Inhibition Selectivity of Grapefruit Juice Components on Human Cytochromes P450

Tassaneeyakul, Wichittra; Guo, Lian‐Qing; Fukuda, Katsuyuki; Ohta, Tomihisa; Yamazoe, Yasushi

doi:10.1006/abbi.2000.1835

Cited by 209 publications

(196 citation statements)

References 29 publications

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“…Vegetable consumption, which is related to vitamin K intake, 1 was evaluated as low or high vegetable intake. Grapefruit intake, which is known to inhibit several CYP, 26 was recorded as yes or no. The patients were followed at the University Medical Centre in Ljubljana, Department for Vascular Diseases (n ¼ 156) and at the General Hospital Murska Sobota (n ¼ 32).…”

Section: Patientsmentioning

confidence: 99%

Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose

Herman¹,

et al. 2005

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Warfarin is an anticoagulant drug with narrow therapeutic index and high interindividual variability in dose requirement. S-warfarin is metabolized mainly by polymorphic cytochrome P450 (CYP) 2C9. We systematically quantified the influence of CYP2C9 genotype, demographic factors and concomitant drug treatment on warfarin metabolism and maintenance dose. The mean warfarin doses were lower in carriers of one (2.71 mg/day, 59 patients) and two polymorphic alleles (1.64 mg/day, 11 patients) than in carriers of two wild-type alleles (4.88 mg/day, 118 patients). Multiple regression analysis demonstrated that CYP2C9 genotype, age, concomitant treatment with warfarin metabolism inducers and lean body weight contributed significantly to interindividual variability in warfarin dose requirement (adjusted R 2 ¼ 0.37). The same factors, except for age, significantly influenced S-warfarin clearance (adjusted R 2 ¼ 0.42). These results can serve as a starting point for designing prospective studies in patients in the initiation phase of genotype-based warfarin therapy.

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Section: Patientsmentioning

confidence: 99%

Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose

Herman¹,

et al. 2005

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“…The inactivation rate constant at an infinite concentration of inactivator (k inact ) and the concentration of inactivator required for a half-maximal rate of inactivation (K I ) were determined from double-reciprocal plots of k app values and inactivator concentrations. 19) Based on time-, concentration-, and NADPH-dependent inactivation kinetics, serpentine (5) appear to be a mechanism-based inhibitor for CYP2D6. The apparent K I and k inact values were calculated to be 0.148 mM and 0.090 min…”

Section: Isolation and Identification Of Constituentsmentioning

confidence: 99%

Cytochrome P450 2D6 (CYP2D6) Inhibitory Constituents of Catharanthus roseus

Usia

Watabe

Kadota

et al. 2005

Biological & Pharmaceutical Bulletin

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Herbal medicines are used concomitantly with conventional prescription drugs, which is a situation that carries the risk of unanticipated adverse drug-herbal pharmacokinetic interactions. It is recognized that cytochrome P450 (CYP) enzyme inactivation is one of the main reasons for pharmacokinetic interactions.1,2) The inactivation of CYP can lead to serious clinical drug interactions, especially when concomitant drugs are metabolized by the same enzyme. The drug interactions cause symptoms of drug overdose, including an exaggerated pharmacological response and/or drug toxicity. 3)One of the mechanism of CYP inactivation involves covalent binding of a reactive intermediate to the enzyme proteins and/or heme, which leads to irreversible inhibition of catalytic function, or a quasi-irreversible coordination of a reactive intermediate to the CYP. 4) In Indonesia, herbal medicines "Jamu" have been used from ancient times until the present, and are consumed by people of different levels. Most of these herbal medicines are unregulated, and many patients do not inform their physician of the herbal medicines they consume. Therefore, interactions between herbal medicines and drugs prescribed clinically are becoming a concern. Thus, we investigated in vitro the cytochrome P450 3A4 (CYP3A4) and 2D6 (CYP2D6) inhibitory activity of Indonesian medicinal plants. We found that MeOH extracts of Zingiber aromaticum (IC 50 , 102 mg/ml) and Piper cubeba (IC 50 , 53 mg/ ml) showed potent inhibitory activity against CYP3A4, while the MeOH extract of Catharanthus roseus revealed very potent inhibition against CYP2D6 with an IC 50 value of 11 mg/ml.5) In addition, we reported the CYP3A4 and CYP2D6 inhibitory constituents of Z. aromaticum 6) and P. cubeba. 7)Catharanthus roseus, also known as Vinca rosea, is a semiwoody evergreen perennial tree that originated in Madagascar. It has been widely cultivated for hundreds of years and can now be found growing wild in most warm regions of the world. The plant has historically been used to treat a wide assortment of diseases. It was used as a folk remedy for diabetes in Europe for centuries, while in Hawai, the plant was boiled to make a poultice to stop bleeding. In China, it was used as an astringent, diuretic, and cough remedy, and in Central and South America it was used as a homemade cold remedy to ease lung congestion, inflammation, and sore throat. 8) In Indonesia, on the other hand, it was used for treatment of malaria, diabetes, constipation, cancer, and hypertension.9) More than 70 alkaloids were isolated from C. roseus, including vincristine and vinblastine which have anticancer properties.8) Because of continued interest in the CYP study, we carried out phytochemical investigation of C. roseus from Indonesia. In this paper, we report the constituents of this plant and their inhibitory activity on the metabolism mediated by CYP3A4 and CYP2D6. We also examined the possibility of mechanism-based inhibition by these constituents. MATERIALS AND METHODS Extraction and IsolationThe aerial...

