The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
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
p53 modulation of the DNA damage response
Helton, E. S., & Chen, X. (2006) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21091 · Cited by 305
Funk, C., Ponelle, C., Scheuermann, G., & Pantze, M. P. (2001) · Molecular Pharmacology · doi:10.1124/mol.59.3.627 · Cited by 298
Stable Expression, Activity, and Inducibility of Cytochromes P450 in Differentiated HepaRG Cells
Anthérieu, S., Chesné, C., Li, R., Camus, S., Lahoz, A., Picazo, L., Turpeinen, M., Tolonen, A., Uusitalo, J., Guguen‐Guillouzo, C., et al. (2009) · Drug Metabolism and Disposition · doi:10.1124/dmd.109.030197 · Cited by 279
Gallagher, E. P., Kunze, K. L., Stapleton, P. L., & Eaton, D. L. (1996) · Toxicology and Applied Pharmacology · doi:10.1006/taap.1996.0326 · Cited by 268
Cellular interactions and metabolism of aflatoxin: An update
McLean, M., & Dutton, M. F. (1995) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(94)00054-7 · Cited by 260
Lübberstedt, M., Müller‐Vieira, U., Mayer, M., Biemel, K. M., Knöspel, F., Knobeloch, D., Nussler, A. K., Gerlach, J. C., & Zeilinger, K. (2010) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/j.vascn.2010.04.013 · Cited by 226
Westerink, W. M. A., & Schoonen, W. G. E. J. (2007) · Toxicology in Vitro · doi:10.1016/j.tiv.2007.06.017 · Cited by 226
HepaRG Cells as an in Vitro Model for Evaluation of Cytochrome P450 Induction in Humans
Kanebratt, K. P., & Andersson, T. B. (2007) · Drug Metabolism and Disposition · doi:10.1124/dmd.107.017418 · Cited by 224
Crewe, H. K., Ellis, S. W., Lennard, M. S., & Tucker, G. T. (1997) · Biochemical Pharmacology · doi:10.1016/s0006-2952(96)00650-8 · Cited by 223
Jossé, R., Aninat, C., Glaise, D., Dumont, J., Fessard, V., Morel, F., Poul, J., Guguen‐Guillouzo, C., & Guillouzo, A. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.107.019901 · Cited by 201
Chang, T. K. H., Yu, L., Maurel, P., & Waxman, D. J. (1997) · PubMed · Cited by 195
Exploratory toxicology as an integrated part of drug discovery. Part I: Why and how
Hornberg, J. J., Laursen, M., Brenden, N., Persson, M., Thougaard, A., Toft, D. B., & Mow, T. J. (2013) · Drug Discovery Today · doi:10.1016/j.drudis.2013.12.008 · Cited by 118
Functional expression, inhibition and induction of CYP enzymes in HepaRG cells
Turpeinen, M., Tolonen, A., Chesné, C., Guillouzo, A., Uusitalo, J., & Pelkonen, O. (2009) · Toxicology in Vitro · doi:10.1016/j.tiv.2009.03.008 · Cited by 117
Zanelli, U., Caradonna, N. P., Hallifax, D., Turlizzi, E., & Houston, J. B. (2011) · Drug Metabolism and Disposition · doi:10.1124/dmd.111.042309 · Cited by 76
Ogimura, E., Sekine, S., & Horie, T. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.11.032 · Cited by 71
Denissenko, M. F., Cahill, J. M., Koudriakova, T. B., Gerber, N., & Pfeifer, G. P. (1999) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(99)00038-x · Cited by 66
High content analysis assay for prediction of human hepatotoxicity in HepaRG and HepG2 cells
Saito, J., Okamura, A., Takeuchi, K., Hanioka, K., Okada, A., & Ohata, T. (2016) · Toxicology in Vitro · doi:10.1016/j.tiv.2016.02.019 · Cited by 62
