Grape

Grape/Drug Interactions:

  • GeneralGeneral: Based on mechanism of action, grape seed extract (GSE) may interact with drugs that use organic anion-transporting polypeptide B substrates in intestinal absorption, because GSE inhibited estrone-3-sulfate uptake in vitro (197).
  • AnalgesicsAnalgesics: A small case series suggested that grape seed extract (GSE) decreased abdominal pain associated with chronic pancreatitis (145). In humans, ingestion of phenacetin together with grape juice led to decreased plasma phenacetin levels compared with controls (65).
  • Angiotensin-converting enzyme (ACE) inhibitorsAngiotensin-converting enzyme (ACE) inhibitors: Proanthocyanidins extracted from Chilean black grape (Vitis vinifera L. cv. Pa?s) seeds and skin inhibited the activity of angiotensin I-converting enzyme (ACE) in vitro (198). In vitro and in animals, oligomeric proanthocyanidins (OPCs) may inhibit angiotensin I-converting enzyme activity by noncompetitive inhibition (199).
  • AntibioticsAntibiotics: Grape preparations or constituents, alone or in combination with other agents, inhibited bacteria growth, including Bacillus cereus ATCC 11778, B. subtilis ATCC 6633, Streptococcus faecalis TISTR 459, Pseudomonas aeruginosa ATCC 25517, Staphylococcus aureus ATCC 25093, Bacillus cereus, Listeria monocytogenes, most of the Lactobacillus strains (with the exception of L. helveticus H.), and others (4; 200; 201; 62). In vitro, grape seed and skin extracts and grape pomace extract showed antibacterial activity against a variety of species (4; 5). The combination of grape seed extract, green tea extract, and tartaric acid, has shown antibacterial activity against Listeria monocytogenes (200).
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In clinical research and in vitro, Pycnogenol? or OPC preparations significantly and dose-dependently reduced platelet aggregation (71; 73; 72). In vitro, polyphenolic grape extract induced dose-dependent inhibition of thrombin receptor (PAR-1) activating peptide (TRAP)-induced and ADP-induced platelet aggregation (195). In vitro, blood containing red wine inhibited platelet adhesion to fibrinogen at high and low shear rates, while blood containing polyphenolic grape extract inhibited adhesion only at a low shear rate (202).
  • AntidepressantsAntidepressants: In vitro, (-)-trans-epsilon-viniferin, a resveratrol dimer, inhibited the uptake of 5-HT by human platelets and rat brain synaptosomes and the uptake of noradrenaline by rat brain synaptosomes (8). The resveratrol dimer also inhibited the activity of human recombinant monoamine oxidases A and B.
  • AntidiabeticsAntidiabetics: In humans, Concord grape juice increased plasma glucose but lacked an effect on plasma insulin vs. control (25).
  • AntidiarrhealsAntidiarrheals: In weaning rats, grape seed procyanidins reduced the incidence of diarrhea (203).
  • AntiemeticsAntiemetics: In clinical trials, grape seed extract caused gastrointestinal disturbances, including nausea and indigestion (68; 82; 84; 83; 77).
  • AntifungalsAntifungals: Grape extract inhibited the growth of Aspergillus niger (5).
  • Antigout agentsAntigout agents: In vitro, OPCs were strong and noncompetitive inhibitors of xanthine oxidase (74).
  • AntihypertensivesAntihypertensives: According to a report of an adverse effect in a clinical study, Endotelon? may cause dizziness and hypertension (68). However, in vitro and clinical studies have shown that OPCs and grape seed extract may reduce hypertension (69; 70; 112; 141).
  • Antihyperuricemic agentsAntihyperuricemic agents: In vitro, OPCs were strong and noncompetitive inhibitors of xanthine oxidase (74).
  • Anti-inflammatoriesAnti-inflammatories: Anti-inflammatory effects of grapes, grape products, and grape constituents have been shown in human, animal, and in vitro research (204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 215).
  • AntilipemicsAntilipemics: In animals, OPCs decreased total cholesterol (216; 217). In a clinical trial, the combination of chromium and GSE significantly decreased LDL cholesterol (136). In animals, there was conflicting evidence on whether grape seed increases, decreases, or maintains HDL concentration; however, a clinical trial found that grape seed did not significantly affect HDL (136; 216; 218). In animals, grape or its constituents restored blood triglycerides, VLDL cholesterol, and serum total lipoprotein levels, and increased HDL cholesterol (219). In vitro, reduced LDL oxidation was observed (220; 69).
