Issue:
119
Page: 8-14
Grape Seed
Vitis vinifera
Family: Vitaceae
by Gayle Engels, Josef Brinckmann
HerbalGram.
2018; American Botanical Council
INTRODUCTION
The Vitaceae or
grape family includes about 900 species in 15 genera. About 70 interfertile
(capable of interbreeding) species compose the genus Vitis. Of these, V.
vinifera is the best known, as well as the most culturally and economically
important.1 Vitis vinifera originated in central Asia, but it
now occurs in many regions of the world as a result of extensive cultivation
and escape.2 It is a perennial liana (woody, climbing vine) that
climbs with coiled tendrils. Grapes were among the first fruits to be
domesticated thousands of years ago, and there are currently an estimated
10,000 cultivars of this single species. The domesticated subspecies V. vinifera
subsp. vinifera (syn. V. vinifera subsp. sativa, or
V. sativa) is monoecious (hermaphroditic), having both male and female
reproductive organs in a single individual. It descended from a wild ancestor V.
vinifera subsp. sylvestris (syn. V. sylvestris), which is
dioecious — having male and female reproductive organs in separate individuals.
The subspecies sylvestris now occurs in the wild from the Atlantic coast
of southwestern Europe to Tajikistan and the western Himalayas in central and
southern Asia.3 More than 90% of the world production of grapes is
from V. vinifera.4 However, other Vitis species,
including V. berlandieri, V. riparia, and V.
rupestris, are used as germplasm resources to breed rootstock for
improved resistance against fungal diseases.5 Other Vitis species
used for wine production, in particular V. labrusca, also provide seed
material for the production of grape seed extract (GSE*).6
GSEs typically are
produced from dried or fresh grape seeds that are obtained as a byproduct of
the juice and wine industries. First, the grape seeds are extracted using a
solvent (e.g., water, or mixtures of water with ethanol or acetone) and then
filtered and subjected to further processing in order to produce GSE that
contains anywhere from 50% to 90% phenolic compounds.7 There is also
a pharmacopeial GSE called “Grape Seeds Oligomeric Proanthocyanidins,” defined
in the United States Pharmacopeia (USP) as the fraction of an extract of
the ripe seeds of V. vinifera containing not less than 75.0% oligomeric
proanthocyanidins (OPCs).8
HISTORY
AND CULTURAL SIGNIFICANCE
The Latin genus
name Vitis means “grape vine,” while the species name vinifera
means “produces wine” or “wine bearing’” and is related to the Latin terms vinum
(“wine”) and vinea (“vineyard”).9 The words “wine,” vin
(French), and Wein (German) stem from the ancient Greek term οίνος (oinos) and the Latin term vinum.10
Swedish botanist
Carl Linnaeus (1707-1778) included Vitis vinifera in his 1749 work Materia
Medica and described its occurrence as “orbis totus temperatus”
(global, temperate). For therapeutic use, he did not describe the seed but
rather the leaf (as Vitis Folia), stating that it was used to treat stranguria
(slow, painful urination) and tussis (cough).11
Grape is
considered a “cultural keystone species” and is associated with divinities and
rituals, evidenced by representations on artifacts of ancient cultures of the
Mediterranean.12 Archaeobotanical evidence of Vitis species
is mainly in the form of waterlogged, mineralized, and charred seeds. It is
difficult to determine whether these seeds originated from wild or cultivated
plants13 because the seeds of V. vinifera subsp. sylvestris
(wild) and V. vinifera subsp. vinifera (cultivated), for
example, are morphologically very similar.14 Domestication of the
cultivated grape reportedly took place between the seventh and the fourth
millennia BCE in the Caucasus region (between the Black Sea and the Caspian
Sea) in present-day Georgia, Armenia, and Azerbaijan,5,15 where the
crop exhibits high genetic diversity. From the Caucasus, cultivation is
believed to have spread to Mesopotamia and Egypt and then throughout the
Mediterranean16 and beyond. Approximately 9,000-year-old grape pips
(seeds) found in the southern Caucasus provide the earliest known archaeological
evidence of grape cultivation.17 Based on botanical, ampelographic
(the science concerned with identification and classification of grape vines),
archaeological, paleontological, historical, ethnographical, and linguistic
studies, Georgia is recognized as one of the earliest sites of grape
domestication.18 Today, the most widely cultivated species in
Georgia are V. vinifera and V. labrusca and their
varieties, including V. labrusca var. izabella (purple), V.
