Next Article in Journal
CsCuAO1 Associated with CsAMADH1 Confers Drought Tolerance by Modulating GABA Levels in Tea Plants
Next Article in Special Issue
Modulating the Activity of the Human Organic Cation Transporter 2 Emerges as a Potential Strategy to Mitigate Unwanted Toxicities Associated with Cisplatin Chemotherapy
Previous Article in Journal
Immp2l Enhances the Structure and Function of Mitochondrial Gpd2 Dehydrogenase
Previous Article in Special Issue
Unique Substrate Recognition and Sodium–Substrate Binding Stoichiometry in a Bacterial Serotonin Transporter, TuriSERT
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 25
Issue 2
10.3390/ijms25020991
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

The Use of an Antioxidant Enables Accurate Evaluation of the Interaction of Curcumin on Organic Anion-Transporting Polypeptides 4C1 by Preventing Auto-Oxidation

by
Toshihiro Sato
1,*,†,
Ayaka Yagi
2,†,
Minami Yamauchi
2,
Masaki Kumondai
1,
Yu Sato
1,
Masafumi Kikuchi
1,2,
Masamitsu Maekawa
1,2,
Hiroaki Yamaguchi
3,4,
Takaaki Abe
5,6,7 and
Nariyasu Mano
1,2
1
Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai 980-8574, Japan
2
Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
3
Department of Pharmacy, Yamagata University Hospital, Yamagata 990-9585, Japan
4
Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan
5
Division of Nephrology, Endocrinology, and Vascular Medicine, Graduate School of Medicine, Tohoku University, Sendai 980-8574, Japan
6
Division of Medical Science, Graduate School of Biomedical Engineering, Tohoku University, Sendai 980-8579, Japan
7
Department of Clinical Biology and Hormonal Regulation, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2024, 25(2), 991; https://doi.org/10.3390/ijms25020991
Submission received: 15 November 2023 / Revised: 9 January 2024 / Accepted: 10 January 2024 / Published: 12 January 2024
(This article belongs to the Special Issue Transport of Nutrients and Ions Relevant to Human Pathophysiology)
Browse Figures
Review Reports Versions Notes

Abstract

:
Flavonoids have garnered attention because of their beneficial bioactivities. However, some flavonoids reportedly interact with drugs via transporters and may induce adverse drug reactions. This study investigated the effects of food ingredients on organic anion-transporting polypeptide (OATP) 4C1, which handles uremic toxins and some drugs, to understand the safety profile of food ingredients in renal drug excretion. Twenty-eight food ingredients, including flavonoids, were screened. We used ascorbic acid (AA) to prevent curcumin oxidative degradation in our method. Twelve compounds, including apigenin, daidzein, fisetin, genistein, isorhamnetin, kaempferol, luteolin, morin, quercetin, curcumin, resveratrol, and ellagic acid, altered OATP4C1-mediated transport. Kaempferol and curcumin strongly inhibited OATP4C1, and the Ki values of kaempferol (AA(−)), curcumin (AA(−)), and curcumin (AA(+)) were 25.1, 52.2, and 23.5 µM, respectively. The kinetic analysis revealed that these compounds affected OATP4C1 transport in a competitive manner. Antioxidant supplementation was determined to benefit transporter interaction studies investigating the effects of curcumin because the concentration-dependent curve evidently shifted in the presence of AA. In this study, we elucidated the food–drug interaction via OATP4C1 and indicated the utility of antioxidant usage. Our findings will provide essential information regarding food–drug interactions for both clinical practice and the commercial development of supplements.

Graphical Abstract

1. Introduction

In recent years, polyphenols have received considerable attention owing to their antioxidant, antiviral, anti-inflammatory, and anticarcinogenic activities [1,2,3,4,5]. Polyphenols have been reported to prevent major chronic diseases, including cardiovascular diseases, cancer, and diabetes [6,7,8]. However, some flavonoids, a group of natural polyphenolic substances abundant in vegetables, fruits, grains, and tea, interact with drugs via transporters and metabolic enzymes [9,10,11,12,13,14] (Supplementary Table S1).
Drug interactions via transporters and metabolic enzymes are considered the main cause of adverse drug reactions [15,16]; thus, drug–drug and drug–endogenous metabolite interaction studies have been widely conducted [17,18,19,20,21]. Quercetin, a flavonoid, has been reported to increase the plasma concentration of pravastatin by inhibiting organic anion-transporting polypeptide (OATP) 1B1 [22]. Consequently, drug transporters, such as OATP, have been investigated, and information on food–drug interactions has increased (Supplementary Table S1). For example, the flavonoid ellagic acid inhibits organic anion transporter (OAT) 1 expressed in renal proximal tubular cells [23].
OATPs are Na+-independent transporters expressed in various tissues, such as the liver, kidney, and small intestine, and contribute to the cellular membrane transport of endogenous substances, such as bile acids and various drugs [17,24,25,26,27]. OATP4C1 is the only member of the OATP family expressed in the kidney, is localized on the basolateral side of proximal tubule cells, and has been reported to contribute to the renal excretion of uremic toxins and some drugs [28,29]. Recently, OATP4C1 has been reported to interact with human immunodeficiency virus protease inhibitors such as ritonavir and saquinavir [18], and remdesivir, an antiviral drug used for the treatment of COVID-19 [19].
Although some flavonoids have been reported to inhibit OATP1B1, OATP1B3, and OATP2B1 [30,31], the inhibition of OATP4C1 has not been studied extensively. The aim of this study was to investigate the food–drug interactions via OATP4C1 to understand the safety profile of food ingredients, including flavonoids, in renal drug excretion.