  • AntineoplasticsAntineoplastics: Grape seed extract (GSE) has been studied extensively in animal and laboratory research to determine potential mechanisms of action for its potential chemotherapeutic effects, with most of the focus on the proanthocyanidins and gallic acid (221; 222; 223; 224; 225; 226; 227; 228; 229). In theory, grape seed may interact with other antineoplastic agents. In in vitro and animal studies, grape or its constituents exhibited antiproliferative and antimutagenic effects in normal and cancerous human and rodent cells (230; 231; 232; 233). In vitro, grape seed proanthocyanidin extract reduced the cytotoxic effects of chemotherapeutic agents, including idarubicin and 4-hydroxyperoxycyclophosphamide (234).
  • Antiobesity agentsAntiobesity agents: In animals, resveratrol, purified from the stem of Vitis coignetiae Pulliat, reduced food intake (235). Concord grape juice (containing approximately 2g/L of phenols) has been consumed, with reduction in waist circumference in otherwise healthy overweight individuals (25).
  • Antivenom agentsAntivenom agents: In human plasma ex vivo, the methanol extract of Vitis vinifera seed inhibited the procoagulation properties of Echis carinatus venom (7). In citrated plasma, edema, hemorrhage, myonecrosis, and coagulation were all reduced, as were the caseinolytic, hyaluronolytic, and fibrinogenolytic activities of the venom. Application of grape seed extract to the bite wound caused by a Russell's viper (Indian Daboia/Vipera russelli) or saw-scaled viper (Echis carinatus) ameliorated local effects of the venom; grape seed extract neutralized proteolytic and hyaluronidase activities and hemorrhage- and edema-inducing activities, and also partially inhibited procoagulant activity and prevented the degradation of fibrinogen chains (6; 7).
  • AntiviralsAntivirals: According to review, resveratrol has antiviral properties (1). In vitro, grape and grape products or constituents inhibited the replication of the recombinant adenovirus vector Ad-5 and the secretion of HbsAg, HbeAg, and HBV DNA; and reduced the infectivity of the human enteric virus surrogates bacteriophage MS2, feline calicivirus (FCV-F9), hepatitis A virus strain HM175, and murine norovirus (MNV-1) (236; 237; 238).
  • Cardiovascular agentsCardiovascular agents: In animals, grape or its constituents improved myocardial contractility index, coronary flow, and oxygen consumption; reduced myocardial ischemia reperfusion injury, myocardial infarction, and blood pressure; restored blood triglycerides, VLDL cholesterol, and serum total lipoprotein levels; and increased HDL cholesterol (239; 18; 240; 219). In vitro, reduced LDL oxidation, and relaxation of intact precontracted aortic rings were observed (220; 69).
  • Cyclooxygenase (COX)-2 inhibitorsCyclooxygenase (COX)-2 inhibitors: In the highly metastatic human melanoma cell lines A375 and Hs294t, exposure to grape seed proanthocyanidins was associated with inhibition of cell migration and reduced levels of cyclooxygenase (COX)-2 and prostaglandin E2 (241).
  • Cyclosporin ACyclosporin A: In rats supplemented with cyclosporin A, black grape extract, or cyclosporine A and black grape extract together for 10 days, malondialdehyde levels in the ovaries were significantly lower in the groups administered black grape extract alone and cyclosporine A plus black grape than in the group that received cyclosporine A alone (242).
  • Cytochrome P450-modifying agentsCytochrome P450-modifying agents: In vitro, GSE reduced CYP450 2E1 activity (66). In vitro research has also shown that grape seed inhibited CYP2C9 and CYP3A4 at 10mcM (243). In humans, grape induced the expression of cytochrome P450 1A2 (CYP1A2) and decreased the levels of drugs metabolized by CYP1A2 (65). It has been suggested that GSPE-induced reduction of CYP1A1 and CYP1B1 may be involved in suppression of carcinogenesis in noncancerous cells (244). In the promyelocytic HL-60 cell and human hepatocarcinoma HepG2 and lines, red grape juice polyphenols modulated the activity of LDL cholesterol and reduced the expression of CYP7A1 and other proteins (245).
  • Dental and periodontal agentsDental and periodontal agents: In human maxillary central incisors in vitro, bleaching of teeth with 38% hydrogen peroxide, followed by treatment with 5% proanthocyanidin solution, was associated with higher shear bond values than in seen in teeth treated with sodium ascorbate after bleaching (246). In laboratory research, application of adhesive containing 5% grape seed proanthocyanidins to acid-etched dentin protected collagen fibrils in the hybrid layer from collagenase digestion (247). Grape seed extract significantly increased the microhardness of artificial root caries in vitro; the authors concluded that GSE may have positive effects on mineralization or remineralization (248).
