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Cited by 16Drug-Induced Hepatotoxicity and ProtectionPharmacogenetics and Drug MetabolismEpigenetics and DNA Methylation

Zebularine upregulates expression of CYP genes through inhibition of DNMT1 and PKR in HepG2 cells

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Nakamura, Kazuaki, Aizawa, Kazuko, Aung, Kyaw Htet, Yamauchi, Junji, Tanoue, Akito·2017·Scientific Reports
DOI 10.1038/srep41093PMC PMC5253741
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Abstract

Drug-induced hepatotoxicity is one of the major reasons cited for drug withdrawal. Therefore, it is of extreme importance to detect human hepatotoxic candidates as early as possible during the drug development process. In this study, we aimed to enhance hepatocyte functions such as CYP gene expression in HepG2 cells, one of the most extensively used cell lines in evaluating hepatotoxicity of chemicals and drugs. We found that zebularine, a potent inhibitor of DNA methylation, remarkably upregulates the expression of CYP genes in HepG2 cells. In addition, we revealed that the upregulation of CYP gene expression by zebularine was mediated through the inhibition of both DNA methyltransferase 1 (DNMT1) and double-stranded RNA-dependent protein kinase (PKR). Furthermore, HepG2 cells treated with zebularine were more sensitive than control cells to drug toxicity. Taken together, our results show that zebularine may make HepG2 cells high-functioning and thus could be useful for evaluating the hepatotoxicity of chemicals and drugs speedily and accurately in in-vitro systems. The finding that zebularine upregulates CYP gene expression through DNMT1 and PKR modulation sheds light on the mechanisms controlling hepatocyte function and thus may aid in the development of new in-vitro systems using high-functioning hepatocytes.

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  • Inhibition of DNA methyltransferase 1 (DNMT1)/double-stranded RNA-dependent protein kinase (PKR) using zebularine can significantly induce a number of CYP450 enzymes (including CYP1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4) in HepG2 cells, accompanied by increased sensitivity to drug toxicity mediated by CYP450-dependent biotransformation.

    “Similarly, inhibition of DNA methyltransferase 1 (DNMT1)/double-stranded RNA-dependent protein kinase (PKR) using zebularine can significantly induce a number of CYP450 enzymes (including CYP1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4) in HepG2 cells, accompanied by increased sensitivity to drug toxicity mediated by CYP450-dependent biotransformation [166].”

    From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [166]

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Authors
Nakamura, K., Aizawa, K., Aung, K. H., Yamauchi, J., & Tanoue, A.
Affiliations
National Research Institute for Child Health and Development (JP)
Corresponding author
Nakamura, Kazuaki
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-01-23
Volume
7
Issue
1
Pages
41093-41093
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep41093
PMC
PMC5253741
OpenAlex
W2582622454
Cited by
16
References
40
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2019: 3 · 2018: 3
FWCI
1.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Center for Child Health and Development
  • Japan Agency for Medical Research and Development
  • Japan Society for the Promotion of Science (25460088)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
zebularine, CYP gene expression, DNMT1, PKR, HepG2 cells, drug-induced liver injury, DNA methylation inhibition, cytochrome P450, hepatocyte function
MeSH terms
DNA (Cytosine-5-)-Methyltransferase 1, Cytidine, Humans, Gene Expression Regulation, Neoplastic, Apoptosis, DNA Methylation, eIF-2 Kinase, Cyclophilins, Hepatocytes, Hep G2 Cells

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