2. Results

2.1. Screening of the Effect of Food Ingredients on OATP4C1-Mediated Transport

To elucidate potential food–drug interactions via OATP4C1, we screened 28 food ingredients (Figure 1 and Figure 2) that are commonly used in drug interaction studies (Supplementary Table S1). Some of these food ingredients are also reported to be the substrates or inhibitors of organic ion transporters and ABC transporters. Inhibitor concentrations were set much higher (100 µM, except for theaflavin [50 µM] due to the solubility upper limit) than those expected in human blood to avoid overlooking the interaction. OATP4C1-mediated transport was strongly inhibited (by > 50%) by six compounds: apigenin, kaempferol, luteolin, morin, quercetin, and curcumin (Figure 3). These compounds exhibited 66%, 75%, 52%, 57%, 50%, and 72% inhibition, respectively. Six other compounds, namely daidzein, fisetin, genistein, isorhamnetin, resveratrol, and ellagic acid, also altered OATP4C1-mediated transport; however, the alteration by these compounds was moderate (> 10% and < 50%) (Figure 3). These compounds exhibited 40%, 24%, 42%, 18%, and 46% inhibition and 13% elevation, respectively. No significant alterations in OATP4C1-mediated transport were observed for the other 16 food ingredients screened (Figure 3).

2.2. Using an Antioxidant to Evaluate the Inhibitory Effects of Food Ingredients

As curcumin is unstable in phosphate buffer at physiological pH [32], ascorbic acid (AA) was used to prevent curcumin degradation during the transport study. We confirmed that AA did not affect OATP4C1-mediated transport (Figure 4A). Next, we evaluated the inhibitory effect of curcumin in the absence or presence of 10, 100, and 1000 µM AA (Figure 4B). A significant increase in curcumin inhibition, from 33% to 63–67%, was observed (Figure 4B). The addition of AA did not change the pH of the reaction solution (control: pH = 7.44; AA 1000 µM: pH = 7.45 in Krebs–Henseleit (KH) buffer). Finally, 10 µM AA was used in the subsequent experiments.
Additionally, we screened the effects of food ingredients on OATP4C1-mediated transport using AA. The results showed that the overall interactions, especially the inhibitory effects, of food ingredients were not significantly different (Supplementary Figure S1). However, the inhibitory effects of some food ingredients, such as daidzein, fisetin, genistein, isorhamnetin, luteolin, morin, and quercetin, were weakened in the presence of AA (Supplementary Figure S1).

2.3. Concentration-Dependent Inhibition by Kaempferol and Curcumin

Next, we evaluated the half-maximum inhibitory concentrations (IC50) and absolute inhibitory constant (Ki) values of kaempferol and curcumin that inhibited OATP4C1 strongly (Equation (1)). These compounds inhibited OATP4C1-mediated transport in a concentration-dependent manner (Figure 5A–D). The IC50 values of kaempferol (AA(−)), kaempferol (AA(+)), curcumin (AA(−)), and curcumin (AA(+)) for OATP4C1 were 29.3, 33.7, 61.1, and 27.5 µM, respectively. The Ki values of kaempferol (AA(−)), kaempferol (AA(+)), curcumin (AA(−)), and curcumin (AA(+)) for OATP4C1 were 25.1, 28.8, 52.2, and 23.5 µM, respectively. The individual parameters of curcumin are summarized in Table 1. As shown in Figure 5C,D, an evident shift in the concentration-dependent curve was observed for curcumin.

2.4. Kinetic Analysis of OATP4C1-Mediated T3 Uptake in The Presence or Absence of Kaempferol and Curcumin

Further, we performed a kinetic analysis to clarify the mechanism of inhibition by curcumin and kaempferol. Alteration in the kinetic curves was observed both in the presence of curcumin and kaempferol (Figure 6). The obtained kinetic parameters (Km, Vmax, and Vmax/Km values) are summarized in Table 2. Kinetic analysis revealed that curcumin and kaempferol addition increased the Km values of OATP4C1-mediated T3 uptake (control, 6.06; curcumin, 20.8; kaempferol, 17.6 (µM)). Moreover, reductions in Vmax/Km values were observed in the presence of those inhibitors (control, 88.8; curcumin, 39.7; kaempferol, 31.8 (µL/mg protein/10 min)).

