Similarities and differences in the expression of drug-metabolizing enzymes between human hepatic cell lines and primary human hepatocytes
Open accessAbstract
In addition to primary human hepatocytes, hepatoma cell lines, and transfected nonhepatoma, hepatic cell lines have been used for pharmacological and toxicological studies. However, a systematic evaluation and a general report of the gene expression spectra of drug-metabolizing enzymes and transporters (DMETs) in these in vitro systems are not currently available. To fill this information gap and to provide references for future studies, we systematically characterized the basal gene expression profiles of 251 drug-metabolizing enzymes in untreated primary human hepatocytes from six donors, four commonly used hepatoma cell lines (HepG2, Huh7, SK-Hep-1, and Hep3B), and one transfected human liver epithelial cell line. A large variation in DMET expression spectra was observed between hepatic cell lines and primary hepatocytes, with the complete absence or much lower abundance of certain DMETs in hepatic cell lines. Furthermore, the basal DMET expression spectra of five hepatic cell lines are summarized, providing references for researchers to choose carefully appropriate in vitro models for their studies of drug metabolism and toxicity, especially for studies with drugs in which toxicities are mediated through the formation of reactive metabolites.
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HepG2 has sharply reduced expression of Phase I CYP450 enzymes compared to primary human hepatocytes, with mRNA levels of key isoforms hundreds of times lower.
“HepG2 is characterized by a sharply reduced expression of Phase I biotransformation enzymes— CYP450 —compared to primary human hepatocytes [102,103,104,105].”
From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [105]
The Results section reports that HepG2 expresses fewer phase I genes than pooled primary hepatocytes and that several critical CYP isoforms are undetectable in HepG2. This supports the reduced-expression statement in the printed citing sentence. The source does not establish the claim’s added figure that mRNA levels of key isoforms are hundreds of times lower; it reports CYP2D6 at less than 5% of the primary-hepatocyte level, without that specific fold difference. (LLM, conf=0.86)
Experimental — accuracy not yet measuredInterindividual differences in the expression of drug metabolizing enzymes affect drug clearance and toxicity.
“there are interindividual differences in the expression of drug metabolizing enzymes, affecting drug clearance and toxicity (Guo et al., 2011)”
From Mitochondrial Dysfunction Induced by Sertraline, an Antidepressant Agent (2012) · cites this paper as Guo et al., 2011
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Cites
Mapping the Genetic Architecture of Gene Expression in Human Liver
Schadt, E. E., Molony, C. M., Chudin, E., Hao, K., Yang, X., Lum, P. Y., Kasarskis, A., Zhang, B., Wang, S. S.-M., Suver, C., et al. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060107 · Cited by 909 · see citing works
Polymorphism of human cytochrome P450 enzymes and its clinical impact
Zhou, S., Liu, J., & Chowbay, B. (2009) · Drug Metabolism Reviews · doi:10.1080/03602530902843483 · Cited by 832 · see citing works
Self-citationWilkening, S., Stahl, F., & Bader, A. (2003) · Drug Metabolism and Disposition · doi:10.1124/dmd.31.8.1035 · Cited by 794 · see citing works
Ando, Y., Saka, H., Ando, M., Sawa, T., Muro, K., Ueoka, H., Yokoyama, A., Saitoh, S., Shimokata, K., & Hasegawa, Y. (2000) · PubMed · Cited by 783 · see citing works
