Cited by 160Drug-Induced Hepatotoxicity and ProtectionPharmacogenetics and Drug MetabolismAnimal testing and alternatives

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Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures

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Yokoyama, Yuichi, Sasaki, Yoshifumi, Terasaki, Natsuko, Kawataki, Taku, Takekawa, Koji, Iwase, Yumiko, Shimizu, Toshinobu, Sanoh, Seigo, Ohta, Shigeru·2018·Biological and Pharmaceutical Bulletin

DOI 10.1248/bpb.b17-00913

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Abstract

Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells. Enzyme activities in differentiated HepaRG cells were comparable to those in human hepatocytes and much higher than those in HepG2 cells, except for SULT activity. Second, we examined the cytotoxicity of hepatotoxic compounds, acetaminophen (APAP), aflatoxin B1 (AFB1), cyclophosphamide (CPA), tamoxifen (TAM), and troglitazone (TGZ) in HepaRG cells and human hepatocytes. AFB1- and CPA-induced cytotoxicities against HepaRG cells were comparable to those against human hepatocytes. Furthermore, the cytotoxicities of these compounds were inhibited by 1-aminobenzotriazole (ABT), a broad CYP inhibitor, in both cells and were likely mediated by metabolic activation by CYP. Finally, toxicogenomics analysis of HepG2 and HepaRG cells after exposure to AFB1 and CPA revealed that numerous p53-related genes were upregulated- and the expression of these genes was greater in HepaRG than in HepG2 cells. These results suggest that gene expression profiles of HepaRG cells were affected more considerably by the toxic mechanisms of AFB1 and CPA than the profiles of HepG2 cells were. Therefore, our investigation shows that HepaRG cells could be useful human hepatic cellular models for toxicity studies.

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Authors: Yokoyama, Y., Sasaki, Y., Terasaki, N., Kawataki, T., Takekawa, K., Iwase, Y., Shimizu, T., Sanoh, S., & Ohta, S.
Affiliations: Hiroshima University (JP)
Tanabe Pharma Corporation (Japan) (JP)
ORCID: Yokoyama, Yuichi
Sanoh, Seigo
Venue: Biological and Pharmaceutical Bulletin
Publisher: Pharmaceutical Society of Japan
Published: 2018-05-01
Volume: 41
Issue: 5
Pages: 722-732
ISSN: 0918-6158 (ISSN-L)
1347-5215
DOI: 10.1248/bpb.b17-00913
OpenAlex: W2788132769
Cited by: 160
References: 37
Citations by year: 2026: 12 · 2025: 19 · 2024: 23 · 2023: 16 · 2022: 17 · 2021: 23 · 2020: 37 · 2019: 8 · 2018: 5
FWCI: 20.08
Type: journal article
Language: en
Open access: diamond
doi.org
Locations: Biological and Pharmaceutical Bulletin (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Keywords: HepaRG cells, cryopreserved human hepatocytes, HepG2 cells, drug metabolism, hepatotoxicity, drug-metabolizing enzymes, CYP enzymes, UGT, sulfotransferase, aflatoxin B1, cyclophosphamide, paracetamol, tamoxifen, troglitazone, 1-aminobenzotriazole, cytochrome P450 inhibition, cytotoxicity, toxicogenomics, in vitro toxicity testing
MeSH terms: Cell Line, Cells, Cultured, Cytochrome P-450 Enzyme System, Drug Evaluation, Preclinical, Pharmaceutical Preparations, Humans, Glucuronosyltransferase, Sulfotransferases, Tumor Suppressor Protein p53, Toxicity Tests, Gene Expression Profiling, Hepatocytes, Hep G2 Cells, Drug-Related Side Effects and Adverse Reactions

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Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures

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