The aim of this study was to investigate the effect of quercetin on P-glycoprotein (P-gp) transport ability in vivo.
Genotype data were available from a total of 165 health volunteers. An open, randomized, two-period crossover clinical trial was performed in eighteen subjects with different MDR1 3435 C/T genotypes. All subjects took 500 mg quercetin or placebo daily from 1st to 13th day or from 43st to 55th day, and 100 mg talinolol was given at the 14th or 56th day. The washout period is 28 days.
In this study, we found the values of area under the curve (AUC)0–48 h, AUC0–∞ and Cmax of talinolol in all subjects significantly decreased (6496.6±2389.9 vs 7809.5±2386.8 ng.h/ml, P=0.04), (8414.7±344.8 vs 10478.2±4195.4 ng.h/ml, P=0.03), (412.9±132.6 vs 543.3±97.9 ng.h/ml, P=0.01) after administration of quercetin, respectively. There were no significant differences in tmax and t1/2 of talinolol. The results also showed AUC0–48 h (5598.6±2202.1 vs 8229.4±1491.7 ng.h/ml, P=0.02) and AUC0–∞ (7110.0±3437.0 vs 12681.2±4828.2 ng.h/ml, P=0.01) of talinolol to be significantly decreased in MDR1 3435 TT individuals administered of quercetin. The Cmax of talinolol in MDR1 3435 TT (382.4±149.1 vs 584.9±115.2 ng/ml, P=0.04) and MDR1 3435 CT (383.5±104.9 vs 554.6±80.6 ng/ml, P=0.01) individuals significantly decreased after the administration of quercetin.
Quercetin significantly induced the activity of P-gp and this induced effect was more obvious in MDR1 3435 TT individuals.
The P-glycoprotein (P-gp) is an ATP-dependent drug efflux transporter encoded by the multi-drug resistance gene (MDR1).1 It is not only highly expressed in many types of cancer cells, but also in normal tissues. P-gp is located on the luminal surface of endothelial cells, and its physiological function is excretion of toxins and xenobiotics out of cells.2 Some of the previous studies showed that functional and structural changes of P-gp contributed to the multi-drug absorption, distribution and excretion.3, 4, 5 De Lannoy6 reported that P-gp affected the distribution of many drugs by limiting the absorption from the gastrointestinal tract and secreting drugs into bile and urine. Fromm7 reported that the expression of P-gp in endothelial cells of the central nervous system prevented penetration of many drugs across the blood–brain barrier. Further study8 showed that the MDR1 gene polymorphism caused inter-individual variability in P-gp expression. Wang et al.9 reported that synonymous MDR1 3435C>T was associated with decreased mRNA and protein levels of P-gp. Johne et al.10 investigated the effect of MDR1 3435C>T polymorphism on steady-state pharmacokinetics of digoxin; their studies found that the area under the curve (AUC)0–4 and Cmax values of digoxin were higher in subjects with 3435 TT genotype than in those with 3435CC-genotyped individuals. However, some studies showed that MDR1 gene polymorphism had no effect on metabolism of talinolol or digoxin.11
Quercetin, a native flavonoid, is named in chemistry as 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4 H-1-benzopyran-4-one. It is widely distributed in daily diet such as onion, apple, berry, tea and red wine and in herbal remedy such as Sophora japonica and Ginkgo biloba.12 Quercetin displays a variety of biological actions such as anti-oxidation, anti-virus, anti-ulcer, anti-allergic and anti-cancer.13, 14, 15 Many studies suggested that quercetin might affect the function of P-gp.16, 17, 18 Wang et al.19 reported that quercetin increased the plasma concentration of digoxin when they were taken together in pigs. Dupuy20 reported that co-administration of quercetin and moxidectin subcutaneously increased moxidectin bioavailability in lambs. They thought the reason was beacuse of the inhibition of P-gp expression by quercetin. However the results of Yu et al.21 showed that quercetin significantly decreased Cmax of cyclosporine by 67.8% and reduced the AUC0–∞ by 43.3%, respectively, which indicated that quercetin decreased the bioavailability of cyclosporine by activating the functions of P-gp. Therefore, studies on the effects of quercetin on P-gp expression were controversial and its mechanism was still unclear. In the present study, we selected talinolol as the probe drug for P-gp to investigate the impact of quercetin on P-gp transport ability in Chinese healthy volunteers with different MDR1 3435 C/T genotypes.