Hewitt, N. J., Gómez Lechón, M. J., Houston, J. B., Hallifax, D., Brown, H. S., Maurel, P., Kenna, J. G., Gustavsson, L., Lohmann, C., Skonberg, C., et al. (2007) · Drug Metabolism Reviews · doi:10.1080/03602530601093489 · Cited by 735 · see citing works
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 · see citing works
An update on in vitro test methods in human hepatic drug biotransformation research: pros and cons
Brandon, E. F. A., Raap, C. D., Meijerman, I., Beijnen, J. H., & Schellens, J. H. M. (2003) · Toxicology and Applied Pharmacology · doi:10.1016/s0041-008x(03)00128-5 · Cited by 569 · see citing works
Westerink, W. M. A., & Schoonen, W. G. E. J. (2007) · Toxicology in Vitro · doi:10.1016/j.tiv.2007.05.014 · Cited by 544 · see citing works
Revealing the architecture of gene regulation: the promise of eQTL studies
Gilad, Y., Rifkin, S. A., & Pritchard, J. K. (2008) · Trends in Genetics · doi:10.1016/j.tig.2008.06.001 · Cited by 531 · see citing works
Liver‐enriched transcription factors and hepatocyte differentiation
Cereghini, S. (1996) · The FASEB Journal · doi:10.1096/fasebj.10.2.8641560 · Cited by 505 · see citing works
LeCluyse, E. L. (2001) · European Journal of Pharmaceutical Sciences · doi:10.1016/s0928-0987(01)00135-x · Cited by 477 · see citing works
Transcription Factors in Liver Development, Differentiation, and Regeneration
Costa, R. H., Kalinichenko, V. V., Holterman, A. L., & Wang, X. (2003) · Hepatology · doi:10.1016/j.hep.2003.09.034 · Cited by 410 · see citing works
Huang, S. M., Strong, J. M., Zhang, L., Reynolds, K. S., Nallani, S. C., Temple, R., Abraham, S., Al-Habet, S. M. H., Baweja, R. K., Burckart, G. J., et al. (2008) · The Journal of Clinical Pharmacology · doi:10.1177/0091270007312153 · Cited by 396 · see citing works
Knasmüller, S., Mersch‐Sundermann, V., Kevekordes, S., Darroudi, F., Huber, W. W., Hoelzl, C., Bichler, J., & Majer, B. J. (2004) · Toxicology · doi:10.1016/j.tox.2004.02.008 · Cited by 359 · see citing works
Hart, S. N., Li, Y., Nakamoto, K., Subileau, E.-A., Steen, D., & Zhong, X.-B. (2010) · Drug Metabolism and Disposition · doi:10.1124/dmd.109.031831 · Cited by 297 · see citing works
Cell Lines: A Tool for In Vitro Drug Metabolism Studies
Gómez‐Lechón, M. J., Donato, M. T., Lahoz, A., & Castell, J. V. (2008) · Current Drug Metabolism · doi:10.2174/138920008783331086 · Cited by 297 · see citing works
Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liverPreprint
Yang, X., Zhang, B., Molony, C. M., Chudin, E., Hao, K., Zhu, J., Gaedigk, A., Suver, C., Zhong, H., Leeder, J. S., et al. (2010) · Genome Research · doi:10.1101/gr.103341.109 · Cited by 271 · see citing works
Human hepatocytes as a tool for studying toxicity and drug metabolism
Gomez-Lechon, M., Donato, M., Castell, J., & Jover, R. (2003) · Current Drug Metabolism · doi:10.2174/1389200033489424 · Cited by 242 · see citing works
Pfeifer, A. M. A., Cole, K. E., Smoot, D. T., Weston, A., Groopman, J. D., Shields, P. G., Vignaud, J.-M., Juillerat, M., Lipsky, M. M., & Trump, B. F. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.11.5123 · Cited by 240 · see citing works
Jennen, D. G. J., Magkoufopoulou, C., Ketelslegers, H. B., van Herwijnen, M. H. M., Kleinjans, J. C. S., & van Delft, J. H. M. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq026 · Cited by 220 · see citing works
Clinical Pharmacogenetics and Potential Application in Personalized Medicine
Zhou, S., Di, Y. M., Chan, E., Du, Y., Chow, V., Xue, C. C., Lai, X., Wang, J., Li, C. G., Tian, M., et al. (2008) · Current Drug Metabolism · doi:10.2174/138920008786049302 · Cited by 211 · see citing works
The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance.
