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 interindividual 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.

Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development—Current State-of-the-Art and Future Perspectives

“…These methods were first presented in the mid-1980s when rat hepatocyte spheroids formed on poly(2-hydroxyethyl methacrylate) or proteoglycancoated ULA surfaces and were shown to maintain viability for several weeks with hepatic functions superior to monolayer culture (Landry et al, 1985;Koide et al, 1989;Tong et al, 1992). However, despite these promising results, the field remained dormant, and spheroid culture emerged as a widely used paradigm only more than 2 decades later (Ingelman-Sundberg and Lauschke, 2021).…”

“…In the following, we provide an updated overview of toxicological screens conducted in 3D human liver models. For other applications, such as mechanistic investigations, comparative studies, or toxicogenomics, we refer the interested reader to recent comprehensive reviews (Zhou et al, 2019;Zhang et al, 2020;Lauschke, 2021;Serras et al, 2021).…”

Advanced human liver models for the assessment of drug-induced liver injury

“…Hepatocytes in pericentral zone 3 express high levels of CYP enzymes and execute xenobiotic metabolism. Artificial hepatic zonation via a Wnt gradient represents zone 3-specific APAP toxicity that forms toxic reactive metabolites through CYP2E1, CYP1A2, and CYP3A4 [5,[37][38][39][40]. Furthermore, inter-organ interactions can be simulated using this bioengineering technology, which mirrors absorption (gut), distribution, metabolism (liver), and excretion (kidney) [34].…”

3D human liver spheroids for translational pharmacology and toxicology

“…We anticipate that liver spheroids will be increasingly used for drug toxicity studies in disease models, including viral hepatitis, alcoholic fatty liver disease, NAFLD and other inflammatory conditions, to evaluate potentially sensitizing parameters that can be difficult to assess using current clinical trial designs. For further toxicogenomic analyses of DILI mechanisms, we refer the interested reader to recent comprehensive reviews on this subject 65,66 …”