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“…benzopyran-7-one) furanocumarins from grapefruit, 18) rutaecarpine and limonene from Evodia rutaecarpa, 19) methylenedioxyphenyl lignans from Piper, 20) kaempferol from Zingiber aromaticum, 21) 5-methoxypsoralen from Foeniculum vulgare, 22) and lignans from Phyllanthus amarus, 23) have all been shown to be responsible for MBI of CYP3A4. Moreover, interactions between these compounds and therapeutic drugs could occur in vivo.…”

Section: )mentioning

confidence: 99%

“…[14][15][16] Mechanism-based inhibition (MBI) of CYP3A4 is characterized by nicotinamide adenine dinucleotide phosphate (NADPH)-, time-, and concentration-dependent enzyme inactivation that occurs when some substrates are converted by CYPs into reactive metabolites. 17) Several phytochemicals, including GF-I-1 (4-[ [6-hydroxy-7 [1] benzopyran-7-one) furanocumarins from grapefruit, 18) rutaecarpine and limonene from Evodia rutaecarpa, 19) methylenedioxyphenyl lignans from Piper, 20) kaempferol from Zingiber aromaticum, 21) 5-methoxypsoralen from Foeniculum vulgare, 22) and lignans from Phyllanthus amarus, 23) have all been shown to be responsible for MBI of CYP3A4. Moreover, interactions between these compounds and therapeutic drugs could occur in vivo.…”

mentioning

confidence: 99%

Mechanism-Based Inhibition of Recombinant Human Cytochrome P450 3A4 by Tomato Juice Extract

Sunaga

Ohkawa

Nakamura

et al. 2012

Biological & Pharmaceutical Bulletin

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This study investigates whether tomato juice can inhibit cytochrome P450 (CYP) 3A4-mediated drug metabolism. Three commercially available, additive-free tomato juices, along with homogenized fresh tomato, were analyzed for their ability to inhibit testosterone 6β-hydroxylation activity using human recombinant CYP3A4. Results were compared to that of grapefruit juice. Ethyl acetate extracts of the tomato juices moderately reduced residual activity of CYP3A4 testosterone 6β-hydroxylation activity by 19.3-26.2% with 0-min preincubation. Residual activity was strongly reduced by 69.9-83.5% at 20-min preincubation, a reduction similar to that of grapefruit juice extract, known to contain constituents of mechanism-based inhibitors. One juice extract (tomato juice C) showed irreversible dose-and preincubation time-dependent and partial nicotinamide adenine dinucleotide phosphate (NADPH)-dependent inhibition of CYP3A4 activity. Furthermore, we examined whether the CYP3A4 inhibitory effect of tomato juice was substrate dependent by examining midazolam 1′-hydroxylation activity and nifedipine oxidation activity, in addition to testosterone 6β-hydroxylation activity. Tomato juice showed a potent inhibitory effect on nifedipine oxidation activity, which was comparable to that on testosterone 6β-hydroxylation activity; however, it showed a weak inhibitory effect on midazolam 1′-hydroxylation activity. We conclude that tomato juice contains one or more mechanism-based and competitive inhibitor(s) of CYP3A4. Additionally, significant CYP3A4 inhibitory activity did not result from lycopene, a major compound in tomato. Although the active compound was uncertain, a strong CYP3A4 inhibitory activity was observed in other solanaceous plants, i.e., potato, eggplant, sweet pepper, and capsicum. Therefore, responsible compounds in tomato are likely commonly shared among solanaceous vegetables.Key words tomato juice; mechanism-based inhibition; food-drug interaction; human recombinant cytochrome P450 3A4 Many foods and/or beverages have recently been found to influence drug metabolism or transport, sometimes resulting in clinically important drug interactions. This food-drug interaction is a critical aspect of pharmacotherapy. Food-drug interaction can be viewed in terms of pharmacokinetics and pharmacodynamics. Pharmacokinetic interactions can involve enzymes and transporters that are implicated in drug absorption, distribution, metabolism, or excretion. Pharmacodynamic interactions involve the pharmacological effect of a drug or physiologic effect of a dietary constituent. 1)Foods that inhibit drug metabolism enzymes, such as cytochrome P450 (CYP), elevate the blood concentration of co-administered drugs, resulting in a food-drug interaction, which sometimes causes adverse effects. [2][3][4] In vitro screening assays with beverages and foods such as beer, red wine, black and herbal tea, garlic, spices, mace, nutmeg, fruits, and fruit juices have all shown the ability to inhibit enzyme-mediated drug metabolism. [5][6][7][8][9][10] CYP...

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Inhibition Selectivity of Grapefruit Juice Components on Human Cytochromes P450

Cited by 209 publications

References 29 publications

Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose

Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose

Cytochrome P450 2D6 (CYP2D6) Inhibitory Constituents of Catharanthus roseus

Mechanism-Based Inhibition of Recombinant Human Cytochrome P450 3A4 by Tomato Juice Extract

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