IJT - CIR - February 2024 - 73S

Burnett et al.
73S
this particular GBE induced disruption of estrous cycle and
caused maternal toxicity, in addition to fetal toxicity. No
adverse effects were observed in the 3.7 or 7.4 mg/kg
bodyweight/d dose groups in any of the different test
groups. The authors concluded that 14.8 mg/kg body weight/d
of this GBE produced adverse effects on the estrous cycle,
fertility, reproductive performance, and hormone levels of
female mice and may cause adverse effects on ovarian
function as an antifertility agent. The highest dose tested was
based on the equivalent to the suggested supplement dose
level for humans of three 260 mg capsules/d.51
The effects of an aqueous GBE (similar to EGb 761®)on
embryo-fetal development were investigated in pregnant
Wistar rats.52 Groups of17 rats received 0, 3.5, 7, or 14 mg/kg/
d of the test material during the tubal transit and implantation
period of pregnancy. The dams were then killed on the 15th
day of pregnancy. The following parameters were evaluated
during the study: clinical symptoms of maternal toxicity;
maternal body weight; feed and water intake; maternal liver,
kidney, and ovary weights; number of corpora lutea; implants
per group ratio; pre- and post-implantation loss per group
ratio; live fetuses mean; dead fetuses percentage; fetus and
placenta weight per offspring ratio; and fetal external malformation.
No significant adverse effects were observed for
any ofthe parameters in the dams or the embryos. The authors
of this study concluded that the studied GBE did not produce
adverse effects in maternal or embryonic rats.
Genotoxicity
In Vitro
Ginkgo Biloba LeafExtract. The specific GBE tested by the NTP
at up to 10,000 μg/plate was mutagenic in an Ames test using
Salmonella typhimurium strains TA98 and TA100 and Escherichia
coli strain WP2 uvrA/pKM101, with and without
metabolic activation.9
The genotoxicity of the same GBE and eight of its constituents
(quercetin; quercetin-3-β-D-glucoside; kaempferol;
isorhamnetin; ginkgolide A; ginkgolide B; ginkgolide C; and
bilobalide) were evaluated in mouse L5178Y cells using a
lymphoma assay and a Comet assay.53 The GBE (.2-1.2 mg/
ml) and the eight constituents were tested in a dimethyl
sulfoxide (DMSO) solution. A dose-dependent increase in
mutant frequency was observed in the studied GBE, quercetin
(10-100 μM), quercetin-3-β-D-glucoside (200-1000 μM), and
kaempferol (10-200 μM) without metabolic activation. DNA
double-strand breaks were also observed in dose-dependent
increases in the studied GBE, quercetin, and kaempferol.
Negative results were observed in the other constituents. A
Western blot analysis confirmed that GBE, quercetin, and
kaempferol activated the DNA damage signaling pathway.
Additionally, GBE produced reactive oxygen species and
decreased glutathione levels in L5178Y cells. An analysis of
loss of heterozygosity in Tk mutants indicated that GBE,
quercetin, and kaempferol resulted in extensive chromosomal
damage. The authors concluded that the studied GBE, quercetin,
and kaempferol are mutagenic in mouse L5178Y cells.
In a comparative review and analysis of published and
unpublished data on the GBE herbal supplement EGb761®,
the authors of the review concluded that the positive findings
in some in vitro genotoxicity tests are associated with cytotoxic
effects of the Ginkgo biloba extract and the use of very
high test concentrations, as compared to therapeutic use
concentrations.54
Gingko Biloba Meristem Cell. Ginkgo Biloba Meristem Cell at
up to 5000 μg/plate was not mutagenic in an Ames test in S.
typhimurium strains TA98, TA100, TA1535, and TA1537 or in
E. coli strain WP2 uvrA/pKM101, with and without metabolic
activation.48
Ginkgo Biloba Meristem Cell did not induce chromosomal
aberrations in Chinese hamster lung cultured cells, with and
without metabolic activation.48 The cells were treated with
210.0 μg/ml without metabolic activation (short-time treatment),
333.6 μg/ml with metabolic activation (short-time
treatment), and 202.2 μg/ml without metabolic activation
(24 h continuous treatment). Short-time treatment was not
defined.
In Vivo
Ginkgo Biloba Leaf Extract. In a micronucleus test in male and
female B6C3F1/N mice performed by the NTP, no increase in
the frequency ofmicronucleated erythrocytes was observed in
peripheral blood of male mice administered 125 to 2000 mg/
kg/d ofa GBE orally for 3 mo.9 Female mice that received the
same doses had results that were deemed equivocal based on a
significant trend test and due to no individual dose group being
significantly elevated over the vehicle control group. A significant
(P < .001) dose-related decreased in the percentage of
circulating polychromatic erythrocytes (PCEs) was observed
in male mice, which may indicate the studied GBE induced
bone marrow toxicity. In the female mice, a significant (P =
.001) decrease in the percentage of circulating PCEs was also
observed, but the response was not as correlated with dose as it
was in the males.
In a reporter gene mutation assay using male B6C3F1 gpt
delta mice, oral dosing of the GBE used in the NTP studies at
up to 2000 mg/kg body weight/d (in corn oi) for 90 d did not
produce remarkable increases in gpt or Spi mutation frequencies
in DNA extracted from the liver.49 No treatmentrelated
clinical signs or deaths were observed during the
treatment period. Relative liver weights were significantly
increased in the 2000 mg/kg group. Hepatocellular hypertrophy
in the centrilobular area and slight focal necrosis were
observed in the 2000 mg/kg group.
This assay was performed in conjunction with a combined
liver comet assay and bone marrow micronucleus assay using
male and female CARKO and wild-type mice. The short-term

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