vinifera var. Rkatsiteli (white), and V. vinifera
var. Saperavi (red). The fermented grape seed residue byproduct of these
species are being studied in Georgia as potential source materials for
commercial production of GSE.6
While there are well-documented traditional medicinal uses of other
plant parts of V. vinifera — for example, the dried leaf (pharmacopeial
name: Vitis viniferae folium),19 the dried fruit or raisin (Uvae
passae or Vitis viniferae fructus), and processed forms such as wine (Vinum)20
— extraction of the seed for functional, nutritional, or therapeutic uses is a
relatively new innovation. Development of GSE traces back to research begun in
the late 1940s, although commercial products did not appear until the 1970s. In
1947, French scientist Jack Arthur Masquelier (1922-2009) extracted a colorless
fraction from peanut (Arachis hypogaea, Fabaceae) skin, proposing that
its major components were oligomers of flavan-3-ol units (e.g., (+)-catechin or
(-)-epicatechin), which today are classified as oligomeric flavan-3-ols. Over
the decades, this led to research into other potential sources of the
compounds, including pine (Pinus spp., Pinaceae) bark and grape seed. By
1970, Masquelier had isolated these flavanols from grape seeds21 and
applied for a patent for his extraction process, which was granted to his
company, Société Civile d’Investigations Pharmacologiques d’Aquitaine (SCIPA),
in 1972 by the French National Institute of Industrial Property (INPI).22
Today, GSE is used as a component of dietary supplement products and natural
health products for venous insufficiency (in which veins have problems sending
blood from the legs back to the heart), to promote wound healing, and to reduce
inflammation.23 It is also used as a functional food additive and
cosmetic ingredient.
In 2003, San Joaquin Valley Concentrates (Fresno, California) submitted
a Generally Recognized as Safe (GRAS) notice to the US Food and Drug
Administration (FDA) for a GSE to be used as an antioxidant or emulsifier
component of food products at levels ranging from 0.01% to 0.08%. The FDA
responded that it had no questions regarding San Joaquin’s conclusion that GSE
is GRAS under the intended conditions of use.24 In the same year,
Polyphenolics, Inc. (Madera, California) submitted a GRAS notice for GSE and
grape pomace extract (GPE) for use as antioxidants in certain fruit beverages
at a concentration of up to 210 parts per million (alone or in combination with
other ingredients). Again, the FDA had no questions regarding Polyphenolics’
conclusion that GSE and GPE are GRAS under the intended conditions of use.25
Subsequently, in 2007, Polyphenolics, Inc. requested and received an
independent GRAS extension expert opinion that justified increasing the
concentration in beverages to up to 845 mg/L (200 mg/8 oz). Enovita, a GSE from
Indena (Milan, Italy), is also GRAS as per an independent GRAS assessment and
conclusion (G. Ris email to T. Smith, June 18, 2018).
In 2008, a new dietary supplement quality standards monograph titled
“Grape Seeds Oligomeric Proanthocyanidins” was proposed for entry into the USP.
