Grapefruit

Scientific Name(s): Citrus paradisi Macfad. Family: Rutaceae

Common Name(s): Grapefruit

Uses

Clinical trials are generally lacking for therapeutic applications. Grapefruit or its juice have potential in influencing weight loss and promoting cholesterol reduction, and have demonstrated antibacterial activity in the urinary tract.

Dosing

Quality clinical trials upon which to base therapeutic dosing recommendations are limited. Improved lipid profiles were achieved with consumption of 1 grapefruit daily for 30 days. Grapefruit juice 8 oz (237 mL), or half of a fresh grapefruit, 3 times a day before each meal for 12 weeks resulted in weight loss in a clinical trial evaluating the effect on metabolic syndrome.

Contraindications

None well defined. In patients with major myocardial structural disorders, pink grapefruit should probably be avoided due to proarrhythmic effects. The potential for drug interaction with grapefruit should be considered in cases where an increase or decrease of the available drug is clinically important.

Pregnancy/Lactation

GRAS (generally recognized as safe) for use as food. Safety and efficacy for dosages above those in foods are unproven.

Interactions

Grapefruit juice has been reported to interact with numerous drugs; however, case reports of significant interactions are rare. Interactions between grapefruit and cyclosporine and some, but not all, calcium channel antagonists and HMG-CoA reductase inhibitors are considered relevant. However, the potential for an interaction with grapefruit should be considered in cases where an increase or decrease of the available drug is clinically important.

Adverse Reactions

Reports of adverse reactions to grapefruit consumption are limited and are largely related to drug interactions. Case reports exist of allergy to pectin and pectin-induced asthma.

Toxicology

Toxicological studies on whole grapefruit are lacking. A meta-analysis of 3 landmark studies evaluating the association of grapefruit consumption and risk of breast cancer found no increased risk. The constituent d-limonene in grapefruit has GRAS status. Grapefruit seed extract has been shown to be toxic to human skin fibroblast cells.

Botany

The grapefruit is a large, dimpled, round citrus fruit measuring 7.6 to 15.2 cm in diameter. It descends from a cross between a pomelo (pummelo) or shaddock ( Citrus grandis ), a large Malaysian citrus, and a sweet orange, and may have originated as a mutation of another type of citrus tree. The fruit grows in clusters similar to grapes, a possible origin of its name. Noteworthy cultivars of grapefruit include: Duncan ("white", seeded); Marsh (seedless); Foster (pink, seeded); Thompson (pink, seedless); and redblush (red, seedless). 1 , 2 , 3 , 4

History

The Greek philosopher Theophrastus (BC 371-287), regarded as the founder of botany, wrote that "citron" could sweeten the breath and was also thought to be an antidote to poison. Later, the Roman naturalist Pliny (AD 23-79) used the word citrus for the first time and labeled the fruit as a medicine. The grapefruit, known at the time as small shaddock, was first mentioned by Griffith Hughes (1707-1758) as the "forbidden fruit" of Barbados. The name grapefruit was said to have been first used in Jamaica in 1814, referring to the clusters of fruit on the trees. In 1823, the grapefruit was introduced in Florida by the French count Odette Phillippe, but it did not gain popularity until the end of the nineteenth century. In the 1930s, the Hollywood Diet, which recommended a limited calorie intake of approximately 800 per day and included grapefruit consumption at each meal, became popular. Worldwide production of grapefruit was projected in 2010 at approximately 5.5 million metric tons, and the juice of the fruit, including concentrate, accounts for approximately 42% of all US-processed grapefruit products. 1 , 2 , 3 , 4

Chemistry

The chemistry of citrus fruits and of grapefruit seed extract is well studied. Components of citrus fruits include sugars, polysaccharides, organic acids, nitrogenous constituents, lipids, carotenoids (that contribute to color), vitamins, minerals, flavonoids, and volatile components that contribute to aroma. 5 , 6 , 7 , 8 , 9 Grapefruit is high in water and fiber. The whole fruit is also a good source of potassium, vitamin C, inositol, bioflavonoids, and pectin; however, the juice alone is not high in pectin. In addition, grapefruit has no fat and is low in calories and sodium. The pink variety contains beta-carotene. Folic acid is also present in grapefruit. The peel contains citral (an aldehyde that antagonizes the effects of vitamin A) and other terpenes, including limonene, which are of interest because of their chemoprotective and cholesterol-solvent properties. 3 , 4 , 9 , 10

Other constituents in grapefruit have been found to affect liver enzymes; 6′,7′-dihydroxybergamottin, a cytochrome P450 inhibitor, has been identified. Naringin, naringenin, limonin, and obacunone also exhibit inhibitory effects in human liver microsomes. 9 , 11 , 12

Uses and Pharmacology

Animal studies are limited due to the relative safety of grapefruit consumption and the availability of clinical trials in healthy human volunteers and in patients with clinical conditions.