  • Dermatologic agentsDermatologic agents: Grape seed proanthocyanidins inhibited ultraviolet (UV)-radiation-induced oxidative stress in human epidermal keratinocytes (23; 249). Grape has been used as a substrate for the synthesis of gamma-aminobutyric acid (GABA) by Lactobacillus plantarum for dermatological uses and compared to the use of pure GABA in a model of human skin (22). In vitro, in melanocytes, oligomeric proanthocyanidins from grape seeds inhibited ultraviolet-induced melanogenesis (250). The free radical-scavenging properties of oligomeric proanthocyanidins (OPCs) are hypothesized to protect skin from the harmful effects of UV radiation (23; 251; 252).
  • Doxorubicin (Adriamycin)Doxorubicin (Adriamycin): In vitro, grape proanthocyanidins reduced cardiotoxicity associated with doxorubicin (253). In animal and in vitro research, proanthocyanidin from grape seeds enhanced the antitumor effect of, and reduced resistance to, doxorubicin (254; 255). In vitro, grape seed extract had synergistic anticancer effects with doxorubicin (256). In animals, grape seed polyphenols reversed the resistance to Adriamycin (doxorubicin) (257).
  • Drugs used for osteoporosisDrugs used for osteoporosis: In vitro, syringetin, a constituent of grape, induced human osteoblast differentiation (258).
  • EstrogensEstrogens: In cultures of human breast cancer cells, resveratrol induced the expression of estrogen-responsive genes (259). In vitro resveratrol from grape exhibited antiestrogenic activity and inhibited the growth of human breast cancer cells (260). According to a review, unclear scientific evidence suggests that resveratrol exhibits estrogenic activity in transfected mammary cancer cells (1).
  • Folate analogsFolate analogs: In vitro, the ability of OPCs to inhibit xanthine oxidase may lead to methotrexate toxicity (74).
  • HepatotoxinsHepatotoxins: Animal studies suggest oligomeric proanthocyanidins (OPCs) may have a hepatoprotective effect (261). In vitro, resveratrol, a constituent of grape, had antiproliferative effects in human liver myofibroblasts (262).
  • ImmunosuppressantsImmunosuppressants: According to review, animal studies show that grape products support the immune system (49). Secondary sources suggest that grape extract stimulates colony-forming efficiency and organogenic potential, and improves the maintenance of epidermal stem cells. In vitro, grape seed extract activated Th1 cells, potentially via induction of interferon-gamma (263).
  • Insulin preparationsInsulin preparations: In fructose-fed rats with insulin-induced cardiac hypertrophy and cardiovascular complications, procyanidins had the greatest effect in reducing insulin resistance in animals fed an anthocyanin grape extract, a procyanidin grape seed extract, or a vitaflavan polyphenolic grape seed extract. In vitro, grape powder suppressed LPS-induced insulin resistance in human adipocytes (214).
  • MethotrexateMethotrexate: In vitro, the ability of OPCs to inhibit xanthine oxidase may lead to methotrexate toxicity (74).
  • Neurologic agentsNeurologic agents: According to a review, resveratrol had neuroprotective properties (1; 20). Grape products have shown beneficial effects in animal models of Parkinson's disease and Alzheimer's disease (16; 264; 265; 266; 267). In a mouse model of Alzheimer's disease, grape seed extract prevented deposition of beta-amyloid and attenuated brain inflammation (264).
  • PhenacetinPhenacetin: In humans, ingestion of phenacetin together with grape juice led to decreased plasma phenacetin levels compared with controls (65).
  • PhotosensitizersPhotosensitizers: In SKH-1 hairless mice, dietary grape seed proanthocyanidins inhibited ultraviolet B (UVB)-induced oxidative stress and reduced UV-induced skin cancer in terms of incidence, multiplicity, and malignant transformation(252; 268). Grape seed proanthocyanidins had photoprotective effects in UV-irradiated normal human melanocytes (250; 249). Secondary sources suggest that grape extract affords UV protection.
  • VasodilatorsVasodilators: In men with coronary heart disease, consumption of red grape polyphenol extract resulted in a significant increase in flow-mediated dilatation of the brachial artery (67). Blood pressure was reduced in rats with cardiovascular disease fed anthocyanin grape extract, procyanidin grape seed extract, and a vitaflavan polyphenolic grape seed extract (240). In vitro, grape caused endothelial-dependent vasorelaxation of isolated rat aortic rings (69).
  • Wound-healing agentsWound-healing agents: In mice the topical application of a grape seed proanthocyanidin extract containing resveratrol increased wound healing (contraction and closure) (269).
  • Xanthine oxidase inhibitorsXanthine oxidase inhibitors: In vitro, OPCs were strong and noncompetitive inhibitors of xanthine oxidase (74).

    • Grape/Herb/Supplement Interactions:

  • AnalgesicsAnalgesics: A small case series suggested that grape seed extract (GSE) decreased abdominal pain associated with chronic pancreatitis (145).