Hirth, J. A., Watkins, P. B., Strawderman, M. S., Schott, A. F., Bruno, R., & Baker, L. H. (2000) · PubMed · Cited by 201 · see citing works
Dykens, J. A., Jamieson, J. D., Marroquin, L. D., Nadanaciva, S., Xu, J. J., Dunn, M. C., Smith, A. R., & Will, Y. (2008) · Toxicological Sciences · doi:10.1093/toxsci/kfn056 · Cited by 195 · see citing works
Hewitt, N. J., LeCluyse, E. L., & Ferguson, S. (2007) · Xenobiotica · doi:10.1080/00498250701534893 · Cited by 178 · see citing works
[42] Use of human hepatocytes to study P450 gene induction
Strom, S. C., Pisarov, L. A., Dorko, K., Thompson, M. T., Schuetz, J. D., & Schuetz, E. G. (1996) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(96)72044-x · Cited by 174 · see citing works
The pivotal role of hepatocytes in drug discovery
Soars, M. G., McGinnity, D. F., Grime, K., & Riley, R. J. (2006) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2006.11.002 · Cited by 172 · see citing works
Cytochrome P-450 mRNA Expression in Human Liver and Its Relationship with Enzyme Activity
Rodríguez‐Antona, C., Donato, M. T., Pareja, E., Gómez‐Lechón, M. J., & Castell, J. V. (2001) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2001.2499 · Cited by 145 · see citing works
Genetic basis of drug metabolism
Ma, M. K., Woo, M. H., & McLeod, H. L. (2002) · American Journal of Health-System Pharmacy · doi:10.1093/ajhp/59.21.2061 · Cited by 140 · see citing works
Goyak, K. O., Page, J. L., Johnson, M. C., Zarbl, H., Strom, S. C., & Omiecinski, C. J. (2007) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2007.03.032 · Cited by 136 · see citing works
Re‐expression of C/EBPα induces CYP2B6, CYP2C9 and CYP2D6 genes in HepG2 cells
Jover, R., Bort, R., Gómez‐Lechón, M. J., & Castell, J. V. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)00746-7 · Cited by 128 · see citing works
Cytogenetic markers of susceptibility: influence of polymorphic carcinogen-metabolizing enzymes.
Norppa, H. (1997) · Environmental Health Perspectives · doi:10.1289/ehp.97105s4829 · Cited by 97 · see citing works
Synthesis and evaluation of functionalized isoindigos as antiproliferative agents
Wee, X. K., Yeo, W. K., Zhang, B., et al. (2009) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2009.09.008 · Cited by 88 · see citing works
Doostdar, H., Duthie, S. J., Burke, M. D., et al. (1988) · FEBS Letters · doi:10.1016/0014-5793(88)81021-4 · Cited by 86 · see citing works
Epoxyeicosatrienoic Acids and/or Their Metabolites Promote Hypoxic Response of Cells
Suzuki, S., Oguro, A., Osada‐Oka, M., Funae, Y., & Imaoka, S. (2008) · Journal of Pharmacological Sciences · doi:10.1254/jphs.08122fp · Cited by 47 · see citing works
In Vitro Cytochrome P450 Inhibition and Induction
Walsky, R. L., & Boldt, S. E. (2008) · Current Drug Metabolism · doi:10.2174/138920008786485128 · Cited by 44 · see citing works
Rudzok, S., Schlink, U., Herbarth, O., et al. (2010) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2010.01.012 · Cited by 37 · see citing works
Henzel, K., Thorborg, C., Hofmann, M. W., Zimmer, G., & Leuschner, U. (2003) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2003.10.017 · Cited by 34 · see citing works
Quantitative Gene Expression Profiles of Human Liver-Derived Cell Lines Exposed to Moderate Hypoxia
Fink, T., Ebbesen, P., & Zachar, V. (2001) · Cellular Physiology and Biochemistry · doi:10.1159/000047798 · Cited by 27 · see citing works
Shiizaki, K., Ohsako, S., Koyama, T., Nagata, R., Yonemoto, J., & Tohyama, C. (2005) · Toxicology Letters · doi:10.1016/j.toxlet.2005.06.003 · Cited by 14 · see citing works
Chao, H., Tsou, T., Chen, H., et al. (2009) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2009.04.090 · Cited by 11 · see citing works
Cytogenetic Markers of Susceptibility: Influence of Polymorphic Carcinogen-Metabolizing Enzymes
Norppa, H. (1997) · Environmental Health Perspectives · doi:10.2307/3433290 · Cited by 11 · see citing works
