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Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells.

Zhang Z, Chen S, Mei H, Xuan J, Guo X, Couch L, Dobrovolsky VN, Guo L, Mei N - Sci Rep (2015)

Bottom Line: In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined.In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II.Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.

ABSTRACT
Ginkgo biloba leaf extract has been shown to increase the incidence in liver tumors in mice in a 2-year bioassay conducted by the National Toxicology Program. In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined. A molecular docking study revealed that quercetin, a flavonoid constituent of Ginkgo biloba, showed a higher potential to interact with topoisomerase II (Topo II) than did the other Ginkgo biloba constituents; this in silico prediction was confirmed by using a biochemical assay to study Topo II enzyme inhibition. Moreover, as measured by the Comet assay and the induction of γ-H2A.X, quercetin, followed by keampferol and isorhamnetin, appeared to be the most potent DNA damage inducer in HepG2 cells. In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II. DNA damage was also observed when cells were treated with commercially available Ginkgo biloba extract product. Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition.

No MeSH data available.


Related in: MedlinePlus

DNA damage induced by three constituents of Ginkgo biloba extract in HepG2 cells.HepG2 cells were exposed to seven constituents (50 μM) of Ginkgo biloba extract (A) or increased concentrations (6.25–100 μM) of quercetin, kaempferol, or isorhamnetin (B) for 4 h. The data points represent the means ± S.D. for three independent experiments, and asterisk indicates p < 0.05 when the treatment group was compared with the concurrent control.
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f5: DNA damage induced by three constituents of Ginkgo biloba extract in HepG2 cells.HepG2 cells were exposed to seven constituents (50 μM) of Ginkgo biloba extract (A) or increased concentrations (6.25–100 μM) of quercetin, kaempferol, or isorhamnetin (B) for 4 h. The data points represent the means ± S.D. for three independent experiments, and asterisk indicates p < 0.05 when the treatment group was compared with the concurrent control.

Mentions: The DNA damaging potential of seven Ginkgo biloba constituents was determined by the Comet assay. HepG2 cells were treated with quercetin, kaempferol, isorhamnetin, ginkgolide A, ginkgolide B, ginkgolide C, or bilobalide at 50 μM for 4 h. Of the constituents tested, quercetin caused the strongest induction of Comet tails (i.e., an increase in DNA breakage) with a tail intensity of 41%, followed by kaempferol (22% tail intensity) and isorhamnetin (11% tail intensity), whereas the other four compounds (ginkgolide A, ginkgolide B, ginkgolide C, and bilobalide) did not show significant DNA damaging effects (Fig. 5A). Concentration-dependent DNA strand breakage by quercetin, kaempferol, or isorhamnetin was further examined with a 4-h treatment; all three constituents caused a concentration-dependent increase in the Comet tail intensity (Fig. 5B). Significant DNA damage was observed at the concentration of ≥25 μM for quercetin and kaempferol, while isorhamnetin caused significant DNA breakage at the concentration of ≥50 μM.


Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells.

Zhang Z, Chen S, Mei H, Xuan J, Guo X, Couch L, Dobrovolsky VN, Guo L, Mei N - Sci Rep (2015)

DNA damage induced by three constituents of Ginkgo biloba extract in HepG2 cells.HepG2 cells were exposed to seven constituents (50 μM) of Ginkgo biloba extract (A) or increased concentrations (6.25–100 μM) of quercetin, kaempferol, or isorhamnetin (B) for 4 h. The data points represent the means ± S.D. for three independent experiments, and asterisk indicates p < 0.05 when the treatment group was compared with the concurrent control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588569&req=5

f5: DNA damage induced by three constituents of Ginkgo biloba extract in HepG2 cells.HepG2 cells were exposed to seven constituents (50 μM) of Ginkgo biloba extract (A) or increased concentrations (6.25–100 μM) of quercetin, kaempferol, or isorhamnetin (B) for 4 h. The data points represent the means ± S.D. for three independent experiments, and asterisk indicates p < 0.05 when the treatment group was compared with the concurrent control.
Mentions: The DNA damaging potential of seven Ginkgo biloba constituents was determined by the Comet assay. HepG2 cells were treated with quercetin, kaempferol, isorhamnetin, ginkgolide A, ginkgolide B, ginkgolide C, or bilobalide at 50 μM for 4 h. Of the constituents tested, quercetin caused the strongest induction of Comet tails (i.e., an increase in DNA breakage) with a tail intensity of 41%, followed by kaempferol (22% tail intensity) and isorhamnetin (11% tail intensity), whereas the other four compounds (ginkgolide A, ginkgolide B, ginkgolide C, and bilobalide) did not show significant DNA damaging effects (Fig. 5A). Concentration-dependent DNA strand breakage by quercetin, kaempferol, or isorhamnetin was further examined with a 4-h treatment; all three constituents caused a concentration-dependent increase in the Comet tail intensity (Fig. 5B). Significant DNA damage was observed at the concentration of ≥25 μM for quercetin and kaempferol, while isorhamnetin caused significant DNA breakage at the concentration of ≥50 μM.

Bottom Line: In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined.In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II.Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.

ABSTRACT
Ginkgo biloba leaf extract has been shown to increase the incidence in liver tumors in mice in a 2-year bioassay conducted by the National Toxicology Program. In this study, the DNA damaging effects of Ginkgo biloba leaf extract and many of its constituents were evaluated in human hepatic HepG2 cells and the underlying mechanism was determined. A molecular docking study revealed that quercetin, a flavonoid constituent of Ginkgo biloba, showed a higher potential to interact with topoisomerase II (Topo II) than did the other Ginkgo biloba constituents; this in silico prediction was confirmed by using a biochemical assay to study Topo II enzyme inhibition. Moreover, as measured by the Comet assay and the induction of γ-H2A.X, quercetin, followed by keampferol and isorhamnetin, appeared to be the most potent DNA damage inducer in HepG2 cells. In Topo II knockdown cells, DNA damage triggered by Ginkgo biloba leaf extract or quercetin was dramatically decreased, indicating that DNA damage is directly associated with Topo II. DNA damage was also observed when cells were treated with commercially available Ginkgo biloba extract product. Our findings suggest that Ginkgo biloba leaf extract- and quercetin-induced in vitro genotoxicity may be the result of Topo II inhibition.

No MeSH data available.


Related in: MedlinePlus