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THE UTILITY OF MICROSCALE HUMAN LIVER CO-CULTURES FOR INVESTIGATING DRUG TOXICITY OUTCOMES

Drug-induced liver injury (DILI) remains a leading cause of acute liver failures and the attrition of pharmaceuticals in both preclinical and clinical settings. Due to species-specific differences in drug metabolism pathways, animal models do not always fully predict human DILI. Thus, there is a need for predictive human liver models, which include hepatocarcinoma-derived cell lines, primary hepatocytes and liver slices. However, cancerous cell lines suffer from abnormal levels of liver functions and morphology, while liver slices do not retain phenotypic functions for more than a few days in vitro. Therefore, isolated primary human hepatocytes are widely considered to be the “gold standard” for drug toxicity assessments; however, in culture formats that rely exclusively on extracellular matrix, hepatocytes display a rapid decline in key functions (i.e. drug metabolism enzymes, transporters), which prevents long-term drug dosing.