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Plant Profiler

Grapefruit (Citrus paradisi)


Citrus paradisi
Synonyms / Common Names / Related Terms
Antioxidants, antioxidizers, vitaminc, bergamottin, bergapten, bergaptol, blond grapefruits, betacarotene, citricidal, Citrus decumana, Citrus maxima, Citrus paradisi, Citrus paradisi Macf., Citrus paradisi Macfayden, Citrus × paradisi, citrus seed, citrus seed extract, guargum, flavonoids, Fresca®, furanocoumarins, geranylcoumarin, grapefruit juice, grapefruit pectin, grapefruit peel, grapefruit seed, grapefruit seed extract, limonoids, naringenin, naringin, nootkatone, organic grapefruit juice, paradisapfel, ParaMicrocidin®, polyamines, pomelo, pummelo grapefruit, putrescine, red grapefruit, red Mexican grapefruit, Rio Red Grapefruit, Rutaceae (family), sesquiterpen, shaddock oil, Sun Drop™, toronja, vitaminc, white grapefruit.


Mechanism of Action

Pharmacology:

  • Constituents: Grapefruit juice appears to irreversibly inhibit the intestinal cytochrome P450 3A4 system, responsible for the first-pass metabolism of many medications. The inhibition of this enzyme system leads to an elevation in blood serum concentration of the drug when administered concurrently with grapefruit juice.
  • Grapefruit juice contains vitamin C, antioxidizers, furanocoumarins (bergamottin, 6',7'-epoxybergamottin, 6',7'-dihydroxybergamottin), flavonoids (naringenin, naringin) and sesquiterpen (nootkatone), bergapten (5-methoxypsoralen), polyamines (e.g. putrescine), and limonoids.18,22,6,4,14,26 Naringin is the most abundant flavonoid in grapefruit juice, present in concentrations of up to 1mM/L.11
  • Structures from the limonoids of Mexican grapefruit were identified as obacunone, nomilin, limonin, deacetylnomilin (DAN), and limonin-17-beta-D-glucopyranoside (LG).4
  • It has been determined that lime and lemon juices can be regarded as a group distinct from grapefruit and pummelo juices, while orange juice appears to belong to a bridging group.27
  • It has been suggested that phenolic compounds can be used as biomarkers of specific poly-phenol rich food, in particular, naringin for grapefruit.28
  • The dried peels of white grapefruit (Citrus paradise) contain high amounts of ascorbic acid and carotenoid content compared to the other fruits in addition to polyphenols.29
  • Anticancer effects: Grapefruit juice contributes a high amount of putrescine to the diet, which may slow the cancer process.26
  • Antioxidant effects: The dried peels of white grapefruit (Citrus paradise) contain high amounts of polyphenols, ascorbic acid, and carotenoids, which suggest an antioxidant potential.29 Bergaptol has shown good radical scavenging activity at different tested concentrations.21 Fresh red grapefruit contains higher quantities of bioactive compounds and has significantly higher antioxidant potential than blond grapefruit as determined by oxygen radical scavenging capacity, 1,1-diphenyl-2-picrylhydrazyl, carotenoid bleaching, and Folin-Ciocalteu assays.25 Citrus limonoids identified as obacunone, nomilin, limonin, deacetylnomilin (DAN), and limonin-17-beta-D-glucopyranoside (LG) found in Mexican grapefruit possess antioxidant properties such as radical scavenging activity.4
  • Antiviral effects: Based on laboratory study, grapefruit juice may have antiviral effects.5
  • Cardiovascular effects: Beneficial cardiovascular effects of grapefruit may be due to the flavonoid content. Diet supplemented with grapefruit pectin or red grapefruit has been shown to inhibit hypercholesterolemia and have a protective effect against atherosclerosis.9,25 However, the grapefruit pectin may have a direct beneficial effect on atherosclerosis by a mechanism independent of cholesterol levels.30 The dried peels of white grapefruit (Citrus paradise) contain high amounts of polyphenols, ascorbic acid, and carotenoids, which may be beneficial in cardiovascular disease.29 In a case report, a patient receiving nifedipine and terazosin had markedly lower blood pressure after consumption of grapefruit juice (no further details provided)10; however, the mechanism of action is not fully understood but may be due to the flavonoids (e.g. naringin).
  • CYP 450 effects: Bergamottin, the primary furanocoumarin extracted from grapefruit juice, has been found to be a mechanism-based inactivator of P450 3A4.31,21,32 Bergamottin has also been found to inhibit the activities of P450s 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in human liver microsomes.31 According to one randomized controlled study, bergamottin is likely responsible for drug interactions with commercial grapefruit juice; although, 6',7'-dihydroxybergamottin and naringin may be more important in grapefruit segments because they are present in higher concentrations.18 However, bergamottin and reversible inhibition were clinically shown not to be the primary substance and mechanism responsible for the inhibition of CYP3A4 activity.17 The naringin capsule alone did not alter the pharmacokinetics of nisoldipine, suggesting that a combination of the active ingredients may be responsible for the grapefruit-drug interactions.33