3. Discussion

In this study, we aimed to understand the effect of food ingredients on the renal excretion of drugs by investigating their interactions via OATP4C1, which is expressed in renal proximal tubular cells. First, we examined whether 28 types of food ingredients, for which transport inhibition was previously analyzed, inhibited OATP4C1-mediated transport. Twelve compounds, including apigenin, daidzein, fisetin, genistein, isorhamnetin, kaempferol, luteolin, morin, quercetin, curcumin, resveratrol, and ellagic acid, were found to significantly alter OATP4C1-mediated transport. Apigenin, kaempferol, luteolin, morin, quercetin, and curcumin inhibited OATP4C1 transport by ≥50% (Figure 3). Six other compounds also moderately altered OATP4C1-mediated transport: daidzein, fisetin, genistein, isorhamnetin, resveratrol, and ellagic acid (Figure 3). Notably, ellagic acid accelerated OATP4C1-mediated transport by 13% instead of inhibiting it. To date, the structure of OATP4C1 has not been clarified; therefore, the binding sites and intermolecular interactions are unknown. Since the possible existence of multiple binding sites has been reported [18], the differences in the binding sites of each compound might affect the strength of the interactions. Although apigenin, daidzein, genistein, quercetin, gallic acid, resveratrol, and ellagic acid have been reported to inhibit other drug transporters, such as hepatic and intestinal OATPs, renal OATs, and P-glycoprotein (P-gp) (Supplementary Figure S1), these compounds showed relatively moderate inhibition of OATP4C1 (Figure 3). Theaflavin, epigallocatechin-3-gallate, caffeic acid, ferulic acid, gallic acid, and ellagic acid, which have been reported to inhibit OATP1B1, OATP1B3, OATP2B1, and renal OATs, did not inhibit OATP4C1-mediated transport (Supplementary Table S1 and Figure 3). Thus, the degree of transport inhibition by food ingredients differed between OATP4C1 and other drug transporters, such as OATPs; however, their details are yet to be elucidated. Moreover, we used much higher concentrations than those expected in human blood to avoid overlooking the interaction. However, the concentrations of the compounds may not reach those used in the inhibition study. Thus, the individual compound may not inhibit OATP4C1 transport by itself in clinical settings.
Next, we performed the transport study using AA to prevent curcumin degradation in the KH buffer. Curcumin can be stabilized by adding antioxidants, such as AA [32]. However, no reports have been made on the use of antioxidants to examine food–drug interactions via transporters. Therefore, we examined the effect of AA on OATP4C1-mediated transport. We found that AA did not affect OATP4C1 transport (Figure 4A). With a reproducibility test, we then confirmed that a significant increase in curcumin inhibition from 33% to 63–67% was observed by preventing curcumin degradation without altering the KH buffer pH (Figure 4B). Notably, curcumin inhibition is not consistent between Figure 3A (72%) and Figure 3B (33%), which may be due to the instability of curcumin in the absence of antioxidants. Furthermore, despite increasing the AA concentration to 100 and 1000 µM, the inhibitory effect of curcumin on transport did not increase compared to the 10-µM AA reaction solution. Thus, 10 µM AA was used in the subsequent experiments. Additionally, we screened the effects of food ingredients on OATP4C1-mediated transport using AA. The results showed that the inhibitory effects of some food ingredients, such as daidzein, fisetin, genistein, isorhamnetin, luteolin, morin, and quercetin, were weakened in the presence of AA (Supplementary Figure S1). The oxidized metabolites of these compounds may have exerted inhibitory effects on OATP4C1-mediated transport, and the inhibitory effects were weakened as a result of stopping the generation of these metabolites in the presence of AA. Further studies are required to elucidate the mechanisms underlying this phenomenon.
Then, we performed a concentration-dependent study using 10 µM AA. The results showed that kaempferol and curcumin inhibited OATP4C1-mediated transport in a concentration-dependent manner both in the absence and presence of 10 µM AA (Figure 5A–D). The individual parameters of curcumin are summarized in Table 1. An obvious shift was observed in the concentration-dependent curve for curcumin (Figure 5C,D).
Curcumin degradation is inhibited by binding to plasma proteins, such as albumin, and over 80% of curcumin reportedly remains in the presence of plasma proteins for up to 1 h [33,34]. Curcumin rapidly degrades in phosphate buffer at pH 7.4, with 80–90% decomposition occurring within 12 min, mainly generating bicyclopentadione derivatives through auto-oxidative transformation [32]. Curcumin has also been reported to inhibit OATP1B1 and OATP1B3 transport, with IC50 values of 3.8 and 34 µM, respectively [35]. That study did not use antioxidants such as AA, suggesting that oxidative degradation of curcumin might have occurred in the experiments. Based on previous evidence, we successfully evaluated curcumin inhibition of OATP4C1-mediated transport and accurately calculated the IC50 and Ki values using AA. Here, we concluded that the utilization of an antioxidant that does not affect the transporter activity for food–drug interaction studies is desirable to accurately calculate parameters such as IC50 and Ki values.
Finally, we performed a kinetic analysis to clarify the mechanism of inhibition by curcumin and kaempferol. The Km value of 6.06 µM in the control was similar to those reported in [18,28]. Alterations in the kinetic curves (Figure 6), increases in the Km values, and reductions in the Vmax/Km values (Table 2) of OATP4C1-mediated T3 uptake were observed in the presence of those inhibitors. The result suggested that these compounds affected OATP4C1-mediated T3 uptake in a competitive manner. Moreover, we confirmed that those inhibitors reduced OATP4C1-mediated clearance of T3 mainly due to the alteration of Km values.
Currently, there is limited information regarding the blood concentrations of food ingredients such as flavonoids. The plasma concentration of flavonoids may not exceed 1 µM with a single flavonoid intake within the range of 10–100 mg [36]. In a normal diet in several countries, the intake of a single flavonoid is reported to be < 100 mg [37,38,39]. Therefore, the blood concentrations of the six food ingredients: apigenin, kaempferol, luteolin, morin, quercetin, and curcumin, identified in this study as OATP4C1 inhibitors, may not be sufficient to inhibit OATP4C1 during normal dietary intake. However, a combination of multiple flavonoids that inhibit P-glycoprotein strengthens its inhibitory effects on the transporter [40]. Therefore, it is possible that additive and/or synergistic inhibitory effects could occur on OATP4C1 when patients consume multiple food ingredients simultaneously. In particular, it is advisable to avoid concurrent intake of kaempferol, curcumin, and substrate drugs of OATP4C1. Furthermore, researchers are developing novel supplements to improve the bioavailability of some flavonoids. Their reports indicated that the blood concentration may exceed 1 µM even when taking a single flavonoid within the range of 10–100 mg [41,42]. When taking such novel supplements, the food–drug interactions via OATP4C1 may occur. However, because information on the pharmacokinetic parameters of food ingredients, such as elimination half-life, is limited, it is challenging to propose specific dosing intervals.

