Inhibition of topoisomerase II by phase II metabolites of resveratrol in human colon cancer cells
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim..
SCOPE: The cytotoxic and genotoxic potential of phase II metabolites of resveratrol (RSV) was investigated in human colon cells with special emphasis on human topoisomerase (TOP) II.
METHODS AND RESULTS: Cell-free screening of topoisomerase II (TOPII) inhibition by the decatenation assay showed inhibitory potential for RSV (≥200 μM) and for the first time for the three human phase II metabolites RSV-3-sulfate (≥200 μM), RSV-3-glucuronide (≥100 μM) and RSV-disulfate (≥100 μM). Conjugation at the C4'-position (RSV-4'-sulfate and RSV-4'-glucuronide) resulted in loss of the inhibitory potential in this assay. Cell-based experiments with RSV and the most abundant metabolite in humans, RSV-3-Sulf, revealed no TOP poisoning in HT29 and Caco-2 cells up to 250 μM. Further, the phase II metabolite exhibited only minor effects in the comet assay and showed negligible cytotoxic effects and apoptotic potential after 1 and 24 h incubation. Fluorescence microscopy and HPLC-DAD analysis identified cellular uptake of RSV and of RSV-3-Sulf although to a lesser extent when compared to RSV. Furthermore, within the cells fractional deconjugation of RSV-3-Sulf to the parent compound was observed.
CONCLUSION: Sulfate- and glucuronide-phase II metabolites might contribute to the genotoxic potential of RSV by inhibition of TOPII activity. By deconjugation at the target site RSV-3-Sulf might serve as a pool of the parent compound.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:59 |
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| Enthalten in: |
Molecular nutrition & food research - 59(2015), 12 vom: 03. Dez., Seite 2448-59 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schroeter, Anika [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 13.12.2016 Date Revised 02.12.2018 published: Print Citation Status MEDLINE |
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| doi: |
10.1002/mnfr.201500352 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM253571421 |
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| 100 | 1 | |a Schroeter, Anika |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of topoisomerase II by phase II metabolites of resveratrol in human colon cancer cells |
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| 500 | |a Date Completed 13.12.2016 | ||
| 500 | |a Date Revised 02.12.2018 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. | ||
| 520 | |a SCOPE: The cytotoxic and genotoxic potential of phase II metabolites of resveratrol (RSV) was investigated in human colon cells with special emphasis on human topoisomerase (TOP) II | ||
| 520 | |a METHODS AND RESULTS: Cell-free screening of topoisomerase II (TOPII) inhibition by the decatenation assay showed inhibitory potential for RSV (≥200 μM) and for the first time for the three human phase II metabolites RSV-3-sulfate (≥200 μM), RSV-3-glucuronide (≥100 μM) and RSV-disulfate (≥100 μM). Conjugation at the C4'-position (RSV-4'-sulfate and RSV-4'-glucuronide) resulted in loss of the inhibitory potential in this assay. Cell-based experiments with RSV and the most abundant metabolite in humans, RSV-3-Sulf, revealed no TOP poisoning in HT29 and Caco-2 cells up to 250 μM. Further, the phase II metabolite exhibited only minor effects in the comet assay and showed negligible cytotoxic effects and apoptotic potential after 1 and 24 h incubation. Fluorescence microscopy and HPLC-DAD analysis identified cellular uptake of RSV and of RSV-3-Sulf although to a lesser extent when compared to RSV. Furthermore, within the cells fractional deconjugation of RSV-3-Sulf to the parent compound was observed | ||
| 520 | |a CONCLUSION: Sulfate- and glucuronide-phase II metabolites might contribute to the genotoxic potential of RSV by inhibition of TOPII activity. By deconjugation at the target site RSV-3-Sulf might serve as a pool of the parent compound | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Colon cancer cells | |
| 650 | 4 | |a DNA damage | |
| 650 | 4 | |a Resveratrol | |
| 650 | 4 | |a Resveratrol metabolites | |
| 650 | 4 | |a Topoisomerase | |
| 650 | 7 | |a Glucuronides |2 NLM | |
| 650 | 7 | |a Stilbenes |2 NLM | |
| 650 | 7 | |a Topoisomerase II Inhibitors |2 NLM | |
| 650 | 7 | |a resveratrol-3-O-4'-disulfate |2 NLM | |
| 650 | 7 | |a resveratrol-4'-O-glucuronide |2 NLM | |
| 650 | 7 | |a Resveratrol |2 NLM | |
| 650 | 7 | |a Q369O8926L |2 NLM | |
| 700 | 1 | |a Groh, Isabel Anna Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Del Favero, Giorgia |e verfasserin |4 aut | |
| 700 | 1 | |a Pignitter, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Schueller, Katharina |e verfasserin |4 aut | |
| 700 | 1 | |a Somoza, Veronika |e verfasserin |4 aut | |
| 700 | 1 | |a Marko, Doris |e verfasserin |4 aut | |
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