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Anthocyanidins modulate the activity of human DNA topoisomerases I and II and affect cellular DNA integrity.
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2005 (English)In: Chemical Research in Toxicology, ISSN 0893-228X, Vol. 18, no 9, 1395-404 p.Article in journal (Refereed) Published
Abstract [en]

In the present study, we investigated the effect of anthocyanidins on human topoisomerases I and II and its relevance for DNA integrity within human cells. Anthocyanidins bearing vicinal hydroxy groups at the B-ring (delphinidin, DEL; cyanidin, CY) were found to potently inhibit the catalytic activity of human topoisomerases I and II, without discriminating between the IIalpha and the IIbeta isoforms. However, in contrast to topoisomerase poisons, DEL and CY did not stabilize the covalent DNA-topoisomerase intermediates (cleavable complex) of topoisomerase I or II. Using recombinant topoisomerase I, the presence of CY or DEL (> or = 1 microM) effectively prohibited the stabilization of the cleavable complex by the topoisomerase I poison camptothecin. We furthermore investigated whether the potential protective effect vs topoisomerase I poisons is reflected also on the cellular level, affecting the DNA damaging properties of camptothecin. Indeed, in HT29 cells, low micromolar concentrations of DEL (1-10 microM) significantly diminished the DNA strand breaking effect of camptothecin (100 microM). However, at concentrations > or = 50 microM, all anthocyanidins tested (delphinidin, cyanidin, malvidin, pelargonidin, and paeonidin), including those not interfering with topoisomerases, were found to induce DNA strand breaks in the comet assay. All of these analogues were able to compete with ethidium bromide for the intercalation into calf thymus DNA and to replace the minor groove binder Hoechst 33258. These data indicate substantial affinity to double-stranded DNA, which might contribute at least to the DNA strand breaking effect of anthocyanidins at higher concentrations (> or = 50 microM).

Place, publisher, year, edition, pages
2005. Vol. 18, no 9, 1395-404 p.
URN: urn:nbn:se:umu:diva-30112DOI: 10.1021/tx050039nPubMedID: 16167831OAI: diva2:280019
Available from: 2009-12-08 Created: 2009-12-07 Last updated: 2009-12-08

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Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine)
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