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DESCRIPTION:
Grape seed proanthocyanidins refer to procyanidin mixtures extracted from grape (Vitis vinifera) seeds. Procyanidins are derivatives of the flavan-3-o1 class of flavonoids. This class includes (+)-catechin, commonly referred to as catechin, and (-)-epicatechin, commonly referred to as epicatechin. Procyanidins are dimers and oligomers of catechin and epicatechin and their gallic acid esters. Procyanidins are widely distributed in the plant kingdom and, in addition to being found in grape seeds, are found in cocoa and chocolate, apples, peanuts, almonds, cranberries, blueberries and in the bark of pines, among other plant sources.
Grape seed proanthocyanidins are mainly comprised of dimers, trimers and tetramers of catechin and epicatechin and their gallates. They also contain smaller amounts of pentamers, hexamers and heptamers of these flavan-3-o1s and their gallates. The procyanidin dimers and oligomers are also known as oligomeric procyanidins (OPCs) and procyanidolic oligomers or PCOs. Grape seed proanthocyanidins comprise approximately 60 to 70% of the polyphenol content of grapes. The procyanidins are colorless in their pure state.
ABSTRACT:
To assess the safety of grape seed extract with less than 5.5% catechin monomers (IH636), 4 groups of male and female Sprague-Dawley rats were provided grape seed extract in the diet at levels of 0 (control), 0.5, 1.0, or 2.0%, for a period of 90 days. All animals survived the duration of the study, and no significant changes in clinical signs, hematological parameters, organ weights, ophthalmology evaluations or histopathological findings were observed. A significant increase in food consumption was observed in male and female rats provided the grape seed extract diets compared to controls, especially in male rats consuming 2.0% grape seed extract. This effect was not accompanied by increases in body weight gains. Grape seed extract appeared to increase the insoluble fraction of the diet. Male rats in the high-dose group exhibited decreased serum iron levels and decreased serum iron/total iron binding capacity ratio compared to controls although all values were within historical limits for Sprague-Dawley rats.
In conclusion, administration of the grape seed extract IH636 to male and female Sprague-Dawley rats in the feed at levels of 0.5%, 1.0%, or 2.0% for 90 days did not induce any toxicologically significant effects.
Active Component and Structure:
Proanthocyanidine is the generic name for compounds that give rise to anthocyanidine when decomposed with an acid. It comes in more than one structure, depending on the type of catechins constituting it, condensing positions, the three-dimensional arrangement of condensing positions, and the number of polymerizations. Grape seed extract is essentially a blend of various flavonoids.
Basic structure of Proanthocyanidine
What is Grape Seed Extract Made of?
Molecular Structure of Grape Seed Extract:
Proanthocyanidins are naturally occurring plant metabolites widely available in fruits, vegetables, nuts, seeds, flowers, and bark. Other plant sources of proanthocyanidins include wine, cranberries, and the leaves of bilberry, birch, ginkgo, and hawthorne. Also known as procyanidins, these substances are the main precursors of the blue-violet and red pigments in plants.
At a symposium entitled “Free Radicals in Biotechnology and Medicine” held in London in 1990, it was reported that esterification of (-)-epicatechin and procyanidin B2 by gallic acid increases their free radical scavenging ability. Information was also introduced revealing the dimeric proanthocyanidins having the C4-C8 linkage have greater free radical scavenging activity than the C4-C6 linkage, and that these gallate esters are only found in the grape seed extract form.
Grape seed extract contains OPCs made up of dimers or trimers of (+)-catechin and (-)-epicatechin. The procyanidin dimers are comprised of procyanidins B1, B2, B3, B4, B5, B6, B7, and B8. There are six procyanidin trimers which include procyanidin C1 and C2. Furthermore, several gallolyl procyanidins, which are most commonly the gallate esters of the dimeric procyanidins, and some free gallic acid are present.
