Inhibitory Effects of Fruit Juices on Cytochrome P450 2C9 Activity in Vitro

School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Nobeoka, Miyazaki 882-8508, Japan.
Bioscience Biotechnology and Biochemistry (Impact Factor: 1.06). 03/2008; 72(2):406-11. DOI: 10.1271/bbb.70511
Source: PubMed


There is limited information on the effect of fruits on human cytochrome P450 (CYP) 2C9 activity. The objective of this study was to determine the effect of fruit juice on CYP2C9-mediated drug metabolism. Nine citrus fruits and eight tropical fruits were chosen. We investigated effects of the fruits on diclofenac 4'-hydroxylation and tolbutamide hydroxylation by human liver microsomes. Among the fruits, pineapple juice showed potent inhibition of CYP2C9 activity. The addition of 25 microl (5.0% v/v) of pineapple juice resulted in almost complete inhibition. Next we examined the inhibitory effect of bromelain, a cysteine protease in pineapple. Bromelain also strongly inhibited CYP2C9 activity. In addition, E-64, a cysteine protease inhibitor, almost entirely blocked inhibition by pineapple juice and bromelain. Thus we found that pineapple juice was a potent inhibitor of CYP2C9, and that the inhibitory effect might be due to the bromelain contained in pineapple.

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    • "In clinical settings, diclofenac plasma levels can be increased by dietary constituents (e.g. grapefruit, pineapple juices) and co-administered medications interfering with its metabolism [41], [42], [43], [44], [45] or plasma protein binding [46]. "
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    ABSTRACT: The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti-inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 µM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl(2) application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 µg/kg) significantly lengthened the QT(c) interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QT(c). Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 µM) decreased the amplitude of rapid (I(Kr)) and slow (I(Ks)) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (I(Ca)) was slightly diminished, but the transient outward (I(to)) and inward rectifier (I(K1)) potassium currents were not influenced. Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve.
    Full-text · Article · Dec 2012 · PLoS ONE
    • "The inhibitory effects of star fruit (Averrhoa carambola) on human CYP3A activity (Hidaka et al., 2004) and pomegranate (Punica granatum L.) juice on the CYP3A-mediated metabolism of carbamazepine in humans (Hidaka et al., 2005) have also been reported. Moreover, pineapple juice showed potent inhibition of CYP2C9 activity in vitro (Hidaka et al., 2008). "
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    ABSTRACT: The effects of six Thai fruits, namely banana, guava, mangosteen, pineapple, ripe mango and ripe papaya, on cytochrome P450 (P450) activities were investigated. The median inhibitory concentrations (IC(50) ) of each of the fruit juices on CYP1A1, CYP1A2, CYP2E1 and CYP3A11 activities were determined. Pineapple juice showed the strongest inhibitory effect against all the evaluated P450 isozyme activities in mouse hepatic microsomes, followed by mangosteen, guava, ripe mango, ripe papaya and banana. The study was further performed in male ICR mice given pineapple juice intragastrically at doses of 10, 20 and 40 mg kg(-1) per day for 7 or 28 days. In a concentration-dependent fashion, the pineapple juice raised ethoxyresorufin O-deethylase, aniline hydroxylase and erythromycin N-demethylase activities, which are marker enzymatic reactions responsible for CYP1A1, CYP2E1 and CYP3A11, respectively. The effect of pineapple juice on the expression of CYP1A1, CYP2E1 and CYP3A11 mRNAs corresponded to their enzymatic activities. However, the pineapple juice significantly decreased methoxyresorufin O-demethylase activity. These observations supported that the six Thai fruits were a feasible cause of food-drug interaction or adverse drug effects owing to their potential to modify several essential P450 activities. Individuals consuming large quantities of pineapple for long periods of time should be cautioned of these potential adverse effects. Copyright © 2012 John Wiley & Sons, Ltd.
    No preview · Article · Dec 2012 · Journal of Applied Toxicology
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    • "One study has reported that pomegranate juice inhibits human CYP2C9 activity in vitro (Nagata et al., 2007). Recently, pine-apple juice was found to significantly inhibit CYP2C9 enzyme in human microsomes (Hidaka et al., 2008). Beside fruit juices, there are few reports wherein activity of CYP2C9 enzyme was modified by certain herbal constituents. "
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    ABSTRACT: To investigate the potential effects of eleven of the most commonly used Saudi folk herbal medications on the metabolic activity of CYP2C9 in human liver microsomes. CYP2C9-mediated 4'-hydroxylation of tolbutamide (TB) to 4'-hydroxytolbutamide (4-OH-TB) was utilized to assess the metabolic activity of CYP2C9. In the present study, an initial screening of the eleven herbs was carried out by incubating TB with microsomes and NADPH in absence or presence of a fixed concentration (25 μg/ml) of alcoholic extracts of different herbs and the metabolite formed was measured by HPLC. Herbs that showed significant effects were further investigated at a lower range of concentration. Among the investigated herbal extracts, only aniseed and curcuma showed statistically significant effects on the formation of 4-OH-TB in human liver microsomes. Curcuma produced a potent inhibition on the metabolite formation and its maximum (about 45% inhibition) was observed at the highest extract concentrations (10 and 25 μg/ml). On the other hand, aniseed significantly activates the formation of 4-OH-TB and the maximum activation (about 55%) was observed at 2.5 μg/ml of aniseed extract. The results of this study have shown that alcoholic extracts of curcuma and aniseed were capable of inhibiting and activating; respectively, the CYP2C9-mediated 4-OH-TB formation in human liver microsomes, suggesting that these herbs have the potential to interact with CYP2C9 drug substrates. None of the other nine investigated herbs was able to produce any statistically significant effect.
    Preview · Article · Jul 2010 · Saudi Pharmaceutical Journal
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