Jetten, M. J., Kleinjans, J. C. S., Claessen, S. M. H., Chesné, C., & van Delft, J. H. M. (2013) · Toxicology in Vitro · doi:10.1016/j.tiv.2013.07.010 · Cited by 56
Kenneke, J. F., Mazur, C. S., Ritger, S. E., & Sack, T. J. (2008) · Chemical Research in Toxicology · doi:10.1021/tx800211t · Cited by 48
Multiparametric assay using HepaRG cells for predicting drug-induced liver injury
貴文, 富., Okamura, H., Satsukawa, M., Yokoi, T., & Konno, Y. (2015) · Toxicology Letters · doi:10.1016/j.toxlet.2015.04.014 · Cited by 38
Dalmadi, B., Leibinger, J., Szeberényi, S., Borbás, T., Farkas, S., Szombathelyi, Z., & Tihanyi, K. (2003) · Drug Metabolism and Disposition · doi:10.1124/dmd.31.5.631 · Cited by 38
Direct toxicity effects of sulfo-conjugated troglitazone on human hepatocytes
Saha, S., New, L. S., Ho, H. K., Chui, W. K., & Chan, E. C. Y. (2010) · Toxicology Letters · doi:10.1016/j.toxlet.2010.03.010 · Cited by 34
Activation of P53 in HepG2 cells as surrogate to detect mutagens and promutagens in vitro
Boehme, K., Dietz, Y., Hewitt, P. G., & Mueller, S. O. (2010) · Toxicology Letters · doi:10.1016/j.toxlet.2010.07.007 · Cited by 32
Gut, I., Danielová, V., Holubová, J., Souček, P., & Klučková, H. (2000) · Archives of Toxicology · doi:10.1007/s002040000141 · Cited by 32
In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes
Suzuki, H., Inoue, T., Matsushita, T., Kobayashi, K., Horii, I., Hirabayashi, Y., & Inoue, T. (2008) · Journal of Applied Toxicology · doi:10.1002/jat.1328 · Cited by 23
貴文, 富., Okamura, H., Yokoi, T., & Konno, Y. (2016) · Journal of Applied Toxicology · doi:10.1002/jat.3371 · Cited by 19
Ogasawara, A., Torimoto, N., Tsuda, N., Aohara, F., Ohashi, R., Yamada, Y., & Taniguchi, H. (2016) · Drug Metabolism Letters · doi:10.2174/1872312810666160822110011 · Cited by 4
Cited by
Sorted by citations
The Curious Case of the HepG2 Cell Line: 40 Years of Expertise
Arzumanian, V. A., Kiseleva, O. I., & Poverennaya, E. V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313135 · Cited by 387
Aflatoxin B1: metabolism, toxicology, and its involvement in oxidative stress and cancer development
Cao, W., Yu, P., Yang, K., & Cao, D. (2021) · Toxicology Mechanisms and Methods · doi:10.1080/15376516.2021.2021339 · Cited by 261
A lung/liver-on-a-chip platform for acute and chronic toxicity studies
Bovard, D., Sandoz, A., Luettich, K., Frentzel, S., Iskandar, A., Marescotti, D., Trivedi, K., Guedj, E., Dutertre, Q., Peitsch, M. C., et al. (2018) · Lab on a Chip · doi:10.1039/c8lc01029c · Cited by 195
A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products
Baltazar, M. T., Cable, S., Carmichael, P. L., Cubberley, R., Cull, T., Delagrange, M., Dent, M. P., Hatherell, S., Houghton, J., Kukić, P., et al. (2020) · Toxicological Sciences · doi:10.1093/toxsci/kfaa048 · Cited by 159
The role of apoptosis in acetaminophen hepatotoxicity
Jaeschke, H., Duan, L., Akakpo, J. Y., Farhood, A. I., & Ramachandran, A. (2018) · Food and Chemical Toxicology · doi:10.1016/j.fct.2018.06.025 · Cited by 135
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