  • AntibacterialsAntibacterials: Grape preparations or constituents, alone or in combination with other agents, inhibited bacteria growth, including Bacillus cereus ATCC 11778, B. subtilis ATCC 6633, Streptococcus faecalis TISTR 459, Pseudomonas aeruginosa ATCC 25517, Staphylococcus aureus ATCC 25093, Bacillus cereus, Listeria monocytogenes, most of the Lactobacillus strains (with the exception of L. helveticus H.), and others (4; 200; 201; 62). In vitro, grape seed and skin extracts and grape pomace extract showed antibacterial activity against a variety of species (4; 5). The combination of grape seed extract, green tea extract, and tartaric acid, has shown antibacterial activity against Listeria monocytogenes (200).
  • Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In humans and in vitro, Pycnogenol? or oligomeric proanthocyanidin (OPC) preparations may significantly and dose-dependently reduce platelet aggregation (71; 73; 72). Examples include Ginkgo biloba and garlic (Allium sativum). Grape seed may also increase blood levels of herbs processed by the liver, such as chasteberry (Vitex agnus-castus). In vitro, polyphenolic grape extract induced dose-dependent inhibition of thrombin receptor (PAR-1) activating peptide (TRAP)-induced and ADP-induced platelet aggregation (195). In vitro, blood containing red wine inhibited platelet adhesion to fibrinogen at high and low shear rates, while blood containing polyphenolic grape extract inhibited adhesion only at a low shear rate (202).
  • AntidepressantsAntidepressants: In vitro, (-)-trans-epsilon-viniferin, a resveratrol dimer, inhibited the uptake of 5-HT by human platelets and rat brain synaptosomes and the uptake of noradrenaline by rat brain synaptosomes (8). The resveratrol dimer also inhibited the activity of human recombinant monoamine oxidases A and B.
  • Antidiarrheal agentsAntidiarrheal agents: In weaning rats, grape seed procyanidins reduced the incidence of diarrhea (203).
  • AntiemeticsAntiemetics: In clinical trials, grape seed extract (GSE) may cause gastrointestinal disturbances, including nausea and indigestion (77; 68; 82; 84; 83).
  • AntifungalsAntifungals: Grape extract inhibited the growth of Aspergillus niger (5).
  • Antigout agentsAntigout agents: In vitro, OPCs were strong and noncompetitive inhibitors of xanthine oxidase (74).
  • Anti-inflammatoriesAnti-inflammatories: Anti-inflammatory effects of grapes, grape products, and grape constituents have been shown in human, animal, and in vitro research (204; 205; 206; 207; 208; 209; 210; 211; 212; 213; 214; 215).
  • AntilipemicsAntilipemics: In animals, OPCs decreased total cholesterol (216; 217). In a clinical trial, the combination of chromium and grape seed extract significantly decreased LDL (136). In animals, there was conflicting evidence on whether grape seed increases, decreases, or maintains HDL concentration; however, a clinical trial found that grape seed did not significantly affect HDL (136; 216; 218). In animals, grape or its constituents restored blood triglycerides, VLDL cholesterol, and serum total lipoprotein levels, and increased HDL cholesterol (219). In vitro, reduced LDL oxidation was observed (220; 69).
  • AntineoplasticsAntineoplastics: Grape seed extract (GSE) has been studied extensively in animal and laboratory research to determine potential mechanisms of action for its potential chemotherapeutic effects, with most of the focus on the proanthocyanidins and gallic acid (221; 222; 223; 224; 225; 226; 227; 228; 229). In theory, grape seed may interact with other herbs or supplements with anticancer effects. In vitro and in animal studies, grape or its constituents exhibited antiproliferative and antimutagenic effects in normal and cancerous human and rodent cells (230; 231; 232; 233).
  • Antiobesity agentsAntiobesity agents: In animals, resveratrol, purified from the stem of Vitis coignetiae Pulliat inhibited food intake (235).
  • AntioxidantsAntioxidants: In clinical trials and in vitro, OPCs had antioxidant properties (270; 74; 271; 272; 143). In human studies, grape or grape constituents demonstrated extensive antioxidant activity, including increased total antioxidant capacity, reduced levels of oxidation products, and increased erythrocyte glutathione reductase and plasma ascorbate (99). In animal studies, free radical production and markers of oxidative stress decreased (242; 240; 219). In vitro, increases were seen in free radical-scavenging activity and platelet nitric oxide release, while free radical release and lipid peroxidation were reduced (4; 273; 274; 230; 18; 220; 275; 276; 277; 278).
