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Cited by 4Drug-Induced Hepatotoxicity and ProtectionAnimal testing and alternativesPlant Toxicity and Pharmacological Properties

Hepa-ToxMOA: a pathway-screening method for evaluating cellular stress and hepatic metabolic-dependent toxicity of natural products

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Park, Se-Myo, Choi, Mi-Sun, Kim, Soojin, Jegal, Hyun, Han, Hyoung-Yun, Chun, Hyang Sook, Kim, Sang Kyum, Oh, Jung-Hwa·2024·Scientific Reports
DOI 10.1038/s41598-024-54634-4PMC PMC10881971
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Abstract

In the field of drug discovery, natural products have emerged as therapeutic agents for diseases such as cancer. However, their potential toxicity poses significant obstacles in the developing effective drug candidates. To overcome this limitation, we propose a pathway-screening method based on imaging analysis to evaluate cellular stress caused by natural products. We have established a cellular stress sensing system, named Hepa-ToxMOA, which utilizes HepG2 cells expressing green fluorescent protein (GFP) fluorescence under the control of transcription factor response elements (TREs) for transcription factors (AP1, P53, Nrf2, and NF-κB). Additionally, to augment the drug metabolic activity of the HepG2 cell line, we evaluated the cytotoxicity of 40 natural products with and without S9 fraction-based metabolic activity. Our finding revealed different activities of Hepa-ToxMOA depending on metabolic or non-metabolic activity, highlighting the involvement of specific cellular stress pathways. Our results suggest that developing a Hepa-ToxMOA system based on activity of drug metabolizing enzyme provides crucial insights into the molecular mechanisms initiating cellular stress during liver toxicity screening for natural products. The pathway-screening method addresses challenges related to the potential toxicity of natural products, advancing their translation into viable therapeutic agents.

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  • HepG2 is suitable for studying general mechanisms of cytotoxicity and cellular stress response but limited for quantitative prediction of metabolism and biotransformation of many compounds.

    “Recent reviews and experimental studies directly interpret HepG2 as a model suitable for solving certain toxicological problems, in particular for studying general mechanisms of cytotoxicity and cellular stress response (e.g., activation of transcription factors activator protein-1 (AP1), p53, nuclear factor-erythroid 2 related factor 2 (Nrf2), and nuclear factor kappa B (NF-κB)) [109,110,111],”

    From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [111]

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Authors
Park, S.-M., Choi, M.-S., Kim, S., Jegal, H., Han, H.-Y., Chun, H. S., Kim, S. K., & Oh, J.-H.
Affiliations
  • Chungnam National University (KR)
  • Korea Institute of Toxicology (KR)
Corresponding author
  • Kim, Sang Kyum
  • Oh, Jung-Hwa
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2024-02-21
Volume
14
Issue
1
Pages
4319-4319
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-024-54634-4
PMC
PMC10881971
OpenAlex
W4392091287
Cited by
4
References
45
Citations by year
2026: 3 · 2024: 1
FWCI
1.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministry of Food and Drug Safety (21162MFDS045)
  • Korea Institute of Toxicology (1711195881)
  • Ministry of Science and ICT, South Korea
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant Toxicity and Pharmacological Properties
Keywords
natural products, hepatotoxicity screening, cellular stress, HepG2 cells, AP-1, p53, Nrf2, NF-κB, S9 fraction, drug-metabolizing enzymes, cytotoxicity
MeSH terms
Gene Expression Regulation, Humans, NF-kappa B, Green Fluorescent Proteins, NF-E2-Related Factor 2, Hep G2 Cells

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