Establishment of a primary human hepatocyte spheroid system for evaluating metabolic toxicity using dacarbazine under conditions of CYP1A2 induction.

Kenta Mizoi, Mayu Hosono, Hajime Kojima, Takuo Ogihara

Drug metabolism and pharmacokinetics 2020 Apr

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Some drugs induce cytochrome P450s (CYPs), and thus may cause increased metabolic toxicity from concomitantly administered agents. Hence, we need a means of evaluating the potential of compounds to cause drug-induced liver injury (DILI) under conditions where inducers of CYP1A2 are present. Here, we present a system for evaluating CYP1A2-mediated metabolic toxicity using three-dimensional (3D) cultures of primary human hepatocyte spheroids treated with the CYP1A2 inducer omeprazole (OPZ). As a test substrate, we employed dacarbazine (DTIC), which causes toxicity during the metabolic process. We measured cell viability, CYP1A2 mRNA expression level and metabolism of DTIC, as well as several markers of hepatic function, i.e. albumin secretion, urea secretion, and aspartate aminotransferase (AST) leakage. Markers of hepatic function were significantly decreased by addition of OPZ and DTIC even under conditions where the cell viability was largely unchanged. This experimental system sensitively detected CYP1A2-mediated metabolic toxicity. Therefore, the developed system should be helpful for evaluating the potential of compounds to cause DILI under conditions where inducers of CYP1A2 are present. Copyright © 2019 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Citation

Kenta Mizoi, Mayu Hosono, Hajime Kojima, Takuo Ogihara. Establishment of a primary human hepatocyte spheroid system for evaluating metabolic toxicity using dacarbazine under conditions of CYP1A2 induction. Drug metabolism and pharmacokinetics. 2020 Apr;35(2):201-206