel, Simpson Anna Bella, Hoogerland Joanne A, Fu Jingyuan
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Front Pharmacol. 2023 Jun 28;14:1223108. doi: 10.3389/fphar.2023.1223108. eCollection 2023.
The liver is the primary organ responsible for the detoxification and metabolism of drugs. To date, a lack of preclinical models that accurately emulate drug metabolism by the human liver presents a significant challenge in the drug development pipeline, particularly for predicting drug efficacy and toxicity. In recent years, emerging microfluidic-based organ-on-a-chip (OoC) technologies, combined with human induced pluripotent stem cell (hiPSC) technology, present a promising avenue for the complete recapitulation of human organ biology in a patient-specific manner. However, hiPSC-derived organoids and liver-on-a-chip models have so far failed to sufficiently express cytochrome P450 monooxygenase (CYP450) enzymes, the key enzymes involved in first-pass metabolism, which limits the effectiveness and translatability of these models in drug metabolism studies. This review explores the potential of innovative organoid and OoC technologies for studying drug metabolism and discusses their existing drawbacks, such as low expression of CYP450 genes. Finally, we postulate potential approaches for enhancing CYP450 expression in the hope of paving the way toward developing novel, fully representative liver drug-metabolism models.
肝脏是负责药物解毒和代谢的主要器官。迄今为止，缺乏能够准确模拟人类肝脏药物代谢的临床前模型，这在药物研发流程中构成了重大挑战，尤其是在预测药物疗效和毒性方面。近年来，新兴的基于微流控的芯片器官（OoC）技术，与人类诱导多能干细胞（hiPSC）技术相结合，为以患者特异性方式全面重现人体器官生物学提供了一条有前景的途径。然而，到目前为止，hiPSC衍生的类器官和芯片肝脏模型未能充分表达细胞色素P450单加氧酶（CYP450），而该酶是首过代谢中的关键酶，这限制了这些模型在药物代谢研究中的有效性和可转化性。本综述探讨了创新的类器官和OoC技术在研究药物代谢方面的潜力，并讨论了它们目前存在的缺点，如CYP450基因表达较低。最后，我们推测了增强CYP450表达的潜在方法，希望为开发新型、具有充分代表性的肝脏药物代谢模型铺平道路。
