Fundamental Toxicological Sciences
Online ISSN : 2189-115X
ISSN-L : 2189-115X
Original Article
Utility of human hepatocyte spheroids for evaluation of hepatotoxicity
Takuo OgiharaHisakazu IwaiYukiko InoueJun KatagiNorihito MatsumotoMakiko Motoi-OhtsujiMotoharu KakikiShinya KanedaTakuya NagaoKumiko KusumotoEmiko OzekiTomoko JomuraSho TanakaTadayoshi UedaKunihiro OhtaTakako OhkuraHiroshi ArakawaDaichi Nagai
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2015 Volume 2 Issue 1 Pages 41-48

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Abstract

Drug-induced hepatotoxicity is a common reason for discontinuing the development of candidate clinical drugs. In the present study, we investigated the utility of three-dimensionally cultured human hepatocytes (spheroids) for prediction of hepatotoxicity, using a panel of model drugs: acetaminophen, benzbromarone, chlorpromazine, cyclosporin A, diclofenac, fialuridine, flutamide, imipramine, isoniazid, ticlopidine and troglitazone. Cultured spheroids showed a significant increase of albumin secretion from 2 to 7 days; the secretion started to decrease at 14 days, but continued from 14 days to 21 days. The morphology of the spheroids was well maintained for 21 days. Long-term exposure of spheroids to hepatotoxic drugs resulted in concentration-dependent depression of albumin secretion and elevation of aspartate aminotransferase (AST) leakage. The estimated 50% effective concentration (IC 50 ) values for decrease of albumin secretion changed from 7 days to 14 days, but similar values were obtained at 14 and 21 days, except for diclofenac. Since the IC50 values and the values of drug concentration inducing 1.2-fold elevation of AST leakage (F1.2) were similar at 14 and 21 days, an incubation period of 14 days was considered sufficient. The coefficient of determination (R2) between IC50 values and F1.2 values of all drugs was 0.335. When cyclosporine A and fialuridine were excluded, the value of R2 became 0.887. The results indicate that the proposed human hepatocyte spheroid assay should be helpful in the evaluation of hepatotoxicity during the early development stage of clinical drug candidates.

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© 2015 The Japanese Society of Toxicology
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