Antimicrobial effects

In vitro screening of a grapefruit seed extract found bactericidal activity against gram negative and positive bacteria to dilutions up to 1:512. 8 , 13 In a series of case reports, chewing and swallowing 5 to 6 grapefruit seeds every 8 hours was effective against Klebsiella , Staphylococcus aureus , and Escherichia coli urinary tract infections, but not against Pseudomonas aeruginosa -resistant strains. 14

Cardiovascular effects

Limited clinical trials have been undertaken, possibly due to the potential for drug interactions. Two trials conducted in post-coronary bypass patients with atherosclerosis demonstrated improved lipid profiles following whole grapefruit and grapefruit juice consumption. 15 , 16 Antioxidant-carrying capacity also improved. Systolic and diastolic blood pressure were unchanged throughout the 30-day study, contrary to results of another study that showed a hypotensive effect for consumption of a hybrid grapefruit/pummelo juice, possibly due to the flavonoid component. 17 , 18 Prolongation of the QTc interval has also been demonstrated in healthy volunteers, as well as in patients with cardiomyopathy, possibly due to the naringenin glycoside content. 19 , 20

Cholelithiasis/nephrolithiasis

Initial animal studies showed the capacity of d-limonene to dissolve gallstones, and in humans, limited studies have confirmed this effect. 10 Decreased potential for renal stone formation has been suggested, but is debated based on studies demonstrating that the consumption of grapefruit juice increases the excretion of citrate, calcium, and magnesium similarly to acute loads of orange and apple juice. 21 , 22 , 23

Other uses
Cancer

Grapefruit constituents pectin, lycopene, and d-limonene have been evaluated for potential chemotherapeutic roles via antioxidant and apoptosis-inducing activity. Clinical trials have produced mixed results. 9 , 10 , 24

Nutritional supplement

Grapefruit is recognized to have value as a dietary supplement, similar to other citrus fruits. Vitamin C status and bleeding scores were improved in a study among patients with periodontitis who consumed 2 grapefruits a day for 2 weeks. 25 Weight loss has been observed in some, but not all, clinical studies possibly because of variable dosage regimens. 16 , 26

Dosage

Quality clinical trials upon which to base therapeutic dosing recommendations are limited. Improved lipid profiles were achieved with consumption of 1 grapefruit daily for 30 days. 16 Grapefruit juice 8 oz (237 mL), or half of a fresh grapefruit, 3 times a day before each meal for 12 weeks resulted in weight loss in a clinical trial evaluating the effect on metabolic syndrome. 26 As a nutritional supplement, consumption of 2 grapefruits a day improved the vitamin C status of patients with periodontitis after 2 weeks. 25

Pregnancy/Lactation

GRAS for use as food. Safety and efficacy for dosages above those in foods are unproven. 27

Interactions

Grapefruit juice has been reported to interact with numerous drugs; however, case reports of interactions are rare. Most studies of grapefruit juice interactions have involved controlled trials in healthy volunteers ingesting the study drug with water and regular- or double-strength grapefruit juice. 28 , 29 , 30 , 31

After 300 mL of grapefruit juice, the recovery half-life for cytochrome P450 3A4 (CYP3A4) activity is approximately 23 hours. Recovery is almost complete within 3 days. Studies have utilized doses of grapefruit juice 250 mL/day up to 3 times daily for 5 to 7 days. 29 , 32

The mechanism of the majority of these interactions involves inhibition of the CYP3A4 in the small intestine, which may elevate drug plasma concentrations and increase the risk of adverse reactions, especially for drugs that are susceptible to a high first pass metabolism (eg, felodipine, amiodarone). In addition, grapefruit juice may decrease plasma concentrations by delaying drug absorption catalyzed by organic anion transporting polypeptide (eg, fexofenadine, digoxin). The instances in which clinical importance of an interaction with grapefruit can be considered relevant include the following: use of a higher than usual dose of a susceptible drug followed by grapefruit/juice consumption for the first time; in severe liver disease; in elderly patients; or in patients with a particular susceptibility to the toxic effects of certain drugs. 28 , 29 , 30 , 31

For a comprehensive listing of drugs that may be affected by grapefruit, see Evidence-Based Grapefruit Interactions appendix .

