Low Concentrations of Flavonoids Are Protective in Rat H4IIE Cells Whereas High Concentrations Cause DNA Damage and Apoptosis,
Open accessAbstract
Dietary flavonoids possess a wide spectrum of biochemical and pharmacological actions and are assumed to protect human health. These actions, however, can be antagonistic, and some health claims are mutually exclusive. The antiapoptotic actions of flavonoids may protect against neurodegenerative diseases, whereas their proapoptotic actions could be used for cancer chemotherapy. This study was undertaken to determine whether a cytoprotective dose range of flavonoids could be differentiated from a cytotoxic dose range. Seven structurally related flavonoids were tested for their ability to protect H4IIE rat hepatoma cells against H(2)O(2)-induced damage on the one hand and to induce cellular damage on their own on the other hand. All flavonoids proved to be good antioxidants in a cell-free assay. However, their pharmacologic activity did not correlate with in vitro antioxidant potential but rather with cellular uptake. For quercetin and fisetin, which were readily taken up into the cells, protective effects against H(2)O(2)-induced cytotoxicity, DNA strand breaks, and apoptosis were detected at concentrations as low as 10-25 micromol/L. On the other hand, these flavonoids induced cytotoxicity, DNA strand breaks, oligonucleosomal DNA fragmentation, and caspase activation at concentrations between 50 and 250 micromol/L. Published data on quercetin pharmacokinetics in humans suggest that a dietary supplement of 1-2 g of quercetin may result in plasma concentrations between 10 and 50 micromol/L. Our data suggest that cytoprotective concentrations of some flavonoids are lower by a factor of 5-10 than their DNA-damaging and proapoptotic concentrations.
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High doses of some antioxidants, such as quercetin and flavonoids, reduce cell survival.
“Studies have also suggested that high doses of some antioxidants, such as quercetin and flavonoids, reduce cell survival35,37,38.”
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- Authors
- Wätjen, W., Michels, G., Steffan, B., Niering, P., Chovolou, Y., Kampkötter, A., Tran-Thi, Q.-H., Proksch, P., & Kahl, R.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Wätjen, Wim
- Venue
- The Journal of Nutrition
- Publisher
- Elsevier BV
- Published
- 2005-03
- Volume
- 135
- Issue
- 3
- Pages
- 525-531
- ISSN
- 0022-3166 (ISSN-L)
- OpenAlex
- W1912855510
- Cited by
- 240
- References
- 49
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 7 · 2023: 6 · 2022: 14 · 2021: 12 · 2020: 9 · 2019: 14 · 2018: 8 · 2017: 17 · 2016: 18 · 2015: 8 · 2014: 26 · 2013: 10 · 2012: 15
- FWCI
- 5.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- flavonoids, quercetin, fisetin, H4IIE cells, hydrogen peroxide-induced cytotoxicity, DNA strand breaks, apoptosis, caspase activation, oligonucleosomal DNA fragmentation, cellular uptake, antioxidant activity, dose-dependent effects, cytoprotection, hepatoprotection, dietary flavonoids
- MeSH terms
- Animals, Cell Line, Cell-Free System, DNA Damage, Flavonoids, Carcinoma, Hepatocellular, Hydrogen Peroxide, Kinetics, Liver Neoplasms, Apoptosis, Cell Line, Tumor, Rats
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