  • AntiveninsAntivenins: In human plasma ex vivo, the methanol extract of Vitis vinifera seed inhibited the procoagulation properties of Echis carinatus venom (7). In citrated plasma, edema, hemorrhage, myonecrosis, and coagulation were all reduced, as were the caseinolytic, hyaluronolytic, and fibrinogenolytic activities of the venom. Application of grape seed extract to the bite wound caused by a Russell's viper (Indian Daboia/Vipera russelli) or saw-scaled viper (Echis carinatus) ameliorated local effects of the venom; grape seed extract neutralized proteolytic and hyaluronidase activities and hemorrhage and edema-inducing activities, and also partially inhibited procoagulant activity and prevented the degradation of fibrinogen chains (6; 7).
  • AntiviralsAntivirals: According to review, resveratrol has antiviral properties (1). In vitro, grape and grape products or constituents inhibited the replication of the recombinant adenovirus vector Ad-5 and the secretion of HbsAg, HbeAg, and HBV DNA; and reduced the infectivity of the human enteric virus surrogates bacteriophage MS2, feline calicivirus (FCV-F9), hepatitis A virus strain HM175, and murine norovirus (MNV-1) (236; 237; 238).
  • Cardiovascular agentsCardiovascular agents: In animals, grape or its constituents improved myocardial contractility index, coronary flow, and oxygen consumption; reduced myocardial ischemia reperfusion injury, myocardial infarction, and blood pressure; restored blood triglycerides, VLDL cholesterol, and serum total lipoprotein levels; and increased HDL cholesterol (239; 18; 240; 219). In vitro, relaxation of intact precontracted aortic rings and reduced LDL oxidation were observed (220; 69). In vitro and in animals, OPCs inhibited angiotensin I-converting enzyme activity by noncompetitive inhibition (199).
  • ChromiumChromium: The combination of chromium, grape seed extract, and zinc resulted in a decrease in systolic blood pressure, hemoglobin A1c, and lipid oxidation (279). The effect of GSWE alone, however, is unclear.
  • CopperCopper: In vitro, grape extract inhibited the copper-induced oxidation of human low-density lipoprotein (LDL) (220).
  • Cyclooxygenase (COX)-2 inhibitorsCyclooxygenase (COX)-2 inhibitors: In the highly metastatic human melanoma cell lines A375 and Hs294t, exposure to grape seed proanthocyanidins was associated with inhibition of cell migration and reduced levels of cyclooxygenase (COX)-2 and prostaglandin E2 (241).
  • Cytochrome P450-modifyingCytochrome P450-modifying: In vitro, grape seed extract reduced CYP450 2E1 activity (66). Grape seed may also increase blood levels of herbs processed by the liver, such as chasteberry (Vitex agnus-castus). In vitro research has also shown that grape seed inhibited CYP2C9 and CYP3A4 (243). In humans, grape induced the expression of cytochrome P450 1A2 (CYP1A2) and decreased the levels of drugs metabolized by CYP1A2 (65).
  • Dental and periodontal agentsDental and periodontal agents: In human maxillary central incisors in vitro, bleaching of teeth with 38% hydrogen peroxide, followed by treatment with 5% proanthocyanidin solution, was associated with higher shear bond values than those in seen in teeth treated with sodium ascorbate after bleaching (246). In laboratory research, application of adhesive containing 5% grape seed proanthocyanidins to acid-etched dentin protected collagen fibrils in the hybrid layer from collagenase digestion (247). Grape seed extract significantly increased the microhardness of artificial root caries in vitro; the authors concluded that GSE may have positive effects on mineralization or remineralization (248).
  • Dermatologic agentsDermatologic agents: Grape seed proanthocyanidins inhibited UV-radiation-induced oxidative stress in human epidermal keratinocytes (23; 249). Grape has been used as a substrate for the synthesis of gamma-aminobutyric acid (GABA) by Lactobacillus plantarum for dermatological uses and compared to the use of pure GABA in a model of human skin (22). In vitro, in melanocytes, oligomeric proanthocyanidins from grape seeds inhibited ultraviolet-induced melanogenesis (250). The free radical-scavenging properties of oligomeric proanthocyanidins (OPCs) are hypothesized to protect skin from the harmful effects of UV radiation (23; 251; 252).
  • Fish oilFish oil: Fractionated phenols from grape pomace extract inhibited the oxidation of lipids in fish oil and frozen muscle (280).
  • FolateFolate: In vitro, OPCs inhibited xanthine oxidase, which may affect folate metabolism (74).
  • Green tea extractGreen tea extract: The combination of grape seed extract, green tea extract, and tartaric acid to marinate chicken, followed by irradiation of the meat, has shown antibacterial activity against Listeria monocytogenes (200). Probiotic bacteria showed better survival in model fruit juice supplemented with vitamin C, grape extract, and green tea extract than in model fruit juice alone (281). In animals, grape extracts and decaffeinated green tea extracts had synergistic anticancer effects (282).