Materials and methods
Primers were synthesized by Invitrogen (Shanghai, China). Taq DNA polymerase, dNTP mixture and restriction endonuclease Sau3aI were products from TaKaRa Biotech (Dalian, China). Ethidium bromide, Tris base, chloroform, phenol, EDTA, acetonitrile, diethyl ether, borate and SDS were of the analytical quality and obtained from commercial sources. The standard preparations of talinolol were purchased from Sigma (St Louis, MO, USA). Methylcyanide and methanol were products of Guangzhou Dima (Guangzhou, China).
One hundred sixty-five volunteers were genotyped for MDR1 variant 3435(C-T) and 18 subjects including six MDR1 3435 CC homozygotes, six MDR1 3435 CT homozygotes and six MDR1 3435 TT homozygote were enrolled to participate in this clinical trial. The mean age of the participants was 20.5±0.5 years and the mean weight was 55.7±5.3 kg. The body mass index was 17.8–23.4 kg/m2. They were judged to be healthy on the basis of physical examination, medical history and laboratory test results. All participants were nonsmokers. They abstained from alcohol and took no medication for at least 2 weeks before entry into the study. All subjects provided written informed consent and the study was approved by the Ethics Committee of Xiangya School of Medicine, Central South University.
All of the participants were asked to abstain from alcohol, coffee and other drugs from screening to the last visit day. Eighteen participants were randomized into two groups. The clinical trial was carried out according to two-phase crossover design protocol. At the first phase, all subjects took 500 mg quercetin or placebo daily from 1st to 13th day, and 100 mg talinolol was given at the 14th day. After 28 days washout period, all subjects took 500 mg quercetin or placebo daily from 43rd to 55th day and 100 mg talinolol was given at the 56th day at the second phase. Participants were kept on a fast overnight before taking talinolol (100 mg with 200 ml water) at 8:00 AM. No food was ingested until 9:30 AM. A heparin lock was inserted into a forearm vein to draw blood samples. A meaure of 5 ml venous blood samples were collected in sodium EDTA bottles at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 h after talinolol administration. Samples were centrifuged and the separation of plasma was carried out within 30 min. The plasma samples were stored at −80 °C until analysis.
Genotyping procedure for MDR1 variant 3435(C-T)
Genomic DNA was extracted from venous blood using standard chloroform–phenol extraction method described previously with a minor modification.22 A PCR–restriction fragment length polymorphism assay was used for the detection of MDR1 variant 3435(C-T) according to the method of Hoffmeyer et al.23 with minor modification. Briefly, the forward primer was 5′-IndexTermTGCTGGTCCTGAAGTTGATCTGTGAAC-3′ and the reverse primer was 5′-IndexTermAGATTAGGCAGTGACTCGATGAAGGCA-3′. The PCR mixture contained 10 mmol/l Tris, 50 mmol/l potassium chloride, 2.5 mmol/l MgCl2, 0.5 mmol/l dNTPs, 4% dimethyl sulfoxide, 0.4 μmol/l of each primer, 1.25 U Taq DNA polymerase and 2.5 μl reverse transcription mixture.The final volume of PCR was 25 μl. The PCR amplification included an initial denaturation at 95 °C for 5 min, 35 cycles of denaturation at 94 °C for 30 s, annealing at 56 °C for 30 s, synthesis at 72 °C for 1 min and a terminal extension for 5 min at 72 °C. The amplified DNA fragments including the MDR1 variant 3435(C-T) polymorphic site was detected by digestion with specific restriction enzymes Sau3aI. The products of PCR were separated by electrophoretic separation on 4% agarose gels.
The plasma concentrations of talinolol were measured by an high-performance liquid chromatography method with ultraviolet visible detection (Agilent 1100 serials HPLC, Santa Clara, CA, USA) (Figure 1). A measure of 0.5 ml plasma was mixed with 50 μl saturated sodium carbonate and 100 μl internal standard solution (28 μg/ml, propranolol) and extracted with 5 ml ethyl ether. After evaporation under a gentle stream of nitrogen, the residue was dissolved in 50 μl mobile phase (10 mmol/l methanoic acid amine solution, 20% acetonitrile), of which 20 μl was injected into the chromatographic column Hypersil-BDS C18 (4.6 mm × 200 mm, 5 μm), the temperature was 40 °C, the flow rate was 1.0 ml/min, the ultraviolet visible detection set at λ=248 nm to assess talinolol concentrations with the internal standard method. The lower limit of quantitation of the talinolol assays was 2.1 ng/ml in plasma, and with a coefficient of variation lower than 10% for five repeated measurements. The within-day and between-day precisions were lower than 10.1%. The accuracy ranged from 95.5 to 108.4% for the mean of five repeated measurements.