A draft monograph was published in the Pharmacopeial Forum for public
comment,26 after which the final monograph became official in the
33rd revision of the USP in 2010.27
In 2012, the company Nutrilinks Sarl (Lausanne, Switzerland) submitted
an application to the European Food Safety Authority (EFSA) for an opinion on
scientific substantiation of its proposed health claim for GSE related to
maintenance of normal venous blood flow. The subject of its application was a
dry extract obtained by extraction of grape seeds with ethanol and ethyl
acetate, and subsequent evaporation, filtration, concentration, and
spray-drying, standardized to total polyphenol content (minimum 35% of gallic
acid, catechins, and epicatechins, and minimum 7% of procyanidin dimers B1, B2,
B3, and B4). The EFSA concluded that the data did not establish a
cause-and-effect relationship between the consumption of this GSE and
maintenance of normal venous blood flow.28 Another application by
the same company was submitted to the EFSA in 2012 for an opinion on scientific
substantiation of a health claim for its GSE related to the elimination of
excess water in the body. The EFSA panel concluded that the applicant’s
proposed claim statement (“helps to drain the body in case of water
accumulation”) in the context of “normal venous circulation in the legs” refers
to the maintenance of normal venous blood flow, and that a claim for GSE and
maintenance of normal venous blood flow had already been assessed and rejected.29
CURRENT AUTHORIZED USES IN COSMETICS, FOODS, AND
MEDICINES
In the United States, GSE is classified as GRAS for certain limited
food uses and appears on the FDA’s list of “Substances Added to Food” (formerly
“Everything Added to Food in the United States,” or EAFUS).30 GSE
may also be used as a component of dietary supplement products, which require
FDA notification within 30 days of marketing if a structure-function claim is
made and product manufacturing that adheres to current Good Manufacturing
Practices (cGMPs).31 In Canada, GSE standardized to 80-85% OPCs is
regulated as an active ingredient of licensed natural health products (NHPs),
which require pre-marketing authorization from the Natural and Non-prescription
Health Products Directorate (NNHPD). Depending on the dosage and strength,
labels of licensed GSE NHPs may carry one or both of the following claim
statements: “Source of antioxidants for the maintenance of good health” and
“Helps to relieve symptoms related to non-complicated chronic venous
insufficiency (CVI), such as sensation of swelling, heaviness and tingling of
the legs.”32
In the European Union, different types of GSE are listed as components
of cosmetic products and are used for various functions (e.g., antidandruff,
antimicrobial, antioxidant, oral care, skin-protecting, and UV-absorbing
functions). “Oleoyl GSE” (obtained by the reaction of oleoyl chloride with
GSE), “Propyl Oleoyl GSE” (obtained by the reaction of oleoyl chloride with the
propyl ether of GSE), and “Undecylenoyl GSE” (obtained by the reaction of GSE
with undecylenoyl chloride) are all used for antioxidant function; “Palmitoyl
GSE” (GSE reaction products with hexadecanoyl chloride) is used for
skin-conditioning function; and “Sodium GSE Phosphate” (sodium salt of a
complex mixture of esters of phosphoric acid and GSE) is used for antioxidant
and skin-conditioning functions.33
MODERN RESEARCH
Proanthocyanidins (PACs) are the major chemical compounds in GSEs. The
PAC content of GSEs typically comprises 5-30% monomers (including catechins,
epicatechins, and other flavan-3-ol monomers), 17-63% oligomers,†
and 11-39% polymers (and their gallic acid esters). GSEs contain primarily
B-type PACs (flavan-3-ol polymers where
the units are linked by a single bond). The large number of grape varieties
used to make GSEs accounts for the varied concentrations of bioactive chemical
compounds in the seeds.7,34
There are a number
of clinical studies on various GSEs for numerous conditions and functions, such
as atherosclerosis prevention,35,36 chronic periodontitis,37
climacteric syndrome,35 estrogen levels,38
hyperlipidemia,36,39,40 hypertension,41,42 idiopathic
male infertility,43 leg swelling during prolonged sitting,44
liver function,45 oxidative stress and reperfusion injury caused by
cardiopulmonary bypass surgery,46 postprandial oxidative stress and
inflammation in persons with metabolic syndrome,47 postprandial
blood glucose,48 renal failure in chronic kidney disease,49
antioxidant capacity and lipid peroxidation in type 2 diabetes mellitus,50
and skin protection from UV radiation.51 Most of these studies are
of varying degrees of quality and, while they all show some positive outcomes,
they are either preliminary studies; were not randomized, double-blind, and
placebo-controlled (RDBPC); did not explain randomization, blinding, or
withdrawals; and/or had a very small study population.
One recent RDBPC
study investigated the effects of GSE supplementation on oxidative stress and
metabolic profiles of female volleyball players. Forty healthy volunteers
(14-24 years old) were randomly assigned to take 300 mg GSE (formulated by
Barij Essence Pharmaceutical Co.; Kashan, Iran; no additional information
provided) or placebo twice a day, with lunch and dinner, for eight weeks.