  • HepatotoxinsHepatotoxins: Animal studies suggest that oligomeric proanthocyanidins (OPCs) may have a hepatoprotective effect in the setting of hepatic injury (261). In vitro, resveratrol, a constituent of grape, had antiproliferative effects in human liver myofibroblasts (262).
  • Hyperglycemics and hypoglycemicsHyperglycemics and hypoglycemics: In humans, Concord grape juice increased plasma glucose but lacked an effect on plasma insulin vs. control (25).
  • HypotensivesHypotensives: According to a report of an adverse effect in a clinical study, Endotelon? may cause dizziness and hypertension (68). However, in vitro and clinical studies have shown that OPCs and grape seed extract may reduce hypertension (69; 70; 112; 141).
  • ImmunomodulatorsImmunomodulators: According to a review, animal studies show that grape products support the immune system (49). Secondary sources suggest that grape extract stimulates colony-forming efficiency and organogenic potential, and improves the maintenance of epidermal stem cells. In vitro, grape seed extract activated Th1 cells, potentially via induction of interferon-gamma (263).
  • IronIron: In humans, iron was found to be absorbed from grape molasses (made from boiling down grape juice) (283). Absorption of iron from grape molasses was comparable to that of ferrous sulfate in nonanemic infants and young children, but was less than that of ferrous sulfate in infants and young children with iron deficiency anemia. In vitro in a Caco-2 cell culture model, however, the use of red grape juice was found to inhibit iron availability from infant cereals, while white grape juice increased its bioavailability (284).
  • Lactobacillus acidophilusLactobacillus acidophilus: Grape pomace polyphenolic extract significantly stimulated the growth of L. acidophilusin vitro (285). According to secondary sources, concomitant administration of grape seed and Lactobacillus acidophilus may prevent Lactobacillus acidophilus colonization of the gastrointestinal tract.
  • Neurologic agentsNeurologic agents: According to review, resveratrol may have neuroprotective properties (1; 20). Grape products have shown beneficial effects in animal models of Parkinson's disease and Alzheimer's disease (16; 264; 265; 266; 267). In a mouse model of Alzheimer's disease, grape seed extract has been shown to prevent deposition of beta-amyloid and attenuated brain inflammation (264).
  • NisinNisin: In laboratory studies, grape seed extract and nisin, a mixture of antimicrobial polypeptides, had additive antibacterial effects on Listeria monocytogenes (201).
  • Nitric oxideNitric oxide: Inhibition of nitric oxide synthesis reduced the stimulatory effect of grape extract on coronary flow in isolated guinea pig heart (239).
  • Osteoporosis agentsOsteoporosis agents: In vitro, syringetin, a constituent of grape, induced human osteoblast differentiation through the bone morphogenetic protein-2/extracellular signal-regulated kinase 1/2 pathway (258).
  • PhotosensitizersPhotosensitizers: In SKH-1 hairless mice, dietary grape seed proanthocyanidins inhibited UVB-induced oxidative stress and reduced UV-induced skin cancer in terms of incidence, multiplicity, and malignant transformation(252; 268). Grape seed proanthocyanidins had photoprotective effects in UV-irradiated normal human melanocytes (250; 249). Secondary sources suggest that grape extract affords UV protection.
  • PhytoestrogensPhytoestrogens: In cultures of human breast cancer cells, resveratrol induced the expression of estrogen-responsive genes (259).
  • ProbioticsProbiotics: In vitro, grape seed extract enriched in flavan-3-ols inhibited the growth of Lactobacillus acidophilus, Streptococcus thermophilus, and Lactobacillus fermentum, as well as some strains of bifidobacteria (286). In contrast, grape pomace polyphenolic extract significantly stimulated the growth of L. acidophilusin vitro (285). Probiotic bacteria showed better survival in model fruit juice supplemented with vitamin C, grape extract, and green tea extract than in model fruit juice alone (281).
  • ResveratrolResveratrol: In vitro, resveratrol potentiated the anticancer effects of grape seed extract (287).
  • Scutellaria baicalensisScutellaria baicalensis: In vitro, Scutellaria baicalensis and grape seed proanthocyanidins had synergistic effects on scavenging reactive oxygen species in vitro (288).
  • Tartaric acidTartaric acid: The combination of grape seed extract, green tea extract, and tartaric acid to marinate chicken, followed by irradiation of the meat, has shown antibacterial activity against Listeria monocytogenes (200).
