Human induced pluripotent stem cell-derived liver-on-a-chip for studying drug metabolism: the challenge of the cytochrome P450 family

Abstract

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.

Keywords: CYP450; OoC; Organoids; drug metabolism; hiPSC.

FIGURE 1

Improving CYP450 expression in a hiPSC-derived liver-on-a-chip. Enhanced CYP450 expression by HLCs could be achieved in three ways: (A) by increasing tissue complexity by the formation of organoids in the optimal supportive matrix and subsequent prematuration, (B) by controlling the composition and concentration of different growth factors in cell medium during hiPSC differentiation and (C) by differentiating hiPSCs in a relevant cellular environment by adding other liver cell types, which will increase CYP450 expression in HLCs. (D) In addition, physiological cues such as shear stress and flow will positively affect CYP450 expression by hiPSCs on-chip by better mimicking liver physiology.

FIGURE 2

hiPSC-OoC Systems: A Promising Model for Personalized Drug Testing. hiPSCs can be differentiated into the cells of interest while maintaining donor-specific phenotypes. Interconnecting multiple organs-on-chip such as the gut, liver, and kidney, allow the study of personalized pharmacokinetic and pharmacodynamic (PK/PD) profiles. In combination with individuals’ microbiome on-chip, a fully representative and personalized system can be obtained to study drug toxicity and metabolism, determine personalized drug dosages, and investigate the effect of patient-specific CYP450 polymorphisms.