Tetramers or greater of these flavonols would be known as polymeric proanthocyanidins and the astringency of the molecule would increase accordingly. Therefore, oligomeric proanthocyanidins are less astringent, bind less strongly to proteins, and are more soluble and mobile in the body.
What's It Made Of?
Vitamin E, flavonoids, linoleic acid, and compounds called procyanidins (also known as condensed tannins, pycnogenols, and oligomeric proanthocyanidins or OPCs) are highly concentrated in grape seeds. These healthful compounds can also be found in lower concentrations in the skin of the grape. Procyanidins are also found in grape juice and wine, but in lower concentrations.
Biological Properties of Grape Seed Extract:
The biological properties of flavonoids, including proanthocyanidins, have been extensively reviewed. In addition to their free radical scavenging and antioxidant activity, proanthocyanidins have been reported to have antibacterial, antiviral, anticarcinogenic, anti-inflammatory, anti-allergic, and vasodilatory actions. Proanthocyanidins have also been shown to inhibit lipid peroxidation, platelet aggregation, capillary permeability and fragility, and to affect enzyme systems including phospholipase A2, cyclooxygenase, and lipoxygenase.
The free radical scavenging abilities of proanthocyanidins have been well documented and command the most attention. In vivo studies have shown grape seed proanthocyanidin extract is a better free radical scavenger and inhibitor of oxidative tissue damage than vitamin C, vitamin E succinate, vitamin C and vitamin E succinate combined, and beta carotene. Moreover, in vitro experimental results have demonstrated proanthocyanidins have specificity for the hydroxyl radicalin addition to having the ability to non-competitively inhibit the activity of xanthine oxidase, a major generator of free radicals, elastase, collagenase, hyaluronidase, and beta-glucuronidase.
OPCs have also demonstrated preferential binding to areas characterized by a high content of glycosaminoglycans (epidermis, capillary wall, gastrointestinal mucosa, etc.). This feature makes them useful for decreasing vascular permeability and enhancing capillary strength, vascular function, and peripheral circulation.
Methods of Analysis:
Grape seed extract is a heterogeneous mixture of gallic acid, monomers, dimers, trimers, tetramers, polymers and other oligomers. The basic building blocks are molecules of catechin, epicatechin, epicatechin gallate, gallic acid esters, glycosides and peptides. Due to the high degree of heterogeneity, several analytical techniques are required to characterize grape seed extract.
TLC (Thin Layer Chromatography)
lack of a non-partisan "commercial" grape seed extract standard
This procedure was proffered by ESA Laboratories and includes normal phase TLC separation of preacetylated powder extracts
In 1998 three independent laboratories (Alpha Chemical Laboratory, Industrial Laboratory, and PhytoChem) validated the TLC method by testing 14 grape seed extracts, bilberry, green tea, pycnogenol and cranberry extracts as well as 13 finished products. This is a qualitative test designed to identify grape seed extract and differentiate it from botanicals that may have similar components.
Physiological Functions:
Proanthocyanidine can scavenge free oxygen radicals and inhibit lipid oxidation; in other words, it has antioxidative properties. Grape seed extract is considered effective in treating the diseases listed below.
INTRODUCTION:
Grape seed extract is a natural extract from the seeds of Vitis vinifera. A multitude of flavonoids are contained in grape seed extract. The most abundant of these are the proanthocyanidins, which are oligomers of monomeric flavan-3-ol units linked by carbon-carbon bonds (1-3). The major flavan-3-ols identified in grape seed extract are (+)-catechin, (-)-epicatechin, and (-)-epicatechin-3-O-gallate (3, 4) (Figure 1). The most basic oligomeric proanthocyanidins are composed of flavan-3-ols units linked together from the C4 of one unit to either the C6 or C8 of the adjacent unit to form the B-type dimers and C-type trimers (1, 5, 6) (Figure 2). The further addition of flavan-3-ol units results in the formation of larger proanthocyanidin oligomers and polymers.
