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Plant Profiler

Cranberry (Vaccinium macrocarpon)


Vaccinium macrocarpon
Synonyms / Common Names / Related Terms
Alpha-linolenic acid, American cranberry, anthocyanins, Arandano Americano, Arandano trepador, ascorbic acid, Azo-cranberry®, bear berry, benzoic acid, black cranberry, bog cranberry, catechins, cinnamic acids, citric acid, coumaroyl iridoid glycosides, ellagitannins, Ericaceae (family), European cranberry, flavonol glycosides, flavanols, flavonoids, gallotannins, grosse moosebeere, isokarpalo, Kranbeere, Kronsbeere, large cranberry, lectins, low cranberry, malic acid, marsh apple, moosebeere, mossberry, mountain cranberry, n-3 fatty acids, n-6 fatty acids, Oxycoccus hagerupii, Oxycoccus macrocarpus, Oxycoccus microcarpus, Oxycoccus palustris, Oxycoccus quadripetalus, phenolic acids, pikkukarpalo, preisselbeere, proanthocyanidins, quinic acid, ronce d'Amerique, stilbenes, substituted cinnamic acids, sweetened dried cranberries, trailing swamp cranberry, triterpenoids, Tsuru-kokemomo, ursolic acid, Vaccinium edule, Vaccinium erythrocarpum, Vaccinium hageruppi, Vaccinium microcarpum, Vaccinium occycoccus, Vaccinium plaustre, Vaccinium vitis.


Mechanism of Action

Pharmacology:

  • Constituents: Six ounces of cranberry juice cocktail (Ocean Spray®), on average, contains 96 calories, 24g carbohydrates, 0.17g crude fiber, 0.02g benzoic acid, 0.28g citric acid, 0.30g malic acid, and 0.45g quinic acid.23 In 94.5g of fresh frozen cranberries, there are an average of 35 calories, 7.8g carbohydrates, 2.1g crude fiber, 0.01g benzoic acid, 0.52g citric acid, 0.48g malic acid, and 0.53g quinic acid.23 Cranberry powder hard gelatin capsules (6.9g in 12 capsules, tested brand manufactured by Murdock Pharmaceuticals) contains 24 calories, 5g carbohydrates, 0.97g crude fiber, 0.001g benzoic acid, 0.46g citric acid, 0.53g malic acid, and 0.50g quinic acid.23 The cranberry juice used in one study contained seven phenolic acids, with 3- and 5-caffeoylquinic acid being the primary components, and 15 flavonol glycosides, with myricetin-3-galactoside and quercetin-3-galactoside being the most prevalent.30 Other constituents of cranberry include coumaroyl iridoid glycosides, flavonoids (anthocyanins, flavonols, ellagitannins, flavonol glycosides, gallotannins, and proanthocyanidins), substituted cinnamic acids, stilbenes, triterpenoids (ursolic acid and its esters), alpha-linolenic acid, n-6 fatty acids, n-3 fatty acids.1,12,34,35,36,37
  • Antibacterial effects: Cranberry is traditionally used to treat or prevent urinary tract infections (UTIs) and many reviews have been written regarding the use of cranberry for this purpose.38,39,40,41 It has been studied in vitro for antibacterial or bacteriostatic properties.42 Cranberry juice at 30-35°C did not have viable cells detected for five to eight days.43 Against specific bacteria, cranberry proanthocyanidins and flavonols inhibited the growth of Streptococcus mutans37 and cranberry phenolics showed antibacterial activity against Helicobacter pylori31. However, another study by Monroy-Torres et al. found that cranberry juice did not affect the growth of Escherichia coli, the bacteria responsible for urinary tract infections.44 To simulate an environment more similar to that found in urinary tract infections, some studies have taken urine from subjects who had ingested cranberry products and tested bacterial growth in this medium.45 Although E. coli is the best-studied organism, in vitro examinations of bacterial adherence to urinary epithelial cells have shown that pre-incubation of Proteus, Pseudomonas, and E. coli with cranberry juice cocktail results in decreased adhesion to epithelial cells.46 This effect has been more pronounced in vitro than in vivo, and cranberry juice has not been found to eradicate the most adherent bacteria. Cranberry supplements (Cranactin® tablet, 400mg three times daily for two days) and ascorbic acid (500mg twice daily for two days) each have decreased deposition rates and numbers of adherent E. coli and Enterococcus faecalis in vitro, but not Pseudomonas aeruginosa, Staphylococcus epidermis, or Candida albicans.47 Recently, investigators used a five-fold concentrated preparation of cranberry juice adjusted to a pH of 7.0 and incubated bacterial strains in broth with cranberry and plain controls. At 24 hours, the cranberry-inoculated broth showed no growth of E. coli, Staphylococcusaureus , Pseudomonas, Klebsiella, and Proteus and decreased growth of Enterococcus faecalis or Salmonella.48 Cranberry has not been shown to be bactericidal.
  • Anticancer effects: Possible chemopreventive mechanisms of action by cranberry phytochemicals include induction of apoptosis in tumor cells, cell cycle arrest, reduced ornithine decarboxylase activity, decreased expression of matrix metalloproteinases associated with prostate tumor metastasis, and anti-inflammatory activities including inhibition of cyclooxygenases.49,10 Proanthocyanidin oligomers, flavonol and anthocyanin glycosides and triterpenoids are all likely contributors to the observed anticancer properties and may act in an additive fashion to block carcinogenesis.50 Several in vitro and animal studies using CAL-27 oral cancer, DU145 androgen-independent prostate carcinoma, HCT116 colon carcinoma, HepG2 human liver cancer, HT-29 colon carcinoma, KB oral cancer, LNCaP prostate tumor, MCF-7 human breast cancer, and U87 glioblastoma multiforme cell lines have shown that cranberry extracts arrest tumor cell proliferation and induce apoptosis with EC50 values of 11.7-87.4mcM.51,52,35,49,34,53 In one animal study, two extracts slowed the growth of explant tumors, and one of the extracts induced complete regression.51
  • Anticoagulant effects: In a few case reports and preliminary studies, ingestion of cranberry increased bleeding and increased INR in patients taking warfarin (Coumadin®).3,4,5,6,7,8,9,25 However, studies in healthy volunteers, patients taking warfarin, and laboratory animals indicate that moderate consumption of cranberry (up to 250mL for up to 10 days) does not affect the anticoagulation effects of warfarin or INR.19,26,20,27,28
  • Anti-inflammatory effects: Cranberry has shown some anti-inflammatory activities, including the inhibition of cyclooxygenases.10 In addition, a cranberry fraction potently inhibited pro-inflammatory cytokine and chemokine responses induced by lipopolysaccharides in vitro .11
  • Antioxidant effects: In in vitro studies, cranberry and its constituents have shown antioxidant activity 54,15,52,35,49,12,55,21, with the antioxidant activity seen specifically by proanthocyanidins54, quercetin, 3,5,7,3',4'-pentahydroxyflavonol-3-O-beta-D-glucopyranoside, 3,5,7,3',4'-pentahydroxyflavonol-3-O-beta-D-galactopyranoside, and 3,5,7,3',4'-pentahydroxyflavonol-3-O-alpha-l-arabinofuranoside52.
  • Antiulcer effects: Cranberry phenolics showed antibacterial activity against Helicobacter pylori in vitro.31
  • Antiviral effects: In a series of in vitro studies, Lipson et al. noted that a commercially available cranberry fruit juice drink had a non-specific antiviral effect towards unrelated viral species, including, bacteriophages T2 and T4 and the simian rotavirus SA-11.56 In addition, high molecular weight materials from cranberry dose-dependently inhibited influenza virus A and B from hemagglutinating red blood cells and reduced the viruses' infectivity in vitro.57
  • Cholesterol effects: In a study of abdominally obese men, ingestion of 250mL of a low-calorie cranberry juice cocktail daily resulted in a significant increase in plasma HDL-cholesterol concentration (+8.6 ± 14.0% vs. 0mL low-calorie cranberry juice cocktail daily; p<0.01), although this increase was not affected by subsequent increased consumption of cranberry juice cocktail.13 LDL and VLDL levels were not affected. In similar studies, cranberry juice supplementation significantly reduced circulating oxidized LDL concentrations, but did not affect plasma lipoprotein-lipid concentrations.14 These results are supported by in vitro study as well.15
  • Cytochrome P450 effects: According to case reports and studies in healthy humans and in vitro, cranberry juice does not inhibit cytochrome CYP2C9, CYP1A2, or CYP3A.19,20,28 However, laboratory studies indicate that cranberry juice may inhibit the function of enteric CYP3A.9
  • Genitourinary effects: Cranberries contain a group of compounds, called proanthocyanidins, which are condensed tannins (Gray, 2002; Lowe and Fagelman, 2001; Kuzminski, 1996;Hutchinson, 2005, 740; Howell, 2005 741}. These are thought to be the key factors in inhibiting E. coli adherence. Other potential active constituents include galabiose, prunin, and phlorizin.58 In in vitro study, cranberry powder significantly decreased the mean adherence of Escherichia coli to vaginal epithelial cells (p<0.001) and cranberry proanthocyanidin extract significantly decreased the mean adherence of E. coli to primary cultured bladder epithelial cells (p<0.001) in a linear, dose-dependent fashion.59 In studies using urine from subjects who had ingested cranberry products, the urine inhibited the adhesion of uropathogenic E. coli strains in a manner dependent on the dose of cranberry product ingested.60,61,62,63
  • Oral plaque formation prevention activity: Data from in vitro and clinical studies suggests that the ability to reduce Streptococci mutans counts in the saliva is due to the anti-adhesion activity of the cranberry constituent.64,65 In addition, an in vitro study found that cranberry constituents may reduce the capacity of Porphyromonas gingivalis to colonize periodontal sites.18
  • Periodontal disease prevention activity: Several mechanisms of action for the benefits of cranberry components in reducing oral diseases, including dental caries and periodontitis, have been suggested.66 Inhibition of acid production, attachment, and biofilm formation by Streptococcus mutan, glucan-binding proteins, extracellular enzymes, carbohydrate production, and bacterial hydrophobicity, are all affected by cranberry components. Two in vitro studies found that cranberry fractions dose-dependently inhibited matrix metalloproteinases and intracellular signaling proteins produced by fibroblasts and macrophages associated with periodontal diseases.16,17
  • Urinary acidification properties: With consumption of cranberry juice up to 4L daily, hippuric acid excretion increases, as does urine volume, leading to no changes in urine pH and minimal increases in hippuric acid concentration (to a level that is insufficient for bacteriostasis).24 One study showed only transient decreases in urinary pH in three of four subjects.32 A study in 40 normal subjects found urinary pH to decrease by 0.5, to a minimum of 5.4, with consumption of 250mL of 80% cranberry juice three times daily for 12 days.33 A limitation of this study was that the beverage contained 80% cranberry juice, as opposed to commercially available cocktails that are 25-33% juice. Notably, bacteriostasis has been achieved at pH levels of 5.5.
  • UTI prophylaxis properties: For many years, it was believe that cranberry prevented urinary tract infections (UTI) by means of urinary acidification. However, it has now been demonstrated that cranberry juice inhibits bacterial adherence to uroepithelial cells by 75% for 60 of 77 E. coli clinical isolates in vitro when controlling for pH.67,68,69,70,71,72 Uropathogenic E. coli adhere to urinary bladder cells because they have substances that mediate adhesion on the hair-like fimbriae or pili on their surfaces. Cranberry juice contains two compounds that have been found to block E. coli adhesion.73,2 One is fructose (present in most fruit juices). It has been found that fructose in guava, pineapple, mango, grapefruit, blueberry, and cranberry juice inhibit the mannose-sensitive type-1 fimbrial adhesin in yeast aggregation assays. The second inhibitor is a high molecular weight compound called proanthocyanidin, found in cranberry and blueberry juices (genus Ericaceae), which acts on the mannose-resistant P fimbriae or pili expressed by uropathogenic E. coli.74,68,75 In vitro, this inhibition is irreversible.
  • Urinary salicylate levels activity: In a study of healthy women who were not taking salicylate drugs, consumption of 250mL of cranberry juice three times daily was associated with an increase (p<0.001) of salicyluric and salicylic acids in urine within one week.29 In addition, two weeks after the start of cranberry juice ingestion, the women showed a small but significant (p<0.05) increase in salicylic acid in plasma.
    Pharmacodynamics/Kinetics:
  • Human studies have not adequately addressed the precise absorption, bioavailability, volume of distribution, metabolism, elimination half-life, onset of action, time to peak, or duration of activity of cranberry.
  • In multiple studies of urinary acidification, urine samples were obtained 2-4 hours after ingestion of cranberry juice, although some trials collected 24-hour urine samples (others do not report the time of collection). One study of plasma antioxidant capacity of cranberry juice determined that plasma phenol levels peaked at one hour, and vitamin C concentrations reached a plateau at two hours.22 Since neither of these are the putative active agents for preventing urinary tract infection, the influence of these findings on dosing is not clear.
  • Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly.25 Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. There was some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin.
  • Metabolism: According to case reports and studies in healthy humans and in vitro, cranberry juice does not significantly inhibit cytochrome CYP2C9, CYP1A2, or CYP3A.19,20,28,76 However, laboratory studies indicate that cranberry juice may inhibit the function of enteric CYP3A.9
  • Excretion: Healthy volunteers who ingested 200mL of cranberry juice excreted six of 12 anthocyanins identified in cranberry in their urine at 24 hours, although the maximum anthocyanin excretion occurred between three and six hours after ingestion.77