To prepare standard curves, 50 μl talinolol standard solution was added to 450 μl blank plasma at concentrations of 12.5, 25, 50, 100, 200, 400, 800 and 1600 ng/ml. The linear regression equation of talinolol was Y=−10.2202+0.00621263 × X (r2=0.998337). The limit of detection under the described conditions was 0.396 ng/ml.
Absorption of talinolol was characterized by peak concentration in plasma (Cmax) and the area under the plasma concentration-time curve. The AUC of talinolol was calculated by the linear trapezoidal role and further extrapolated to infinity by dividing the last experimental concentration by the terminal slope (k). The terminal elimination rate constant (λ) was determined by log-linear regression and the terminal elimination half-life (t1/2) was determined by the relationship t1/2=0.693/k. The Cmax and time to peak concentration (Tmax) were assigned by visual inspection of the data.
One-way analysis of variance was used to compare pharmacokinetic parameters of different genotypes groups. Paired t-test was used to analyze differences in extent of change between different treatment phases. Statistical analyses were performed with SPSS software version 13.0 for windows (SPSS Inc., an IBM Company, Chicago, IL, USA). A P-value<0.05 was considered statistically significant.
Genotype identification for MDR1 variant 3435(C-T)
One hundred sixty-five healthy volunteers were genotyped for MDR1 3435 C/T. The allelic frequency of MDR1 3435 C/T was 18.9%. After digestion with endonuclease enzyme and electrophoresis with 4% agarose gel, MDR1 3435 C/T was detected: MDR1 3435 CC produced 158+39 bp, CT produced 197+158+39bp, and TT produced 197bp.
Effects of MDR1 3435 C/T genetic ploymorphism on talinlol pharmacokinetics in subjects with or without quercetin
The changes in pharmacokinetic parameters of talinolol and comparisons of different MDR1 3435 C/T-genotyped groups with quercetin and without quercetin were summarized in Table 1, Table 2, and Table 3, respectively.
After 2 weeks quercetin supplementation, the plasma concentration of talinolol had a great change. The AUC0–48 h (6496.6±2389.9 vs 7809.5±2386.8 ng.h/ml, P<0.05), AUC0–∞ (8414.7±344.8 vs 10478.2±4195.4 ng.h/ml P<0.05) and Cmax of talinolol decreased significantly (412.9±132.6 vs 543.3±97.9 ng/ml, P<0.05) in subjects who were sequentially administered quercetin. There were no significant differences in tmax and t1/2 of talinolol between the individuals who were sequentially administered quercetin or placebo (Table 1, Figure 2).
The Cmax (584.9±115.2 vs 500.3±96.2 ng/ml, P<0.05), AUC0–48 h (8229.4±1491.7 vs 7372.7±2485.7 ng.h/ml, P<0.05) and AUC0–∞ (12681.2±4828.2 vs 9000.8±3153.2 ng.h/ml, P<0.05) increased in MDR1 3435 TT individuals compared with MDR1 3435CC individuals. The t1/2 (26.1±8.1 vs 16.1±4.3 h, P<0.05) decreased in MDR1 3435 TT individuals compared with MDR1 3435CC individuals (Table 2). Moreover, the Cmax (382.4±149.1 vs 574.9±115.2 ng/ml, P<0.05), AUC0–48 h and AUC0–∞ of talinolol decreased significantly (5598.6±2202.1 vs 8229.4±1491.7 ng.h/ml, P<0.05; 7110.0±3437.0 vs 12681.2±4828.2 ng.h/ml, P<0.05) in MDR1 3435 TT individuals who were sequentially administered quercetin then talinolol. The Cmax of talinolol decreased significantly (383.5±104.9 vs 554.6±80.6 ng/ml, P<0.05) in MDR1 3435 CT individuals who were sequentially administered quercetin then talinolol. All of the pharmacokinetic parameters had no significant difference between the medcine treatment group and control group in MDR1 3435 CC individuals (Table 3).