4. Materials and Methods

4.1. Materials

Ferulic acid (99%) was purchased from Sigma Aldrich (St. Louis, MO, USA). Ascorbic acid and quercetin (≤100%) were purchased from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan). Caffeic acid (≥98%), curcumin (100%), hesperidin (90%), rutin (95.0–101.5%), and triiodothyronine (T3) were purchased from Nacalai Tesque, Inc. (Kyoto, Japan). Gallic acid (≥98%), chlorogenic acid (≥95%), ellagic acid (≥95%), sesamin (≥95%), epigallocatechin-3-gallate (≥96%), genistein (≥98%), daidzein (≥95%), luteolin (≥98%), theaflavin (≥98%), isoquercetin (98%), and morin (100%) were purchased from Cayman Chemical Company (Ann Arbor, MI, USA). Resveratrol (>99.0%), fisetin (>96.0%), isorhamnetin (>95.0%), and troxerutin (90%) were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Cyanidin chloride (99%) was purchased from Nagara Science Co. Ltd. (Gifu, Japan). Apigenin (≥98%) was purchased from LKT Laboratories, Inc. (St. Paul, MN, USA). Kaempferol (98%), myricetin (98%), and naringin (98%) were purchased from BDL Pharmatech Ltd. (Shanghai, China). Hyperoside (90–100%) was purchased from Toronto Research Chemicals Inc. (Toronto, ON, Canada). Neohesperidin (≥98%) was purchased from Chem-Impex International, Inc. (Wood Dale, IL, USA). All other chemicals were commercially available and had the highest possible purity.

4.2. Cell Culture

The MDCKII cells transfected with OATP4C1 or an empty vector were established in our laboratory [18]. OATP4C1/MDCKII and mock cells were cultured in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum (Gibco, Thermo Fisher Scientific Inc., Waltham, MA, USA) and G418 (0.5 mg/mL; Nacalai Tesque, Inc.) at 37 °C under 5% CO2 and 95% humidified air.

4.3. Transport Study

The cellular uptake of T3 was measured in monolayer cell cultures grown in 24-well plates. Cells were seeded at a density of 2.0 × 105 cells/well. Thereafter, the cells were incubated in a culture medium containing 5 mM sodium butyrate for 24 h before the uptake study. The cells were washed once with KH buffer (118 mM NaCl, 23.8 mM NaHCO3, 4.83 mM KCl, 0.96 mM KH2PO4, 1.20 mM MgSO4, 12.5 mM N-(2-hydroxyethyl) piperazine-N’-2-ethanesulfonic acid, 5.0 mM D-glucose, and 1.53 mM CaCl2; pH 7.4), followed by preincubation in KH buffer. Cellular uptake was initiated by adding T3-containing KH buffer with or without each flavonoid. Uptake was terminated after 10 min by replacing the incubation buffer with ice-cold KH buffer. The cells were washed twice with ice-cold KH buffer. The concentration of T3 was measured using liquid chromatography/tandem mass spectrometry (LC/MS/MS). Cellular uptake was presented as the uptake amount divided by the amount of cellular protein quantified using the Bradford protein assay. The experiment was performed in triplicate (n = 3) and repeated three times. Flavonoids, except ellagic acid, were dissolved in dimethyl sulfoxide (DMSO) at a final concentration of less than 0.5%. A stock solution of ellagic acid (20 mM) was obtained by dissolving it in 0.05 M NaOH and was further diluted to 100 µM in KH buffer (the pH was adjusted to 7.4).

4.4. Using an Antioxidant to Evaluate the Inhibitory Effects of Food Ingredients

Curcumin is unstable in phosphate buffers at physiological pH [32]. Therefore, AA was used to prevent curcumin degradation during the transport study. Appropriate AA concentrations were determined as follows:
(1)
The effect of 10, 100, and 1000 µM AA on OATP4C1-mediated transport was evaluated.
(2)
The inhibitory effect of curcumin was evaluated in the absence or presence of 10, 100, and 1000 µM AA.
Finally, 10 µM AA was determined to be the appropriate concentration of AA and was used in the subsequent transport studies.