  • VasodilatorsVasodilators: In men with coronary heart disease, consumption of red grape polyphenol extract resulted in a significant increase in flow-mediated dilatation of the brachial artery (67). Blood pressure was reduced in rats with cardiovascular disease fed anthocyanin grape extract, procyanidin grape seed extract, and a vitaflavan polyphenolic grape seed extract(240). In vitro, grape caused endothelial-dependent vasorelaxation of isolated rat aortic rings (69).
  • Vitamin CVitamin C: Probiotic bacteria showed better survival in model fruit juice supplemented with vitamin C, grape extract, and green tea extract than in model fruit juice alone (281). Although one study showed Leucoselect?-phytosome (an OPC preparation) to have no effect on vitamin C levels (271), anecdotal reports have indicated that flavonoids from grape seed enhance the absorption and effectiveness of vitamin C.
  • Vitamin EVitamin E: Although one study showed Leucoselect?-phytosome (an OPC preparation) had no effect on vitamin E levels (271); anecdotal reports have indicated that grape seed enhances the effectiveness of vitamin E.
  • Vulnerary agentsVulnerary agents: In mice the topical application of a grape seed proanthocyanidin extract containing resveratrol increased wound healing (contraction and closure) (269).
  • ZincZinc: The combination of chromium, grape seed extract, and zinc resulted in a decrease in systolic blood pressure, hemoglobin A1c, and lipid oxidation (279).

    • Grape/Food Interactions:

  • BeefBeef: White grape extract inhibited the oxidation of lipid and protein in beef patties stored for nine days at 4?C, regardless of the oxygen and carbon dioxide composition of the atmosphere during packing(289). Grape seed extract (GSE) maintained the level of thiobarbituric acid reactive substances (TBARS) (as well as the fresh flavor and odor) of cooked frozen sausage (containing lean beef, pork fat, and salt) in storage for 18 months, compared with control and ascorbate-treated meat; propyl gallate had the same effect as GSE on flavor and odor (290)
  • Butyl hydroxy toluene (BHT)Butyl hydroxy toluene (BHT): At concentrations of 40 and 60mg of gallic acid equivalents (GAE), extracts from two varieties of grapes had an effect similar to that of butyl hydroxyl toluene (BHT) in significantly inhibiting the oxidation of processed and cooked chicken meat during a 14-day refrigerated storage period (291).
  • CheeseCheese: Cheese to which grape extract or other natural crude polyphenolic compounds had been added during the cheesemaking process showed structural changes, including roughness and granularity (292). Cheese to which polyphenolic compounds, such as crude grape extract were added at a concentration of 0.5mg/mL during the cheesemaking process, exhibited effective free radical scavenging (293).
  • ChickenChicken: Extracts from two varieties of grapes significantly inhibited the oxidation of processed and cooked chicken meat. At concentrations of 40 and 60mg of GAE, the extracts had an effect similar to that of butyl hydroxyl toluene (BHT) (291). The combination of grape seed extract, green tea extract, and tartaric acid to marinate chicken, followed by irradiation of the meat, has shown antibacterial activity against Listeria monocytogenes (200). Grape seed extract in frozen, ground chicken thigh meat inhibited thiobarbituric acid reactive substances (TBARS) formation and mitigated the pro-oxidative effects of sodium chloride without affecting moisture content or pH (294).
  • Fish and fish oilFish and fish oil: Fractionated phenols from grape pomace extract inhibited the oxidation of lipids in fish oil and frozen muscle (280). Galloylated procyanidins extended the shelf life of horse mackerel meat stored at 4?C more for more than eight days, compared to control fish, and maintained the levels of endogenous alpha-tocopherol, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) (295).
  • Green teaGreen tea: The combination of grape seed extract, green tea extract, and tartaric acid to marinate chicken, followed by irradiation of the meat, has shown antibacterial activity against Listeria monocytogenes (200).
  • Lactobacillus acidophilus-containing foodsLactobacillus acidophilus-containing foods: According to secondary sources, concomitant administration of grape seed and Lactobacillus acidophilus may prevent Lactobacillus acidophilus colonization of the gastrointestinal tract.
  • NisinNisin: In vitro, use of grape seed extract and the food preservative nisin resulted in increased reduction of Listeria monocytogenes (201).

    • Grape/Lab Interactions:

  • Blood lipidsBlood lipids: In animal or human studies, grapes, grape products, or grape constituents have been shown to decrease total cholesterol, have variable effects on HDL cholesterol, or reduce triglycerides or LDL cholesterol (216; 217; 136; 296; 218; 219; 12).
  • Blood pressureBlood pressure: According to a report of an adverse effect in a clinical study, Endotelon? may cause hypertension (68). However, in vitro and clinical studies have shown that OPCs and grape seed extract may reduce hypertension (69; 70; 112; 141).
