In article
Post by StevePost by r***@yahoo.comJ Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2007 Jul;
25(3):211-44.
Ginkgo biloba leaf extract: biological, medicinal, and toxicological
effects.
Chan PC, Xia Q, Fu PP.
National Institute of Environmental Health Sciences, Research Triangle
Park, NC.
Ginkgo biloba leave extract is among the most widely sold herbal
dietary supplements in the United States. Its purported biological
effects include: scavenging free radical; lowering oxidative stress;
reducing neural damages, reducing platelets aggregation; anti-
inflammation; anti-tumor activities; and anti-aging. Clinically, it
has been prescribed to treat CNS disorders such as Alzheimer's disease
and cognitive deficits. It exerts allergy and changes in bleeding
time. While its mutagenicity or carcinogenic activity has not been
reported, its components, quercetin, kaempferol and rutin have been
shown to be genotoxic. There are no standards or guidelines regulating
the constituent components of Ginkgo biloba leave extract nor are
exposure limits imposed. Safety evaluation of Ginkgo biloba leave
extract is being conducted by the U.S. National Toxicology Program.
PMID: 17763047 [PubMed - in process]
Quercetin and rutin are genotoxic? Since when? At what dose?
http://pmid.us/15735088
Low concentrations of flavonoids are protective in rat H4IIE cells
whereas high concentrations cause DNA damage and apoptosis.
Wätjen W, et al.
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.
http://pmid.us/full:15735088
Cytotoxicity of flavonoids. The intrinsic cytotoxicity of the 7
flavonoids differed greatly. Although quercetin [50% effective
concentration (EC50) = 35 ± 4 µmol/L] and fisetin (EC50 = 48 ± 3
µmol/L) were relatively toxic, taxifolin, rutin, and catechin (up to
500 µmol/L) did not reduce cell viability (no EC50 determined). The
order of cytotoxic potential in H4IIE cells was quercetin > fisetin >
myricetin > morin > taxifolin = catechin = rutin using the MTT assay
and thus roughly resembled the order of cellular uptake. With the
neutral red assay, quercetin and morin exhibited a lower toxicity than
in the MTT assay, whereas the toxicity of the other flavonoids
remained almost the same (Table 2), suggesting that mitochondria are a
more sensitive target of these 2 flavonoids. After 3 h of incubation,
the time at which the comet assay was performed, no EC50 could be
determined for all flavonoids tested up to concentrations of 500
µmol/L (data not shown).
Contribution of oxidative stress to flavonoid-induced cytotoxicity.
Preincubation of H4IIE cells with antioxidants (50 µmol/L
{alpha}-tocopherol, 500 µmol/L ascorbic acid, 500 µmol/L
N-acetylcysteine, 1000 µmol/L glutathione) or the metal chelator
desferoxamine (25 µmol/L) did not protect against quercetin-induced
cytotoxicity. In the case of ascorbic acid, a further increase in
flavonoid-mediated cytotoxicity occurred (data not shown). Incubation
of H4IIE cells with high concentrations of flavonoids (up to 500
µmol/L) for 24 h did not increase the formation of MDA, a marker of
oxidative stress (Table 2).
Induction of DNA strand breaks by flavonoids. Incubation of H4IIE
cells with quercetin increased comet formation in a time- and
concentration-dependent manner. A dose-response curve was found with
saturation at 250 µmol/L (500 µmol/L quercetin: image length, 36.0 ±
5.7 µm). Fisetin also induced DNA breakage (Fig. 4). There was a
slight increase in DNA strand breaks after incubation with morin but
no increase in DNA "comet" formation after incubation with taxifolin,
rutin, catechin, or myricetin (Table 2).
[...]
It was the major aim of our study to determine the margin of exposure
for cytoprotective and cytotoxic actions of flavonoids in a cell
culture system. We achieved this with 2 of the compounds tested,
quercetin and fisetin, which were readily taken up by the cells.
Protection against H2O2-induced cytotoxicity, DNA strand breaks, and
caspase-3 activation were detected at 1025 µmol/L of quercetin and
fisetin. On the other hand, these compounds induced cytotoxicity, DNA
strand breaks, oligonucleosomal DNA fragmentation, and caspase-3
activation on their own at concentrations between 50 and 250 µmol/L.
This finding is of interest because it may be possible to distinguish
a cytoprotective dose range from a proapoptotic dose range. To protect
human health, the latter range should be avoided in the consumption of
flavonoid-containing food supplements, but may be appropriate in an
attempt to support cancer chemotherapy by flavonoid drugs. It should
be noted, however, that the 2 dose ranges overlap to a certain extent.
For instance, on the one hand, 50 µmol/L fisetin significantly
protected against the large number of DNA strand breaks caused by 500
µmol/L H2O2 (from 54 to 22 µm) but can itself induce DNA strand breaks
to a minor extent at this concentration (22 µm) in the absence of H2O2.
[...]
In summary, we found that quercetin and fisetin were readily taken up
into H4IIE cells and protected against H2O2-induced cytotoxicity, DNA
strand breaks, and apoptosis at concentrations of 1025 µmol/L;
however, these compounds themselves induced cytotoxicity, DNA strand
breaks, oligonucleosomal DNA fragmentation and caspase activation at
concentrations between 50 and 250 µmol/L. The other flavonoids tested
were good antioxidants in a cell-free assay; their pharmacologic
activity did not correlate with in vitro antioxidant potential but
rather with cellular uptake. Our data suggest that cytoprotective
concentrations of some flavonoids are lower by a factor of 510 than
their DNA-damaging and proapoptotic concentrations. These results have
implications also for humans in terms of risk assessment and in the
modulation of isolated food constituents; they should be carefully
studied because flavonoids are used increasingly in dietary
supplements.