4.5. Concentration-Dependent Inhibition by Kaempferol and Curcumin

We investigated the concentration-dependent inhibition by kaempferol and curcumin, which resulted in more than 70% inhibition of OATP4C1-mediated T3 uptake. The inhibition curve was fitted to the Rodbard model. The half-maximum inhibitory concentration (IC50) values of the food ingredients were calculated using JMP Pro 16 (SAS Institute Inc., Cary, NC, USA). The absolute inhibitory constant (Ki) was then derived using the following equation (Equation (1)) [21,43]: where [S] is the substrate concentration and Km is the Michaelis–Menten constant. The experiment was performed in triplicate (n = 3) and repeated three times.
K i = I C 50 1 + [ S ] K m

4.6. Kinetic Analysis of OATP4C1-Mediated T3 Uptake in the Presence or Absence of Kaempferol and Curcumin

We performed the kinetic analysis to clarify the mechanism of inhibition by curcumin and kaempferol, which showed strong inhibition on OATP4C1-mediated T3 uptake. The kinetic curves were fitted to the Michaelis–Menten equation. The kinetic parameters (Km, Vmax, and Vmax/Km values) of the food ingredients were calculated using JMP Pro 16. The experiment was performed in duplicate (n = 2) and repeated three times.

4.7. Sample Preparation

The cells were scraped and homogenized in 200 µL water after uptake termination. Deproteinization was performed by adding equal volumes of pravastatin-containing acetonitrile as an internal standard. After vortexing, the mixture was centrifuged at 15,000× g for 5 min at 20 °C, and the supernatant was collected.

4.8. Liquid Chromatography/Tandem Mass Spectrometry Conditions

LC/MS/MS was used to measure the T3 concentrations. A Shimadzu Nexera HPLC System (Shimadzu Corporation, Kyoto, Japan) equipped with a Cosmosil 5C18-MS-II column (Nacalai Tesque, Inc.) was used for chromatographic separation. The mobile phase was water/acetonitrile (70:30, v/v) containing 0.1% acetic acid at a flow rate of 0.2 mL/min. The column temperature was maintained at 40 °C and the sample injection volume was 5 µL.
Mass spectrometry was performed using an API 5000 tandem mass spectrometer (Sciex LLC, Framingham, MA, USA). The T3 concentration was measured in negative ion mode. Selected reaction monitoring (SRM) was performed and the SRM transitions monitored were m/z 650 > 127 for T3 and m/z 423 > 101 for pravastatin. The collected data were analyzed using the Analyst software (version 1.5; SCIEX LLC).

4.9. Statistical Analysis

Data are expressed as the mean ± SE. Multiple statistical comparisons were made using one-way analysis of variance (ANOVA), followed by Tukey’s test. The data were analyzed using JMP Pro 16 (SAS Institute Inc.). Statistical significance was set at p-values < 0.05.

5. Conclusions

We clarified food–drug interactions via the renal drug transporter OATP4C1 and discussed the differences between other drug transporters and OATP4C1. This is the first report to propose the utilization of an antioxidant for the evaluation of food–drug interactions via transporters. Our findings demonstrated that the addition of ascorbic acid was beneficial in evaluating the effect of curcumin on OATP4C1-mediated transport. Our results suggest the usefulness of an antioxidant such as ascorbic acid when assessing the interaction of easily oxidized compounds on transporters or metabolic enzymes. We believe that this study provides novel information for food–drug interaction studies of drug transporters.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms25020991/s1. References [44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79] are cited in the Supplementary Materials.

