Toxicogenomics of drug induced liver injury–from mechanistic understanding to early prediction.

Abstract

Despite rigorous preclinical testing, clinical attrition rates in drug development remain high with drug-induced liver injury (DILI) remaining one of the most frequent causes of project failures. To understand DILI mechanisms, major efforts are put into the development of physiologically relevant cell models and culture paradigms with the aim to enhance preclinical to clinical result translation. While the majority of toxicogenomic studies have been based on cell lines, there are emerging trends toward the predominant use of stem cell-derived organoids and primary human hepatocytes in complex 3D cell models. Such studies have been successful in disentangling diverse toxicity mechanisms, including genotoxicity, mitochondrial injury, steatogenesis and cholestasis and can aid in distinguishing hepatotoxic from nontoxic structural analogs. Furthermore, by leveraging inter-individual differences of cells from different donors, these approaches can emulate the complexity of polygenic risk scores, which facilitates personalized drug-specific DILI risk analyses. In summary, toxicogenomic studies into drug-induced hepatotoxicity have majorly contributed to our mechanistic understanding of DILI and the incorporation of organotypic human 3D liver models into the preclinical testing arsenal promises to enhance biological insights during drug discovery, increase confidence in preclinical safety and minimize the translational gap.