Flavonoids and flavan-3-ols are partially metabolized to lactones and phenolic acids by the intestinal microflora (7, 8). These flavonoid and flavan-3-ol metabolites are absorbed through the intestinal lumen and are further metabolized by methylation, oxidation, or glucuronic conjugation. Flavonoids and their metabolites are eliminated mainly through urinary and fecal excretion and, to a certain extent, via respired carbon dioxide (9-12).
In addition to being present in the seeds of grapes, proanthocyanidins occur naturally in black and green teas, chocolate, coffee, cacao, red wine, and many fruits (7). A vast amount of literature has been published that provides evidence that these flavonoids possess antioxidant properties, free radical scavenging, and chelation abilities (6, 13-25). Flavonoids have been reported to exert anti-inflammatory actions and to modulate immune function (26, 27). By reducing the permeability and fragility of capillaries, they also have a protective effect against vascular disorders (28). Flavonoids exert a cholesterol-lowering effect by enhancing reverse cholesterol transport and bile acid excretion, and by decreasing the intestinal absorption of dietary cholesterol (29-31). The results of epidemiological studies indicate an inverse relationship between cancer and the consumption of flavonoid-containing foods, especially fruits and green tea (32-35). The anti-carcinogenic properties of flavonoids and proanthocyanidins in particular are associated with cytotoxicity to cancer cells (36, 37) and their ability to enhance the activity of enzymes that detoxify carcinogenic hydrocarbons by oxidation (7, 35). Additional epidemiological studies on flavonoid consumption indicate an inverse relationship between dietary intake of flavonoids and coronary heart disease and stroke (38-41). By acting as free radical scavengers proanthocyanidins inhibit lipid peroxidation (22, 28, 42-45), a free-radical chain reaction that can produce cytotoxicity, disrupt lipid-containing membranes, and initiate low-density lipoprotein oxidation (46-49), a contributing factor to the development of atherosclerosis (50, 51). Flavonoids decrease the risk of cardiovascular disease by inhibiting platelet aggregation and thrombosis (52-57), and by exerting a sparing effect on other antioxidants, such as vitamins E and C (52, 58). By reducing oxidative stress, proanthocyanidins from grape seed exert a cardioprotective effect against ischemia reperfusion injury (59) and also protect gastric mucosal (60) and glial cells (61) from oxidative-stress induced injury.
Due to the increasing interest in flavonoids as dietary supplements (taken in caplet form with a typical daily dose being between 50 and 150mg) and a growing understanding of their potential health benefits, the safety of these substances must be established. The objective of the present study was to assess the oral toxicity of a water extracted grape seed extract with less than 5.5% catechin monomers following administration to rats via dosed feed for a period of 90 days. At the highest concentration of 2.0 w/w % IH636 in the chow, the rats were consuming the extract at approximately 2g/Kg body weight/day or 10-20 times the average human intake of plant derived proanthocyanidins.
What is grape seed extract?
Grape seed extract is a naturally occurring plant substance that contains a concentrated source of antioxidant nutrients known as oligomeric proanthocyanidins. These antioxidants can help protect against the effects of internal and external stresses. Scientists have demonstrated that oligomeric proanthocyanidins, more commonly known as OPCs, are more powerful antioxidants than vitamins C, E and beta-carotene.
What is the history of grape seed extract?
Scientists first became interested in grape seed extract in the latter part of the 20th Century due to an outgrowth of research about the "French Paradox." The French Paradox shows a low incidence of heart disease (nearly half that of the United States) among the French despite a high incidence of known dietary and other contributing factors to heart disease. Some scientists believe that the secret of the French Paradox is red wine, which is an integral part of the French diet. Further research suggests that OPCs present in red wine can promote cardiovascular health. Grape seeds have been found to be the richest source of OPCs.
A potent antioxidant:
Original OPCs are twenty times more powerful than vitamin C and fifty times more powerful than vitamin E in their ability to scavenge free radicals. OPCs are able to "donate" electrons to unstable free radicals and to neutralize them without the danger of becoming unstable themselves.