Participants kept dietary records on one weekend day and two weekdays, and
physical activity records on weeks two, four, and six of the study. Fasting
blood samples were obtained before and after the intervention and centrifuged,
and the total antioxidant capacity (TAC), total glutathione (GSH, an
antioxidant), malondialdehyde (MDA, a marker of oxidative stress), nitrous
oxide (NO), creatine phosphokinase (CPK), fasting plasma glucose (FPG), serum
triglycerides, serum insulin, and very low-density lipoprotein (VLDL),
low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total
cholesterol levels were measured. The GSE group experienced a significant
increase in GSH compared to placebo, and a significant decrease in MDA compared
to placebo. Additionally, GSE supplementation resulted in decreased serum
insulin concentrations, decreased scores on the homeostasis model assessment
for insulin resistance index, and increased scores on the quantitative insulin
sensitivity check index compared to placebo, all of which are considered
beneficial effects on insulin metabolism. There were no significant changes in
CPK, TAC, NO, FPG, or serum lipid concentrations compared to placebo.52
Two meta-analyses
have reported on clinical studies investigating the effects of GSE on
cardiovascular risk markers. The first, conducted in 2011, included nine
randomized, controlled trials published between 2000 and 2009 (N = 390) that
focused on at least one of the following: systolic blood pressure (SBP),
diastolic blood pressure (DBP), heart rate, triglycerides, C-reactive protein
(CRP), or total, LDL-, or HDL-cholesterol. This meta-analysis concluded that
GSE supplementation was associated with significantly lowered SBP and heart
rate with no significant effects on DBP, CRP, or serum lipid levels. While the
reduction in SBP was modest compared to that seen with prescription
antihypertensive drugs, it may still be meaningful since it is estimated that
“every 3 mm Hg reduction in SBP could reduce the risk of all-cause mortality by
4%, mortality after stroke by 8%, and mortality after coronary artery disease
by 5%.” The authors opined that GSE might have cardioprotective effects beyond
SBP and heart rate reductions, and that larger studies should be done
evaluating different dosages of GSE with longer follow-up durations.53
A more recent
meta-analysis from 2016 included 12 articles (16 randomized trials, N = 810)
that analyzed the effects of GSE on blood pressure over at least two weeks. Of
the 16 clinical trials, four studied GSE’s effects in patients with prehypertension
and stage 1 hypertension, four included healthy subjects, three in patients
with metabolic syndrome, two in patients with hypertension, two in women with
at least one menopausal symptom, and one in patients with above-average
vascular risk. Overall, GSE was associated with significant changes in SBP and
DBP. Significant decreases in SBP and DBP occurred more often in subjects under
50 years of age, while significant decreases in SBP alone occurred in obese
subjects and patients with metabolic syndrome. Additionally, the authors
identified study design, randomization, and baseline blood pressure as possible
causes of heterogeneity (variability between the studies). Therefore, they
recommend confirmation of their findings through a “large-scale, long-term,
multiple-dose randomized controlled trial, especially among hypertensive
patients.”54
At least seven
clinical trials have studied GSE in combination with other ingredients for a
variety of uses. Five of these addressed skin conditions. One found that skin
radiance (e.g., for pink and olive skin tones) was significantly improved with
six weeks of oral treatment with 150 mg per day of SkinAx2 (a
product containing GSE, superoxide dismutase-rich melon [Cucumis melo
var. cantalupensis, Cucurbitaceae] concentrate, vitamin C, and
zinc; Activ’Inside; Libourne, France).55 Another oral supplement
with 27.5 mg GSE, 210 mg biomarine complex, 54 mg vitamin C, 4 mg zinc, and
28.76 mg tomato (Solanum lycopersicum, Solanaceae) extract (Imedeen
Man.Age.Ment; Ferrosan Laboratórios S/A; Copenhagen, Denmark) taken twice a day
for 30 days improved skin hydration, dermal ultrasound density, reduction of
skin pH, and overall signs of skin aging in men.56 Likewise, an oral
supplement (Imedeen Time Perfection; Ferrosan S/A; Copenhagen, Denmark) with
105 mg BioMarine Complex, 14.8 mg LycoPhence GS (lycopene and GSE), and 30 mg
acerola (Malpighia spp., Malpighiaceae) taken for 120 days was
associated with improvements in skin hydration and pH, ultrasound density, and
a histological increment of collagen and elastic fibers.57 An SPF 30
sunscreen containing GSE, vitamins E and C, and ubiquinone (Dr. Peter Hansen