Author Contributions

T.S., A.Y., M.Y. and M.M. participated in the research design; T.S., A.Y. and M.Y. conducted the experiments and data analysis; T.S., A.Y., M.Y., M.K. (Masaki Kumondai), Y.S., M.K. (Masafumi Kikuchi), M.M., H.Y., T.A. and N.M.: manuscript writing and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Japan Society for the Promotion of Science KAKENHI (Grant 20K16037 and 22K15311) and a research grant from the Mishima Kaiun Memorial Foundation, Tokyo, Japan (T.S.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The authors declare that all the data supporting the findings of this study are available within the paper and its Supplementary Materials Data.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Batiha, G.E.-S.; Beshbishy, A.M.; Ikram, M.; Mulla, Z.S.; El-Hack, M.E.A.; Taha, A.E.; Algammal, A.M.; Elewa, Y.H.A. The pharmacological activity, biochemical properties, and pharmacokinetics of the major natural polyphenolic flavonoid: Quercetin. Foods 2020, 9, 374. [Google Scholar] [CrossRef] [PubMed]
  2. Bahrami, A.; Makiabadi, E.; Jalali, S.; Heidari, Z.; Assadi, M.; RashidKhani, B. Dietary intake of polyphenols and the risk of breast cancer: A case-control study. Clin. Nutr. Res. 2021, 10, 330–340. [Google Scholar] [CrossRef] [PubMed]
  3. Cheon, M.; Chung, M.; Park, Y. Association between dietary intake of flavonoids and cancer recurrence among breast cancer survivors. Nutrients 2021, 13, 3049. [Google Scholar] [CrossRef] [PubMed]
  4. Hatono, M.; Ikeda, H.; Suzuki, Y.; Kajiwara, Y.; Kawada, K.; Tsukioki, T.; Kochi, M.; Suzawa, K.; Iwamoto, T.; Yamamoto, H.; et al. Effect of isoflavones on breast cancer cell development and their impact on breast cancer treatments. Breast Cancer Res. Treat. 2021, 185, 307–316. [Google Scholar] [CrossRef] [PubMed]
  5. Shen, N.; Wang, T.; Gan, Q.; Liu, S.; Wang, L.; Jin, B. Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chem. 2022, 383, 132531. [Google Scholar] [CrossRef] [PubMed]
  6. Del Bo’, C.; Bernardi, S.; Marino, M.; Porrini, M.; Tucci, M.; Guglielmetti, S.; Cherubini, A.; Carrieri, B.; Kirkup, B.; Kroon, P.; et al. Systematic Review on Polyphenol Intake and Health Outcomes: Is there Sufficient Evidence to Define a Health-Promoting Polyphenol-Rich Dietary Pattern? Nutrients 2019, 11, 1355. [Google Scholar] [PubMed]
  7. Koch, W. Dietary polyphenols—Important non-nutrients in the prevention of chronic noncommunicable diseases. A systematic review. Nutrients 2019, 11, 1039. [Google Scholar] [CrossRef]
  8. Petrescu, A.M.; Paunescu, V.; Ilia, G. The antiviral activity and cytotoxicity of 15 natural phenolic compounds with previously demonstrated antifungal activity. J. Environ. Sci. Health B 2019, 54, 498–504. [Google Scholar] [CrossRef]
  9. Mueller, S.C.; Uehleke, B.; Woehling, H.; Petzsch, M.; Majcher-Peszynska, J.; Hehl, E.-M.; Sievers, H.; Frank, B.; Riethling, A.-K.; Drewelow, B. Effect of St John’s wort dose and preparations on the pharmacokinetics of digoxin. Clin. Pharmacol. Ther. 2004, 75, 546–557. [Google Scholar] [CrossRef]
  10. Qiao, J.; Gu, C.; Shang, W.; Du, J.; Yin, W.; Zhu, M.; Wang, W.; Han, M.; Lu, W. Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro. Food Chem. Toxicol. 2011, 49, 1410–1415. [Google Scholar] [CrossRef]
  11. Jeon, H.; Jang, I.J.; Lee, S.; Ohashi, K.; Kotegawa, T.; Ieiri, I.; Cho, J.Y.; Yoon, S.H.; Shin, S.G.; Yu, K.S.; et al. Apple juice greatly reduces systemic exposure to atenolol. Br. J. Clin. Pharmacol. 2013, 75, 172–179. [Google Scholar] [CrossRef] [PubMed]
  12. Albassam, A.A.; Markowitz, J.S. An appraisal of drug-drug interactions with green tea (Camellia sinensis). Planta Med. 2017, 83, 496–508. [Google Scholar] [CrossRef] [PubMed]
  13. Kim, T.E.; Shin, K.H.; Park, J.E.; Kim, M.G.; Yun, Y.M.; Choi, D.H.; Kwon, K.J.; Lee, J. Effect of green tea catechins on the pharmacokinetics of digoxin in humans. Drug Des. Devel. Ther. 2018, 12, 2139–2147. [Google Scholar] [CrossRef] [PubMed]
  14. Prely, H.; Herledan, C.; Caffin, A.G.; Baudouin, A.; Larbre, V.; Maire, M.; Schwiertz, V.; Vantard, N.; Ranchon, F.; Rioufol, C. Real-life drug–drug and herb–drug interactions in outpatients taking oral anticancer drugs: Comparison with databases. J. Cancer Res. Clin. Oncol. 2022, 148, 707–718. [Google Scholar] [CrossRef] [PubMed]
  15. Palleria, C.; Roberti, R.; Iannone, L.F.; Tallarico, M.; Barbieri, M.A.; Vero, A.; Manti, A.; De Sarro, G.; Spina, E.; Russo, E. Clinically relevant drug interactions between statins and antidepressants. J. Clin. Pharm. Ther. 2020, 45, 227–239. [Google Scholar] [CrossRef] [PubMed]