  • Bronchial and conjunctival provocation testsBronchial and conjunctival provocation tests: A case report described a 16 year-old woman with positive bronchial and conjunctival provocation tests specific to grape vine (Vitis vinifera) pollen (92).
  • Coagulation panelCoagulation panel: In clinical research and in vitro, Pycnogenol? or oligomeric proanthocyanidin (OPC) preparations significantly and dose-dependently reduced platelet aggregation (71; 73; 72).
  • ErythroagglutinationErythroagglutination: Lectins isolated from Vitis vinifera L. cv. Chardonnay grape berries agglutinated human and rabbit erythrocytes in vitro (297).
  • Fatty acidsFatty acids: In a small study of the effect of grape procyanidins on markers of oxidative stress in healthy volunteers, fatty acids in erythrocyte membranes showed a higher level of polyunsaturated fats (298).
  • FolateFolate: In vitro, OPCs may inhibit xanthine oxidase, which may affect folate metabolism (74).
  • GlucoseGlucose: In humans, Concord grape juice increased plasma glucose but lacked an effect on plasma insulin vs. control (25).
  • IgE levelIgE level: A case report described a 16 year-old woman with elevated IgE levels specific to grape vine (Vitis vinifera) pollen (92).
  • Immune panelImmune panel: According to a review, animal studies show that grape products support the immune system (49). Secondary sources suggest that grape extract stimulates colony-forming efficiency and organogenic potential, and improves the maintenance of epidermal stem cells. In vitro, grape seed extract activated Th1 cells, potentially via induction of interferon-gamma (263).
  • Inflammatory mediatorsInflammatory mediators: In systemic sclerosis patients, Activin, a grape seed-derived proanthocyanidin extract, reduced plasma levels of ICAM-1, VCAM-1, and E-selectin (204). In animal models, grape seed extract reduced levels of proinflammatory cytokines (205; 206; 207). In normal and disease-model human cells in culture, grape extracts or constituents inhibited the expression of inflammatory markers, including cyclooxygenase (COX)-2 (208; 209; 210; 211; 212; 213; 214). In vitro, a polyphenol-rich grape powder extract (GPE) attenuated inflammation in human macrophages and adipocytes by reducing tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL-1beta, IL-8, interferon-gamma-inducible protein-10 (IP-10), and cyclooxygenase-2; mechanisms of action may include attenuation of activated MAPkinases, NF-kappaB, and AP-1 (c-jun) (214).
  • IronIron: In humans, iron was found to be absorbed from grape molasses (made from boiling down grape juice) (283). Absorption of iron from grape molasses was comparable to that of ferrous sulfate in nonanemic infants and young children, but was less than that of ferrous sulfate in infants and young children with iron deficiency anemia. In vitro in a Caco-2 cell culture model, however, the use of red grape juice was found to inhibit iron availability from infant cereals, while white grape juice increased its bioavailability (284).
  • LDL oxidationLDL oxidation: In vitro, reduced LDL oxidation was observed (220; 69).
  • Liver function panelLiver function panel: In animals, oligomeric proanthocyanidins (OPCs) had a hepatoprotective effect in the setting of hepatic injury (261). In vitro, resveratrol, a constituent of grape, had antiproliferative effects in human liver myofibroblasts (262).
  • Mast cell serine proteasesMast cell serine proteases: In humans, exercise-induced anaphylaxis following ingestion of grapes was accompanied by an increase in serum tryptase level (184).
  • Plasma uratePlasma urate: In humans, when exercise was followed by consumption of grape juice, the increase in plasma urate was greater than that seen with exercise or grape juice alone, but not significantly different from the sum of the two individual values (299).
  • Platelet activationPlatelet activation: In humans, grape juice, but not orange juice or grapefruit juice, inhibited collagen-induced platelet aggregation ex vivo (11). In healthy humans, commercial grape juice reduced the IC50 for thrombin-induced platelet aggregation, and commercial grape juice plus resveratrol increased this value (300). Antiplatelet aggregation or adhesion effects were also shown ex vivo or in vitro (301; 195; 278; 202; 302; 303).
  • Uric acidUric acid: In vitro, OPCs were strong and noncompetitive inhibitors of xanthine oxidase (74).
  • Viral titersViral titers: According to review, resveratrol has antiviral properties (1). In vitro, grape and grape products or constituents inhibited the replication of the recombinant adenovirus vector Ad-5 and the secretion of HbsAg, HbeAg, and HBV DNA; and reduced the infectivity of the human enteric virus surrogates bacteriophage MS2, feline calicivirus (FCV-F9), hepatitis A virus strain HM175, and murine norovirus (MNV-1) (236; 237; 238).