Abstract
Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that in-vitro liver models are capable of detecting DILI-positive compounds and their underlying mechanisms, prior to their approval and administration to patients or volunteers in clinical trials. Metabolism-dependent DILI is an important mechanism of drug-induced toxicity, which often involves the CYP450 family of enzymes, and is associated with the production of a chemically reactive metabolite and/or inefficient removal and accumulation of potentially toxic compounds. Unfortunately, many of the traditional in-vitro liver models fall short of their in-vivo counterparts, failing to recapitulate the mature hepatocyte phenotype, becoming metabolically incompetent, and lacking the longevity to investigate and detect metabolism-dependent DILI and those associated with chronic and repeat dosing regimens. Nevertheless, evidence is gathering to indicate that growing cells in 3D formats can increase the complexity of these models, promoting a more mature-hepatocyte phenotype and increasing their longevity, in vitro. This review will discuss the use of 3D in vitro models, namely spheroids, organoids, and perfusion-based systems to establish suitable liver models to investigate metabolism-dependent DILI.
Highlights
Drug-induced liver injury (DILI) is associated with a large proportion of withdrawn drugs [1] and is a leading cause of acute liver failure [2]
The model was unable to detect NAPQI, the toxic metabolite of acetaminophen, which was likely due to low CYP1A2 and CYP2E1 activity, but this may have been detectable at higher doses [143], as the concentration of acetaminophen used (10 μM) in this study was much less than the IC50 (i.e., TC50) values reported for primary human hepatocytes (PHHs) spheroids, which tend to be above 320 μM [12]
The cells used in these models will often be phenotypically different from in-vivo hepatocytes
Summary
Drug-induced liver injury (DILI) is associated with a large proportion of withdrawn drugs [1] and is a leading cause of acute liver failure [2].
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