Pharmacodynamics/Kinetics:

  • Human studies have not adequately addressed the precise absorption, bioavailability, volume of distribution, metabolism, elimination half-life, onset of action, time to peak, or duration of activity of cranberry.
  • In multiple studies of urinary acidification, urine samples were obtained 2-4 hours after ingestion of cranberry juice, although some trials collected 24-hour urine samples (others do not report the time of collection). One study of plasma antioxidant capacity of cranberry juice determined that plasma phenol levels peaked at one hour, and vitamin C concentrations reached a plateau at two hours.22 Since neither of these are the putative active agents for preventing urinary tract infection, the influence of these findings on dosing is not clear.
  • Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly.25 Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S- or R-warfarin pharmacokinetics or plasma protein binding. There was some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin.
  • Metabolism: According to case reports and studies in healthy humans and in vitro, cranberry juice does not significantly inhibit cytochrome CYP2C9, CYP1A2, or CYP3A.19,20,28,76 However, laboratory studies indicate that cranberry juice may inhibit the function of enteric CYP3A.9
  • Excretion: Healthy volunteers who ingested 200mL of cranberry juice excreted six of 12 anthocyanins identified in cranberry in their urine at 24 hours, although the maximum anthocyanin excretion occurred between three and six hours after ingestion.77

References
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