  • Grapefruit juice may affect hepatic and intestinal CYP3A4 dose-dependently. One clinical study found that a high dose (double strength three times per day for three days) of grapefruit juice appeared to inhibit hepatic and intestinal CYP3A4 whereas a normal dose (single strength single dose) appeared to inhibit intestinal but not hepatic CYP3A4.12 Drug interactions with grapefruit juice that occur by inhibition of CYP3A enzymes may also affect the activity of influx (e.g. OATPs) and efflux (e.g. P-glycoprotein) transporters.34 Grapefruit also appears to activate P-gp-mediated efflux of drugs that are substrates of P-glycoprotein, potentially partially counteracting the CYP3A-inhibitory effects of grapefruit.13 Bergaptol and geranylcoumarin were found to be potent inhibitors of debenzylation activity of CYP3A4 enzyme.21
  • Drugs that are substrates of cytochrome P450 isoform CYP1A2 may not be inhibited by grapefruit juice in a clinically significant manner.16
  • Enzymatic activity (esterase inhibition): The active components of grapefruit juice responsible for its esterase-inhibitory effect were identified.35 The esterase-inhibitory potential of 10 constitutive flavonoids and furanocoumarins toward p-nitrophenylacetate (PNPA) hydrolysis was investigated. The furanocoumarins bergamottin, 6',7 dihydroxybergamottin, and bergapten, and the glycoside flavonoids naringin and hesperidin, at concentrations found in grapefruit juice or higher, did not inhibit the hydrolysis of PNPA by purified porcine esterase and human liver microsomes. However, the flavonoid aglycones morin, galangin, kaempferol, quercetin, and naringenin showed appreciable inhibition of PNPA hydrolysis in purified porcine esterase and human and rat liver systems. In Caco-2 cells, demonstrated to contain minimal CYP3A activity, the permeability coefficient of the prodrugs lovastatin and enalapril was increased in the presence of the active flavonoids kaempferol and naringenin, consistent with inhibition of esterase activity. In rats, oral coadministration of kaempferol and naringenin with these prodrugs led to significant increases in plasma exposure to the active acids. In addition, in portal vein-cannulated rats, coadministration of lovastatin with kaempferol (10mg/kg) led to a 154% and a 113% increase in the portal plasma exposure to the prodrug and active acid, respectively, compared with coadministration with water. The contribution of CYP3A inhibition was demonstrated to be minimal.
  • Intestinal effects: In a case series of 15 patients with atopic eczema, 150mg oral grapefruit seed extract (ParaMicrocidin®) three times daily for one month reduced intestinal Candida spp., Geotrichum spp., and hemolytic coliforms and slightly inhibited Staphylococcus aureus and aerobic spore formers.7 All patients noted improvement in constipation, flatulence, abdominal discomfort, and night rest after four weeks of treatment.
  • Neurologic effects: The effects of the cuticle and epicuticular waxes of grapefruit on the photodegradation and penetration of chlorpyrifos-methyl were studied. 36 No pesticide was detected in samples of grapefruit pulp. The waxes and cuticle appear to have some effect on the photodegradation and penetration of chlorpyrifos-methyl.
  • Renal effects: In a clinical trial of seven healthy subjects with no history of kidney stones ingesting a soft drink containing grapefruit juice diluted (10%) in mineral water, grapefruit juice significantly (p=0.021) increased urinary excretion of citrate (25.8 ± 9.3 vs. 18.7 ± 6.2mg/hour), calcium (6.7 ± 4.3 vs. 3.3 ± 2.3mg/hour, p=0.015), and magnesium (2.9 ± 1.5 vs. 1.0 ± 0.7mg/hour, p=0.003) compared to mineral water ingestion.3 However, two large epidemiological studies linked drinking grapefruit juice to an increased risk of kidney stones.1,2
  • Weight loss effects: Although the mechanism of grapefruit in weight loss is unknown, it has been shown to decrease weight as part of a weight-reduction diet.8
  • Other effects: In vivo study has found that the dietary flavonoids in grapefruit juice may inhibit the enzyme 11β-hydroxysteroid dehydrogenase, which oxidizes cortisol to inactive cortisone in a concentration dependent manner.11 High doses were observed to cause an apparent mineralocorticoid effect and theoretically, some individuals might increase their potassium clearance if they drink large amounts of grapefruit juice.
  • Naringenin, the principal flavonoid in grapefruit, inhibited the lipidation and subsequent secretion of apoB-containing lipoproteins primarily by limiting the accumulation of triglycerides in the endoplasmic reticulum lumen, secondary to microsomal triglyceride transfer protein (MTP) inhibition.37,38

Pharmacodynamics/Kinetics:

  • Absorption: Methoxyflavanones from grapefruit appear to be absorbed from the juice.39
  • Bioavailability: The interaction potential of high amounts of grapefruit juice with CYP3A4 substrates dissipates within three to seven days after ingestion of the last dose of grapefruit juice.15,40 Cumulative urinary recovery of naringin and hesperidin in one study indicated low bioavailability (<25%) of the grapefruit substituents.39 Bioavailability and unbound fraction (f(u)) are major determinant factors of calcium antagonist-grapefruit juice interaction; a drug with smaller bioavailability or lower f(u) is likely to exhibit a more potent interaction and vice versa.19
  • Metabolism: Absorbed citrus flavanones may undergo glucuronidation before urinary excretion.39
  • Excretion: The urinary excretion ratio of the endogenous 6 beta-hydroxycortisol and cortisol ratio was significantly decreased (p=0.036) by grapefruit juice in one clinical study.41 In one in vitro study, 6',7'-dihydroxybergamottin (DHB) rapidly inhibited CYP3A4 activity in a substrate-independent fashion with maximal inhibition (≥85%) generally occurring within 30 minutes.42 In contrast, bergamottin (BG) had a slower onset and exhibited substrate-dependent inhibition.
  • Median Inhibition Concentration: An in vitro study evaluating the CYP3A4 inhibitory properties of the various substituents found in grapefruit juice identified bergapten (5-methoxypsoralen) with the lowest IC50 value (19-36mcM) to be the most potent CYP3A4 inhibitor and proposed that more than one component of grapefruit juice may be responsible for its CYP3A4 inhibitory activity.43
  • In human liver microsomes, the mean IC50 for grapefruit juice versus CYP3A (triazolam alpha-hydroxylation) was 0.55%, without preincubation of inhibitor with microsomes.20
  • The alkyloxy-furanocoumarin analogues were found to inhibit CYP3A4 activity in a dose dependent manner, with observed IC50 values ranging from 0.13 ± 0.03 to 49.3 ± 1.9mcM.23
  • Bergaptol and geranylcoumarin were found to be potent inhibitors of debenzylation activity of CYP3A4 enzyme with an IC50 value of 24.92 and 42.93mcM, respectively.21
  • Furanocoumarin dimers showed potent dose-dependent inhibition of CYP3A4 activity in both liver and intestine; IC50 values ranged from 0.021 ± 0.002 to 0.146 ± 0.041mcM (mean ± S.D. N=3). Of the four dimmers evaluated further, all showed time-dependent inhibition of CYP3A4 activity. 88Prop showed moderate inhibition of both CYP2C19 and CYP1A2 with IC50 values of 4.42 ± 0.01 and 1.98 ± 0.34 microM, 88Octa was found to inhibit CYP2C19 (IC50=3.16 ± 0.01mcM) and 58Prop to inhibit CYP1A2 (IC50=2.39 ± 0.77mcM). Minimal inhibition of CYP2D6 and CYP2C9 was observed (IC50>10mcM).24

References
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  2. Curhan, G. C., Willett, W. C., Rimm, E. B., Spiegelman, D., and Stampfer, M. J. Prospective study of beverage use and the risk of kidney stones. Am J Epidemiol  2-1-1996;143(3):240-247. 8561157
  3. Trinchieri, A., Lizzano, R., Bernardini, P., Nicola, M., Pozzoni, F., Romano, A. L., Serrago, M. P., and Confalanieri, S. 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. 12408462
  4. Mandadi, K. K., Jayaprakasha, G. K., Bhat, N. G., and Patil, B. S. Red Mexican grapefruit: a novel source for bioactive limonoids and their antioxidant activity. Z Naturforsch[C] 2007;62(3-4):179-188. 17542482
  5. Lipson, S. M., Sethi, L., Cohen, P., Gordon, R. E., Tan, I. P., Burdowski, A., and Stotzky, G. Antiviral effects on bacteriophages and rotavirus by cranberry juice. Phytomedicine 2007;14(1):23-30. 17140784
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  7. Ionescu G, Kiehl R, Wichmann-Kunz F, and et al. Oral citrus seed extract in atopic eczema: in vitro and in vivo studies on intestinal microflora. J Orthomol Med 1990;5(3):155-157.
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  10. Pisarik, P. Blood pressure-lowering effect of adding grapefruit juice to nifedipine and terazosin in a patient with severe renovascular hypertension. Arch Fam.Med 1996;5(7):413-416. 8665000
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  14. Mertens-Talcott, S. U., De Castro, W. V., Manthey, J. A., Derendorf, H., and Butterweck, V. Polymethoxylated flavones and other phenolic derivates from citrus in their inhibitory effects on P-glycoprotein-mediated transport of talinolol in Caco-2 cells. J Agric Food Chem 4-4-2007;55(7):2563-2568. 17348674
  15. Lilja, J. J., Kivisto, K. T., and Neuvonen, P. J. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther 2000;68(4):384-390. 11061578
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  40. Takanaga, H., Ohnishi, A., Murakami, H., Matsuo, H., Higuchi, S., Urae, A., Irie, S., Furuie, H., Matsukuma, K., Kimura, M., Kawano, K., Orii, Y., Tanaka, T., and Sawada, Y. Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects. Clin Pharmacol Ther 2000;67(3):201-214. 10741622
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