Adverse Reactions

Reports of adverse reactions to grapefruit consumption are limited. Grapefruit juice has been associated with hypotension 17 , 18 and deep vein thrombosis (presumed to be due to an interaction with ethinyl estradiol). 33 Prolongation of the QTc interval has been demonstrated in healthy volunteers and patients with cardiomyopathy. 19 , 20 Case reports exist of allergy to pectin and pectin-induced asthma. 34

Toxicology

Toxicological studies on whole grapefruit are lacking. A meta-analysis of 3 landmark studies evaluating the association of grapefruit consumption and risk of breast cancer (European Prospective Investigation into Cancer and Nutrition [EPIC], the Nurses' Health Study, and the Multiethnic Cohort Study of Diet and Cancer) found no increased risk of breast cancer (hazards ratio = 1.06 [95% CI, 0.95 to 1.19]); however, the possibility of an association could not be ruled out. 35 , 36 , 37 The constituent d-limonene in grapefruit has GRAS status. 10 Grapefruit seed extract has been shown to be toxic to human skin fibroblast cells up to concentrations of 1:128 but not 1:512 in antibacterial studies. 13

Bibliography

1. Citrus x paradisi Macfad. USDA, NRCS. 2007. The PLANTS Database. ( http://plants.usda.gov , 1 January 2011). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. Davidson A, Knox C. Grapefruit, pomelo, ugli. In: Fruit: A Connoiseur's Guide and Cookbook . New York, NY: Simon and Schuster; 1991:66.
3. Ensminger ME, Ensminger AH. Grapefruit. In: Foods & Nutrition Encyclopedia . Vol 1. 2nd ed. Boca Raton, FL: CRC Press; 1993; 1097-1099.
4. Carper J. Grapefruit. In: The Food Pharmacy: Dramatic New Evidence That Food is Your Best Medicine . New York, NY: Bantam Books. 1988:213-215.
5. Sakamoto S, Sato K, Maitani T, Yamada T. Analysis of components in natural food additive “grapefruit seed extract” by HPLC and LC/MS [in Japanese]. Eisei Shikenjo Hokoku . 1996;(114):38-42.
6. Ranganna S, Govindarajan VS, Ramana KV. Citrus fruits—varieties, chemistry, technology, and quality evaluation. Part II. Chemistry, technology, and quality evaluation. A. Chemistry. Crit Rev Food Sci Nutr . 1983;18(4):313-386.
7. Ranganna S, Govindarajan VS, Ramana KV. Citrus fruits. Part II. Chemistry, technology, and quality evaluation. B. Technology. Crit Rev Food Sci Nutr . 1983;19(1):1-98.
8. Reagor L, Gusman J, McCoy L, Carino E, Heggers JP. The effectiveness of processed grapefruit-seed extract as an antibacterial agent: I. An in vitro agar assay. J Altern Complement Med . 2002;8(3):325-332.
9. Giamperi L, Fraternale D, Bucchini A, Ricci D. Antioxidant activity of Citrus paradisi seeds glyceric extract. Fitoterapia . 2004;75(2):221-224.
10. Sun J. D-Limonene: safety and clinical applications. Altern Med Rev . 2007;12(3):259-264.
11. Edwards D, Bellevue FH 3rd, Woster PM. Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos . 1996;24(12):1287-1290.
12. Fukuda K, Ohta T, Yamazoe Y. Grapefruit component interacting with rat and human P450 CYP3A: possible involvement of non-flavonoid components in drug interaction. Biol Pharm Bull . 1997;20(5):560-564.
13. Heggers JP, Cottingham J, Gusman J, et al. The effectiveness of processed grapefruit-seed extract as an antibacterial agent: II. Mechanism of action and in vitro toxicity. J Altern Complement Med . 2002;8(3):333-340.
14. Oyelami OA, Agbakwuru EA, Adeyemi LA, Adedeji GB. The effectiveness of grapefruit ( Citrus paradisi ) seeds in treating urinary tract infections. J Altern Complement Med . 2005;11(2):369-371.
15. Gorinstein S, Caspi A, Libman I, Katrich E, Lerner HT, Trakhtenberg S. Fresh israeli jaffa sweetie juice consumption improves lipid metabolism and increases antioxidant capacity in hypercholesterolemic patients suffering from coronary artery disease: studies in vitro and in humans and positive changes in albumin and fibrinogen fractions. J Agric Food Chem . 2004;52(16):5215-5222.