R&D; Stada; Bad Vilbel, Germany) effectively protected the subjects’ skin
against infrared A radiation.58 Finally, a nonsteroidal topical
cream (MD2011001; no other information provided) containing GSE, vitamin E, and
epigallocatechin gallate (EGCG) provided a faster and statistically significant
improvement in atopic dermatitis in patients who used it for 28 days, compared
to placebo.59
One RDBPC study investigated the benefits of a nutritional supplement in
low-income patients recently diagnosed with hyperlipidemia (N = 191; 18-65
years old). Subjects were randomly assigned to receive a placebo or a
proprietary phytonutrient supplement (PreLipid; Preventions Meds, Inc.;
Lebanon, NJ; no additional information provided) containing red yeast rice (a
product of a yeast [Monascus purpureus, Elaphomycetaceae] grown
on white rice [Oryza sativa, Poaceae]) powder, GS powder, niacin, folic
acid, and black pepper (Piper nigrum, Piperaceae) powder. Subjects
taking PreLipid experienced significant reductions in LDL-C and non-HDL-C at 12
weeks compared to placebo.60
Another RDBPC study investigated the effects of 150 mg GSE (MegaNatural
BP; Polyphenolics; Madera, CA) in a fruit juice blend (provided by Coca-Cola)
on blood pressure and metabolic indices in men and women with prehypertension
(N = 28; 25-65 years old). Subjects were randomly assigned to take placebo or
300 mg GSE/juice blend per day in two doses for 12 weeks. By week six, the GSE
group experienced significantly reduced SBP (5.6%) and DBP (4.7%) compared to
placebo. The higher the subjects’ baseline BP, the greater the reduction they
experienced; in some cases, subjects taking the GSE/juice blend experienced
nearly double the SPB and DBP reduction of those in the placebo group. While
not significant, fasting insulin and insulin sensitivity of subjects in the GSE/juice
blend group tended to improve after six weeks.61
FUTURE OUTLOOK
The International Union for Conservation of Nature (IUCN) assigns wild V.
vinifera to the conservation category of Least Concern (LC), meaning
that the species is not considered to be threatened.2 In any case,
GSE is produced from seeds of the widely cultivated grape that is used for
production of juices and wines worldwide. Nonetheless, long-term survival of
crop wild relatives remains critical for preserving genetic diversity. Some wild
grape species are becoming threatened in Europe due to habitat loss,
competition with alien grape species, and intensive deforestation.62
Perhaps the biggest concern is economic adulteration of GSE, which has a
direct impact on its safety and efficacy. In 2016, the American Botanical
Council (ABC)-American Herbal Pharmacopoeia (AHP)-National Center for Natural
Products Research (NCNPR) Botanical Adulterants Prevention Program published a
Botanical Adulterants Bulletin on GSE, reporting that “adulteration of GSE in
commercial products appears to be a significant problem.” In one of the studies
cited in the bulletin, samples of several commercial GSE products contained no
GSE at all and were composed primarily of peanut skin extract. Although peanut
skin extracts should not exhibit allergenic potential comparable to that of
peanuts themselves (due to no protein content), allergenicity could still be
possible due to contact with the peanut protein. Besides the obvious matter of
consumer fraud, persons with peanut allergies who unwittingly consume these
products could experience adverse reactions. Other known adulterants of GSE
include pine bark, green tea (Camellia sinensis, Theaceae) extract, and
other PAC-rich (e.g., propelargonidin-containing) extracts from non-grape seed
sources.7
While GSE is a relatively new item of commerce, evidence that supports
its various beneficial uses as a functional component of cosmetic, food,
dietary supplement, and natural health products continues to grow. To ensure
the safety and efficacy of GSE for its intended uses, all finished product
brands and marketers should specify the production and procurement of only well-characterized
GSE for use in consumer products. For example, the USP quality standards
monograph Grape Seeds Oligomeric Proanthocyanidins provides a useful basis for
a company to establish a scientifically valid specification with suitable tests
and methods for verifying identity, composition, strength, and purity.
—Gayle Engels and Josef Brinckmann
* The acronym GSE should
not be confused with the acronym GFSE, which refers to grapefruit (Citrus
paradisi, Rutaceae) seed extract, an entirely different material. In some
original publications on GFSE adulteration, the authors use “GSE” to refer to
grapefruit seed extract.
†The
authors define oligomers as PACs that have 2-7 units.
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