  16. Kumondai, M.; Kikuchi, M.; Mizuguchi, A.; Hayashi, N.; Ui, M.; Hirama, T.; Okada, Y.; Sato, Y.; Sato, T.; Maekawa, M.; et al. Therapeutic drug monitoring of blood sirolimus and tacrolimus concentrations for polypharmacy management in a lymphangioleiomyomatosis patient taking two cytochrome P450 3A inhibitors. Tohoku J. Exp. Med. 2023, 260, 29–34. [Google Scholar] [CrossRef]
  17. Sato, T.; Yamaguchi, H.; Kogawa, T.; Abe, T.; Mano, N. Organic anion transporting polypeptides 1B1 and 1B3 play an important role in uremic toxin handling and drug-uremic toxin interactions in the liver. J. Pharm. Pharm. Sci. 2014, 17, 475–484. [Google Scholar] [CrossRef]
  18. Sato, T.; Mishima, E.; Mano, N.; Abe, T.; Yamaguchi, H. Potential drug interactions mediated by renal organic anion transporter OATP4C1. J. Pharmacol. Exp. Ther. 2017, 362, 271–277. [Google Scholar] [CrossRef]
  19. Sato, T.; Maekawa, M.; Mano, N.; Abe, T.; Yamaguchi, H. Role of OATP4C1 in renal handling of remdesivir and its nucleoside analog GS-441524: The first approved drug for patients with COVID-19. J. Pharm. Pharm. Sci. 2021, 24, 227–236. [Google Scholar] [CrossRef]
  20. Petric, Z.; Žuntar, I.; Putnik, P.; Bursać Kovačević, D. Food–drug interactions with fruit juices. Foods 2020, 10, 33. [Google Scholar] [CrossRef]
  21. Yamauchi, M.; Sato, T.; Otake, A.; Kumondai, M.; Sato, Y.; Kikuchi, M.; Maekawa, M.; Yamaguchi, H.; Abe, T.; Mano, N. Bile acid–drug interaction via organic anion-transporting Polypeptide 4C1 is a potential mechanism of altered pharmacokinetics of renally excreted drugs. Int. J. Mol. Sci. 2022, 23, 8508. [Google Scholar] [CrossRef] [PubMed]
  22. Wu, L.-X.; Guo, C.-X.; Chen, W.-Q.; Yu, J.; Qu, Q.; Chen, Y.; Tan, Z.-R.; Wang, G.; Fan, L.; Li, Q.; et al. Inhibition of the organic anion-transporting polypeptide 1B1 by quercetin: An in vitro and in vivo assessment. Br. J. Clin. Pharmacol. 2012, 73, 750–757. [Google Scholar] [CrossRef] [PubMed]
  23. Whitley, A.C.; Sweet, D.H.; Walle, T. The dietary polyphenol ellagic acid is a potent inhibitor of hOAT1. Drug Metab. Dispos. 2005, 33, 1097–1100. [Google Scholar] [CrossRef] [PubMed]
  24. Hagenbuch, B.; Meier, P.J. The superfamily of organic anion transporting polypeptides. Biochim. Biophys. Acta 2003, 1609, 1–18. [Google Scholar] [CrossRef] [PubMed]
  25. Hagenbuch, B.; Meier, P.J. Organic anion transporting polypeptides of the OATP/SLC21 family: Phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflug. Arch. 2004, 447, 653–665. [Google Scholar] [CrossRef] [PubMed]
  26. Kullak-Ublick, G.A.; Stieger, B.; Meier, P.J. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 2004, 126, 322–342. [Google Scholar] [CrossRef]
  27. Suga, T.; Yamaguchi, H.; Sato, T.; Maekawa, M.; Goto, J.; Mano, N. Preference of conjugated bile acids over unconjugated bile acids as substrates for OATP1B1 and OATP1B3. PLoS ONE 2017, 12, e0169719. [Google Scholar] [CrossRef]
  28. Mikkaichi, T.; Suzuki, T.; Onogawa, T.; Tanemoto, M.; Mizutamari, H.; Okada, M.; Chaki, T.; Masuda, S.; Tokui, T.; Eto, N.; et al. Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc. Natl Acad. Sci. USA 2004, 101, 3569–3574. [Google Scholar] [CrossRef]
  29. Toyohara, T.; Suzuki, T.; Morimoto, R.; Akiyama, Y.; Souma, T.; Shiwaku, H.O.; Takeuchi, Y.; Mishima, E.; Abe, M.; Tanemoto, M.; et al. SLCO4C1 transporter eliminates uremic toxins and attenuates hypertension and renal inflammation. J. Am. Soc. Nephrol. 2009, 20, 2546–2555. [Google Scholar] [CrossRef]
  30. Mandery, K.; Balk, B.; Bujok, K.; Schmidt, I.; Fromm, M.F.; Glaeser, H. Inhibition of hepatic uptake transporters by flavonoids. Eur. J. Pharm. Sci. 2012, 46, 79–85. [Google Scholar] [CrossRef]
  31. Kondo, A.; Narumi, K.; Ogura, J.; Sasaki, A.; Yabe, K.; Kobayashi, T.; Furugen, A.; Kobayashi, M.; Iseki, K. Organic anion-transporting polypeptide (OATP) 2B1 contributes to the cellular uptake of theaflavin. Drug Metab. Pharmacokinet. 2017, 32, 145–150. [Google Scholar] [CrossRef] [PubMed]
  32. Nimiya, Y.; Wang, W.; Du, Z.; Sukamtoh, E.; Zhu, J.; Decker, E.; Zhang, G. Redox modulation of curcumin stability: Redox active antioxidants increase chemical stability of curcumin. Mol. Nutr. Food Res. 2016, 60, 487–494. [Google Scholar] [CrossRef] [PubMed]
  33. Wang, Y.J.; Pan, M.H.; Cheng, A.L.; Lin, L.I.; Ho, Y.S.; Hsieh, C.Y.; Lin, J.K. Stability of curcumin in buffer solutions and characterization of its degradation products. J. Pharm. Biomed. Anal. 1997, 15, 1867–1876. [Google Scholar] [CrossRef] [PubMed]
  34. Leung, M.H.M.; Kee, T.W. Effective stabilization of curcumin by association to plasma proteins: Human serum albumin and fibrinogen. Langmuir 2009, 25, 5773–5777. [Google Scholar] [CrossRef] [PubMed]