It has been proved that P-gp has an important role in drug metabolism. Many studies found that drug metabolism in vivo could be regulated by modulating the expression or activity of P-gp.24, 25, 26 A large number of studies have shown that quercetin has modulatory effect on the function and expression of P-gp.27, 28 Abs et al.29 investigated the function of P-gp in HepG2 cells by measuring the intracellular and extracellular concentration of rhodamine123 (a probe drug for P-gp) and found that Lipopolysaccharide(LPS) causes an inhibiting effect on P-gp, and the quercetin reestablish the P-gp activity in HepG2 cells induced by LPS. Kim et al.30 reported that quercetin elevated the plasma concentrations of fexofenadine, probably by the inhibition of P-gp-mediated efflux in healthy humans. However, in this study our results showed that the AUC0–48, AUC0–∞ and Cmax of talinolol significantly decreased in participants who received quercetin. Those findings indicated that the quercetin can induce the function of P-gp. We speculated one of the important reasons for the difference between Kim’s study and ours, which was due to different dosage of quercetin (daily for 7 days with 1500 mg quercetin vs daily for 13 days with 500 mg quercetin). Of course, the basic state of the differenct subjects (such as MDR1 genotype) may be a cofounding factor. But it should be noted that quercetin exhibited a concentration-dependent biphasic effect on P-gp. Mitsunaga et al.31 reported that low concentrations of quercetin indirectly activated P-gp whereas high concentrations of quercetin inhibited P-gp in vitro and in vivo. They speculated low concentrations of quercetin indirectly activated the transport of vincistine by enhancing the phosphorylation and hence the activity of P-gp, whereas high concentrations of quercetin inhibited P-gp. Pieter et al.32 investigated the effect of quercetin on the excretion of ridomine123 in cultured cells. The results showed the bile excretion index and bile clearance (Clbile) of ridomine123 increased, which demonstrated that quercetin can induce the activity of P-gp. In addition, some studies showed that the intracellular concentration of ridomine123 increased with increasing concentration of quercetin. They thought the reason was non-specific impact on membrane fluidity and promotion of membrane permeability by quercetin. Further studies33, 34 found quercetin can promote expression of P-gp through the activation of pregnane X receptor(PXR), constitutive androstane receptor(CAR) and aryl hydrocarbon receptor(AhR). In the present study, we found that quercetin can enhance the ability of P-gp and reduce the absorption of talinolol. Therefore, we thought that quercetin can enhance the transcriptional expression of P-gp through the activation of PXR, CAR and AhR, and not by direct binding. Goncalo C et al.35 reported quercetin is primarily metabolized to glucuronides and sulfoglucuronides and, to a minor extent, to sulfates. Moreover, they found that when the o-catechol group is not involved in conjugation reactions; the antioxidant activity of quercetin dose not decrease significantly and the quercetin metabolites contribute to the antioxidant potential of plasma. The quercetin and its major metabolites have similar biological activity, which indicated that both of them can induce the activity of P-gp to a certain extent. So we hypothesized that uptake of quercetin daily may be a benefit to human health under normal physiological conditions because it can consolidate the barrier formed by P-gp. However, in order to prevent drug interactions and avoid reduction of the therapeutic effects, when HIV protease inhibitor clarithromycin and sedative hypnotics transported by P-gp are taken, we should avoid taking quercetin together and restrict the intake of flavonoid-containing foods.36, 37, 38
The MDR1 gene polymorphisms have significant impact on the function of P-gp. So we investigated the function of P-gp and the effect of quercetin on P-gp expression in different MDR1 3435 C/T-genotyped subjects. We found that there was the highest level of talinolol bioavailability in MDR1 3435 TT, the middle level in MDR1 3435 CT and the lowest level in MDR1 3435CC individuals without administration of quercetin, which indicated that the MDR1 3435 C/T gene polymorphisms contributed to the change of P-gp function, and P-gp function decreased in MDR1 3435 TT individuals. The data in this study also showed that the AUC0–48, AUC0–∞ and Cmax of talinolol significantly increased in MDR1 3435 TT subjects, co-administered with quercetin. The AUC0–48, AUC0–∞ and Cmax of talinolol showed a strong downward trend in MDR1 3435 CT and MDR1 3435CC individuals who were sequentially administered quercetin then talinolol, but the pharmacokinetic parameters had no significant difference between the subjects with or without administration of quercetin. So we think that quercetin can induce the function of P-gp, and this induction is related to MDR1 3435 C/T genotype.
In conclusion, the findings in this study showed that quercetin significantly induced the activity of P-gp/MDR1 in vivo. The induction was partially related to the MDR1 3435 genotype, more obvious in MDR1 3435 TT individuals especially. More attention should be paid to the patients using drugs belonging to substrates for P-gp, and taking quercetin should be restricted, especially in MDR1 3435 TT individuals.
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We thank these volunteers for their support in this study. We also thank the grants support of the National High-Tech R&D Program of China (863 Program; 2012AA02A517), National Natural Science Foundation of China (81173129), Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China (IRT0946), and supported by Hunan Provincial Natural Science Foundation of China (12JJ7006).
The authors declare no conflict of interest.
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Wang, S., Duan, K., Li, Y. et al. Effect of quercetin on P-glycoprotein transport ability in Chinese healthy subjects. Eur J Clin Nutr 67, 390–394 (2013) doi:10.1038/ejcn.2013.5
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