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Gómez-Lechón, M. J., Tolosa, L., Conde, I., & Donato, M. T. (2014) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2014.967680 · Cited by 199 · see citing works
Yokoyama, Y., Sasaki, Y., Terasaki, N., Kawataki, T., Takekawa, K., Iwase, Y., Shimizu, T., Sanoh, S., & Ohta, S. (2018) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b17-00913 · Cited by 160 · see citing works
Heslop, J. A., Rowe, C., Walsh, J., Sison-Young, R., Jenkins, R., Kamalian, L., Kia, R., Hay, D., Jones, R. P., Malik, H. Z., et al. (2017) · Archives of Toxicology · doi:10.1007/s00204-016-1694-y · Cited by 141 · see citing works
Mitochondrial Dysfunction Induced by Sertraline, an Antidepressant Agent
Li, Y., Couch, L., Higuchi, M., Fang, J.-L., & Guo, L. (2012) · Toxicological Sciences · doi:10.1093/toxsci/kfs100 · Cited by 120 · see citing works
Self-citationMicroengineered Liver Tissues for Drug Testing
Khetani, S. R., Berger, D. R., Ballinger, K. R., Davidson, M. D., Lin, C., & Ware, B. R. (2015) · SLAS Technology · doi:10.1177/2211068214566939 · Cited by 116 · see citing works
Human Organoids for Predictive Toxicology Research and Drug Development
Matsui, T., & Shinozawa, T. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.767621 · Cited by 109 · see citing works
In Vitro Three‐Dimensional Liver Models for Nanomaterial DNA Damage Assessment
Llewellyn, S. V., Niemeijer, M., Nymark, P., Moné, M. J., van de Water, B., Conway, G. E., Jenkins, G. J. S., & Doak, S. H. (2021) · Small · doi:10.1002/smll.202006055 · Cited by 41 · see citing works
Chen, S., Wu, Q., Li, X., Li, D., Mei, N., Ning, B., Puig, M., Ren, Z., Tolleson, W. H., & Guo, L. (2021) · Journal of Environmental Science and Health, Part C · doi:10.1080/26896583.2021.1880242 · Cited by 44 · see citing works
Self-citationMechanisms of tolvaptan-induced toxicity in HepG2 cells
Wu, Y., Beland, F. A., Chen, S., Liu, F., Guo, L., & Fang, J.-L. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.03.015 · Cited by 41 · see citing works
Self-citationMicrofluidic Liver-on-a-Chip for Preclinical Drug Discovery
Fu, J., Qiu, H., & Tan, C. S. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15041300 · Cited by 42 · see citing works
The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease
Kotlyarova, A., Iskrina, A., & Kotlyarov, S. (2026) · International journal of molecular sciences · doi:10.3390/ijms27083399 · Cited by 5 · see citing works
- Authors
- Guo, L., Dial, S., Shi, L., Branham, W., Liu, J., Fang, J.-L., Green, B., Deng, H., Kaput, J., & Ning, B.
- Affiliations
- National Center for Toxicological Research (US)
- United States Department of Health and Human Services (US)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 39
- Issue
- 3
- Pages
- 528-538
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC3061558
- OpenAlex
- W2097746233
- Cited by
- 348
- References
- 41
- Citations by year
- 2026: 19 · 2025: 28 · 2024: 18 · 2023: 28 · 2022: 31 · 2021: 28 · 2020: 31 · 2019: 19 · 2018: 22 · 2017: 26 · 2016: 25 · 2015: 27 · 2014: 17 · 2013: 10 · 2012: 12
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (#N01‐DK‐7–0004/HHSN267200700004C, HHSN267200700004C)
- U.S. Food and Drug Administration
- National Institute of Diabetes and Digestive and Kidney Diseases (N01-DK-70004)
- U.S. National Library of Medicine (HHSN267200700004C, HHSN267200700004G)
- Office of Women's Health
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- drug-metabolizing enzymes, primary human hepatocytes, hepatoma cell lines, HepG2 cells, Huh7 cells, Hep3B cells, gene expression profiles, reactive metabolites, hepatotoxicity
- MeSH terms
- Algorithms, Biological Transport, Cell Line, Cells, Cultured, Drug Evaluation, Preclinical, Humans, Inactivation, Metabolic, Pharmacokinetics, RNA, Messenger, Gene Expression Regulation, Enzymologic, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Hepatocytes, Membrane Transport Proteins, Cell Line, Tumor
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