Biological and Pharmaceutical Bulletin, volume 41, issue 5, pages 722-732
Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures
YOKOYAMA Yuichi
1, 2
,
Sasaki Yoshifumi
1
,
Terasaki Natsuko
1
,
Kawataki Taku
1
,
Takekawa Koji
1
,
Iwase Yumiko
1
,
Shimizu Toshinobu
1
,
Sanoh Seigo
2
,
Ohta Shigeru
2
1
Safety Research Laboratories, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation
|
2
Graduate School of Biomedical and Health Sciences, Hiroshima University
|
Publication type: Journal Article
Publication date: 2018-02-13
Quartile SCImago
Q2
Quartile WOS
Q4
Impact factor: 2
ISSN: 09186158, 13475215
General Medicine
Pharmacology
Pharmaceutical Science
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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YOKOYAMA Y. et al. Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures // Biological and Pharmaceutical Bulletin. 2018. Vol. 41. No. 5. pp. 722-732.
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YOKOYAMA Y., Sasaki Y., Terasaki N., Kawataki T., Takekawa K., Iwase Y., Shimizu T., Sanoh S., Ohta S. Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures // Biological and Pharmaceutical Bulletin. 2018. Vol. 41. No. 5. pp. 722-732.
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TY - JOUR
DO - 10.1248/bpb.b17-00913
UR - https://doi.org/10.1248%2Fbpb.b17-00913
TI - Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures
T2 - Biological and Pharmaceutical Bulletin
AU - YOKOYAMA, Yuichi
AU - Sasaki, Yoshifumi
AU - Terasaki, Natsuko
AU - Kawataki, Taku
AU - Takekawa, Koji
AU - Iwase, Yumiko
AU - Shimizu, Toshinobu
AU - Sanoh, Seigo
AU - Ohta, Shigeru
PY - 2018
DA - 2018/02/13 00:00:00
PB - Pharmaceutical Society of Japan
SP - 722-732
IS - 5
VL - 41
SN - 0918-6158
SN - 1347-5215
ER -
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@article{2018_YOKOYAMA
author = {Yuichi YOKOYAMA and Yoshifumi Sasaki and Natsuko Terasaki and Taku Kawataki and Koji Takekawa and Yumiko Iwase and Toshinobu Shimizu and Seigo Sanoh and Shigeru Ohta},
title = {Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures},
journal = {Biological and Pharmaceutical Bulletin},
year = {2018},
volume = {41},
publisher = {Pharmaceutical Society of Japan},
month = {feb},
url = {https://doi.org/10.1248%2Fbpb.b17-00913},
number = {5},
pages = {722--732},
doi = {10.1248/bpb.b17-00913}
}
Cite this
MLA
Copy
YOKOYAMA, Yuichi, et al. “Comparison of Drug Metabolism and Its Related Hepatotoxic Effects in HepaRG, Cryopreserved Human Hepatocytes, and HepG2 Cell Cultures.” Biological and Pharmaceutical Bulletin, vol. 41, no. 5, Feb. 2018, pp. 722-732. https://doi.org/10.1248%2Fbpb.b17-00913.