Original OPCs in Beyond Grape Seed protects cells and tissue by neutralizing free radicals and blocking destructive enzymes. These OPCs penetrate both water and fat cellular membranes. OPCs even have the capacity to cross the blood-brain barrier. They maintain the structure and integrity of the veins, arteries and capillaries, which ensures efficient circulation.
Beyond Grape Seed helps strengthen the entire vascular system. OPCs prevent capillary leakage in the legs, eyes and skin reducing fluid retention. Without OPCs, destructive enzymes are free to attack the structure of the blood vessels. Free radicals further degenerate these vessels, causing lesions that become traps for bad cholesterol (LDL). Once LDL cholesterol has been trapped it attracts calcium. Cholesterol and calcium build up to form plaque, which narrows the arteries and encourages blood clot formation.
MECHANISM OF ACTION:
Grape seed proanthocyanidins have been found to have a number of antioxidant activities in the laboratory. These include scavenging of hydroxyl and peroxyl radicals, and inhibition of the oxidation of low-density lipoprotein (LDL). The inhibitory potential related to lipid peroxidation appears to increase with the degree of polymerization of the molecules. That is, grape seed proanthocyanidins with a greater number of catechin and epicatechin units appear to have more potent inhibitory activity than those with fewer catechin and epicatechin units. Further, the position of linkage between inter-flavan units also appears to influence lipid peroxidation inhibitory activity. Procyanidin isomers with a 4-6 inter-flavan linkage appear to show stronger inhibitory activity than those with a 4-8 linkage. Finally, the presence of a gallate group also appears to affect the inhibitory activity of the procyanidins with respect to lipid peroxidation. A procyanidin dimer with a gallate group linked at the 3-hydroxy position appears to show much greater inhibition of lipid peroxidation than a dimer without such a group.
Grape seed proanthocyanidins have shown anti-inflammatory, anticarcinogenic and anti-atherogenic activities, again in the laboratory. These activities are thought to be due, in large part, to the antioxidant activities of these molecules. These proanthocyanidins have been found to be cytotoxic for some human cancer lines in culture. Upregulation of apoptosis by the proanthocyanidins in these cancer lines is another possible mechanism for their possible anticarcinogenic activity.
Diets and Test Materials:
Animals were fed Ralston Purina Rodent Chow pre-ground to meal form, ad libitum. Drinking water was also provided to the animals ad libitum. Grape seed extract with less than 5.5% catechin monomers (IH636) was obtained from Dry Creek Nutrition, Inc. Five lots of IH636 were blended to form a composite batch. The composite batch was blended with the rodent chow to provide test diets containing levels of 0 (control), 0.5, 1.0, and 2.0% of IH636 (Average dose levels are presented in Table 1). A sixth lot was used separately at the end of the study. All lots complied with the current chemical and microbiological specifications for the product. The standard rodent chow without the test material was provided to the control group.
All diets were frozen at -21° to -19°C upon receipt. The diets were refrigerated at 4° to 6°C, protected from light after opening, and were maintained at room temperature (18° to 25°C) 24 hours prior to feeding to the animals. The presence of Grape Seed Extract in the chow was demonstrated using the classical Folin-Ciocalteu and Porter visible spectroscopy methodologies for determining the presence of polyphenols and proanthocyanidins, respectively. Samples of 0 (control), 0.5, 1.0, and 2.0% Grape Seed Extract in chow were first extracted with methanol then subjected to the analyses. Greater absorbance at 760 nm (Folin-Ciocalteu) and 550 nm (Porter) for the samples with added Grape Seed Extract than the control was indicative of the addition of Grape Seed Extract to the chow.
Attainment of the target concentrations and content uniformity of the Grape Seed Extract in the different test diets were determined by absorbance spectroscopy at 280 nm of methanol extracts of the chow. Standard regression analyses were performed. Target concentration attainment and content uniformity were defined as sample concentrations being within +/- two methodology standard deviations of the mean concentration at the three levels of IH636 in the different test diets.