16. Gorinstein S, Caspi A, Libman I, et al. Red grapefruit positively influences serum triglyceride level in patients suffering from coronary atherosclerosis: studies in vitro and in humans. J Agric Food Chem . 2006;54(5):1887-1892.
17. Reshef N, Hayari Y, Goren C, Boaz M, Madar Z, Knobler H. Antihypertensive effect of sweetie fruit in patients with stage I hypertension. Am J Hypertens . 2005;18(10):1360-1363.
18. Nilsson I. Grapefruit juice caused hypotension [in Swedish]. Lakartidningen . 1997;94(3):112-113.
19. Zitron E, Scholz E, Owen RW, et al. QTc prolongation by grapefruit juice and its potential pharmacological basis: HERG channel blockade by flavonoids. Circulation . 2005;111(7):835-838.
20. Piccirillo G, Magrì D, Matera S, et al. Effects of pink grapefruit juice on QT variability in patients with dilated or hypertensive cardiomyopathy and in healthy subjects. Transl Res . 2008;151(5):267-272.
21. Hönow R, Laube N, Schneider A, Kessler T, Hesse A. Influence of grapefruit-, orange- and apple-juice consumption on urinary variables and risk of crystallization. Br J Nutr . 2003;90(2):295-300.
22. Trinchieri A, Lizzano R, Bernardini P, et al. Effect of acute load of grapefruit juice on urinary excretion of citrate and urinary risk factors for renal stone formation. Dig Liver Dis . 2002;34(suppl 2):S160-S163.
23. Goldfarb DS, Asplin JR. Effect of grapefruit juice on urinary lithogenicity. J Urol . 2001;166(1):263-267.
24. van Breemen RB, Pajkovic N. Multitargeted therapy of cancer by lycopene. Cancer Lett . 2008;269(2):339-351.
25. Staudte H, Sigusch BW, Glockmann E. Grapefruit consumption improves vitamin C status in periodontitis patients. Br Dent J . 2005;199(4):213-217.
26. Fujioka K, Greenway F, Sheard J, Ying Y. The effects of grapefruit on weight and insulin resistance: relationship to the metabolic syndrome. J Med Food . 2006;9(1):49-54.
27. Ernst E. Herbal medicinal products during pregnancy: are they safe? BJOG . 2002;109(3):227-235.
28. Huang SM, Hall SD, Watkins P, et al; Center for Drug Evaluation and Research and Office of Regulatory Affairs, Food and Drug Administration, Rockville, MD, USA. Drug interactions with herbal products and grapefruit juice: a conference report. Clin Pharmacol Ther . 2004;75(1):1-12.
29. Bressler R. Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs. Geriatrics . 2006;61(11):12-18.
30. Mertens-Talcott SU, Zadezensky I, De Castro WV, Derendorf H, Butterweck V. Grapefruit-drug interactions: can interactions with drugs be avoided? J Clin Pharmacol . 2006;46(12):1390-1416.
31. Kiani J, Imam SZ. Medicinal importance of grapefruit juice and its interaction with various drugs. Nutr J . 2007;6:33.
32. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Time course of recovery of cytochrome P450 3A function after single doses of grapefruit juice. Clin Pharmacol Ther . 2003;74(2):121-129.
33. Grande LA, Mendez RD, Krug RT, Verschuyl EJ. Attention—grapefruit! Lancet . 2009;373(9670):1222.
34. Ferdman RM, Ong PY, Church JA. Pectin anaphylaxis and possible association with cashew allergy. Ann Allergy Asthma Immunol . 2006;97(6):759-760.
35. Spencer EA, Key TJ, Appleby PN, et al. Prospective study of the association between grapefruit intake and risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control . 2009;20(6):803-809.
36. Kim EH, Hankinson SE, Eliassen AH, Willett WC. A prospective study of grapefruit and grapefruit juice intake and breast cancer risk. Br J Cancer . 2008;98(1):240-241.
37. Monroe KR, Murphy SP, Henderson BE, et al. Dietary fiber intake and endogenous serum hormone levels in naturally postmenopausal Mexican American women: the Multiethnic Cohort Study. Nutr Cancer . 2007;58(2):127-135.

Copyright © 2009 Wolters Kluwer Health

Hide
(web3)