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Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures
Open accessAbstract
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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“Primary (cryopreserved) human hepatocytes (PHHs) are the best in vitro hepatocyte models in current drug discovery research.7,8)”
From Cryopreservation of Hepatocyte Organoid-Derived Cells Generated from Human iPS Cells (2025) · cites this paper as [8]
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Cites
Can the pharmaceutical industry reduce attrition rates?
Kola, I., & Landis, J. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1470 · Cited by 4,167
Infection of a human hepatoma cell line by hepatitis B virus
Gripon, P., Rumin, S., Urban, S., Seyec, J. L., Glaise, D., Cannie, I., Guyomard, C., Lucas, J., TREPO, C. G., & Guguen‐Guillouzo, C. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.232137699 · Cited by 1,288
Guillouzo, A., Corlu, A., Aninat, C., Glaise, D., Morel, F., & Guguen‐Guillouzo, C. (2006) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2006.12.003 · Cited by 714
Aninat, C., Piton, A., Glaise, D., Charpentier, T. L., Langouët, S., Morel, F., Guguen‐Guillouzo, C., & Guillouzo, A. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.006759 · Cited by 708
Gerets, H. H. J., Tilmant, K., Gerin, B., Chanteux, H., Depelchin, B. O., Dhalluin, S., & Atienzar, F. A. (2012) · Cell Biology and Toxicology · doi:10.1007/s10565-011-9208-4 · Cited by 698
Westerink, W. M. A., & Schoonen, W. G. E. J. (2007) · Toxicology in Vitro · doi:10.1016/j.tiv.2007.05.014 · Cited by 544
Mechanisms of Drug Toxicity and Relevance to Pharmaceutical Development
Guengerich, F. P. (2010) · Drug Metabolism and Pharmacokinetics · doi:10.2133/dmpk.dmpk-10-rv-062 · Cited by 397
Evaluation of HepaRG Cells as an in Vitro Model for Human Drug Metabolism Studies
Kanebratt, K. P., & Andersson, T. B. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.107.020016 · Cited by 355
Guo, L., Dial, S., Shi, L., Branham, W., Liu, J., Fang, J.-L., Green, B., Deng, H., Kaput, J., & Ning, B. (2011) · Drug Metabolism and Disposition · doi:10.1124/dmd.110.035873 · Cited by 348
Roy, P., Yu, L. J., Crespi, C. L., & Waxman, D. J. (1999) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(24)15302-0 · Cited by 321
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Metadata
- 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)
- 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
- 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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