The stability of IH636 in the rodent chow was determined by absorbance spectroscopy at 280 nm and comparison to a "fingerprint" HPLC chromatogram. Standard regression analyses were performed on the UV spectroscopy. Stability was defined as sample concentrations being within +/- two methodology standard deviations of the mean concentration at the three levels of IH636 in the rodent chow and no new unidentified chromatographic peaks at greater than 0.01 area percent appearing in the "fingerprint" chromatogram. For the "fingerprint" HPLC analysis, methanol extracts of the chow samples were dried. The dried samples were reconstituted with 30% ethanol/70% water to make 1000 ppm solutions. 25m l of the 1000 ppm solution were injected onto a Zorbax SB-C18 4.6 x 150 mm, 5µ column maintained at 30 ºC. The injected material was eluted at 0.5 ml/min with a mobile phase gradient from 2.5% acetic acid/97.5% water to 2.5% acetic acid/17.5% water/80% acetonitrile in 85 minutes. The eluting material was monitored at 280 nm.
Grape Seed Extraction:
Grape Seed isolates were prepared by batch extraction with 100% water from dried grape seeds at up to 82 ºC for up to 40 minutes. These isolates were purified by ultrafiltration and chromatography according to the process of Nafisi-Movaghar et al. (64) to produce IH636.
Loss on drying (LOD) and ash were determined on neat IH636 by AOAC methods 925.09 and 923.03, respectively. IH636 is a complicated mixture of chemical classes. It was separated into an ethyl acetate and aqueous soluble fractions to facilitate chemical analysis by the method of Oszmianski and Sapis. The amino acid content of IH636 was then determined by hydrolysis of an aliquot of the aqueous soluble fraction followed by the methodology of Battaglia et al. The oligomeric polyphenols (OPC) content of IH636 was determined from the ethyl acetate soluble fraction by the methods of Vonk et al. and Sun et al. The monomeric proanthocyanidins in IH636 were quantified from the ethyl acetate soluble fraction according to the method of Fuleki and daSilva. The phytosterol content was determined by the method of Indyk, after a saponification and extraction of an aliquot of the ethyl acetate soluble fraction. The fatty acid content was quantified from the ethyl acetate soluble fraction by the method of Mehta et al. The polysaccharide content of IH636 was determined from the aqueous soluble fraction by the method of Lopez-Barajas et al..
RESULTS AND DISCUSSION
Grape Seed Extract Characterization and Stability:
The chemical composition of IH636 is shown in Table 2. It was possible to complete a mass balance of IH636 with 100% accountability. The non-polyphenolic components in IH636 are typical compounds found in plant material. The target concentrations, content uniformity, and stability of the Grape Seed Extract in the various chows were demonstrated to a 95% confidence level. No losses of IH636 were incurred due to instability under the storage conditions of –6 to –20 ºC for 94 days. No new unidentified compounds were detected in the IH636 in rodent chow during the course of the stability study. All six batches of IH636 used in the study complied with the Final Product Specifications with respect to the overall proanthocyanidin and monomer contents, heavy metal analysis and microbial contamination.
Figure 1. Structures of the major flavan-3-ols identified in grape seed extract.
Proanthocyanidin B-1 Dimer Proanthocyanidin C-1 Trimmer
Figure 2. Structures of proanthocyanidin oligomers. The oligomeric proanthocyanidins are composed of flavan-3-ols units linked together from the C4 of one unit to either the C6 or C8 of the adjacent unit.
Figure 3. Body weights (g) for male Sprague-Dawley Rats
Figure 4. Body weights (g) for female Sprague-Dawley Rats Body weights (g) for female Sprague-Dawley Rats
Figure 5. Cumulative food consumption (g) for male Sprague-Dawley Rats
Figure 6. Cumulative food consumption (g) for female Sprague-Dawley Rats