  35. Sun, X.; Li, J.; Guo, C.; Xing, H.; Xu, J.; Wen, Y.; Qiu, Z.; Zhang, Q.; Zheng, Y.; Chen, X.; et al. Pharmacokinetic effects of curcumin on docetaxel mediated by OATP1B1, OATP1B3 and CYP450s. Drug Metab. Pharmacokinet. 2016, 31, 269–275. [Google Scholar] [CrossRef] [PubMed]
  36. Scalbert, A.; Williamson, G. Dietary intake and bioavailability of polyphenols. J. Nutr. 2000, 130, 2073S–2085S. [Google Scholar] [CrossRef] [PubMed]
  37. Kimira, M.; Arai, Y.; Shimoi, K.; Watanabe, S. Japanese intake of flavonoids and isoflavonoids from foods. J. Epidemiol. 1998, 8, 168–175. [Google Scholar] [CrossRef]
  38. Jun, S.; Shin, S.; Joung, H. Estimation of dietary flavonoid intake and major food sources of Korean adults. Br. J. Nutr. 2016, 115, 480–489. [Google Scholar] [CrossRef]
  39. Jacques, P.F.; Cassidy, A.; Rogers, G.; Peterson, J.J.; Dwyer, J.T. Dietary flavonoid intakes and CVD incidence in the Framingham Offspring Cohort. Br. J. Nutr. 2015, 114, 1496–1503. [Google Scholar] [CrossRef]
  40. Ferreira, A.; Santos, A.O.; Falcão, A.; Alves, G. In vitro screening of dual flavonoid combinations for reversing P-glycoprotein-mediated multidrug resistance: Focus on antiepileptic drugs. Food Chem. Toxicol. 2018, 111, 84–93. [Google Scholar] [CrossRef]
  41. Ullmann, U.; Haller, J.; Decourt, J.P.; Girault, N.; Girault, J.; Richard-Caudron, A.S.; Pineau, B.; Weber, P. A single ascending dose study of epigallocatechin gallate in healthy volunteers. J. Int. Med. Res. 2003, 31, 88–101. [Google Scholar] [CrossRef] [PubMed]
  42. Antony, B.; Merina, B.; Iyer, V.S.; Judy, N.; Lennertz, K.; Joyal, S. A pilot cross-over study to evaluate human oral bioavailability of BCM-95® CG (BiocurcumaxTM), a novel bioenhanced preparation of curcumin. Indian J. Pharm. Sci. 2008, 70, 445–449. [Google Scholar] [CrossRef] [PubMed]
  43. Brouwer, K.L.R.; Keppler, D.; Hoffmaster, K.A.; Bow, D.A.J.; Cheng, Y.; Lai, Y.; Palm, J.E.; Stieger, B.; Evers, R.; International Transporter Consortium. In vitro methods to support transporter evaluation in drug discovery and development. Clin. Pharmacol. Ther. 2013, 94, 95–112. [Google Scholar] [CrossRef] [PubMed]
  44. Wang, X.; Wolkoff, A.W.; Morris, M.E. Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1 (OATP-C) modulators. Drug Metab. Dispos. 2005, 33, 1666–1672. [Google Scholar] [CrossRef] [PubMed]
  45. Mandery, K.; Bujok, K.; Schmidt, I.; Keiser, M.; Siegmund, W.; Balk, B.; König, J.; Fromm, M.F.; Glaeser, H. Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1. Biochem. Pharmacol. 2010, 80, 1746–1753. [Google Scholar] [CrossRef] [PubMed]
  46. Huo, X.; Meng, Q.; Wang, C.; Wu, J.; Zhu, Y.; Sun, P.; Ma, X.; Sun, H.; Liu, K. Targeting renal OATs to develop renal protective agent from traditional Chinese medicines: Protective effect of Apigenin against Imipenem-induced nephrotoxicity. Phytotherapy Res. 2020, 34, 2998–3010. [Google Scholar] [CrossRef] [PubMed]
  47. Navrátilová, L.; Applová, L.; Horký, P.; Mladěnka, P.; Pávek, P.; Trejtnar, F. Interaction of soy isoflavones and their main metabolites with hOATP2B1 transporter. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2018, 391, 1063–1071. [Google Scholar] [CrossRef]
  48. An, G.; Wang, X.; Morris, M.E. Flavonoids Are Inhibitors of Human Organic Anion Transporter 1 (OAT1)–Mediated Transport. Drug Metab. Dispos. 2014, 42, 1357–1366. [Google Scholar] [CrossRef]
  49. Jin, H.; Zhu, Y.; Wang, C.; Meng, Q.; Wu, J.; Sun, P.; Ma, X.; Sun, H.; Huo, X.; Liu, K.; et al. Molecular pharmacokinetic mechanism of the drug-drug interaction between genistein and repaglinide mediated by P-gp. Biomed. Pharmacother. 2020, 125, 110032. [Google Scholar] [CrossRef]
  50. Mohos, V.; Fliszár-Nyúl, E.; Ungvári, O.; Kuffa, K.; Needs, P.W.; Kroon, P.A.; Telbisz, Á.; Özvegy-Laczka, C.; Poór, M. Inhibitory Effects of Quercetin and Its Main Methyl, Sulfate, and Glucuronic Acid Conjugates on Cytochrome P450 Enzymes, and on OATP, BCRP and MRP2 Transporters. Nutrients 2020, 12, 2306. [Google Scholar] [CrossRef]
  51. Li, Z.; Tian, S.; Wu, Z.; Xu, X.; Lei, L.; Li, Y.; Wang, B.; Huang, Y. Pharmacokinetic herb-disease-drug interactions: Effect of ginkgo biloba extract on the pharmacokinetics of pitavastatin, a substrate of Oatp1b2, in rats with non-alcoholic fatty liver disease. J. Ethnopharmacol. 2021, 280, 114469. [Google Scholar] [CrossRef]
  52. Fan, X.; Bai, J.; Hu, M.; Xu, Y.; Zhao, S.; Sun, Y.; Wang, B.; Hu, J.; Li, Y. Drug interaction study of flavonoids toward OATP1B1 and their 3D structure activity relationship analysis for predicting hepatoprotective effects. Toxicology 2020, 437, 152445. [Google Scholar] [CrossRef] [PubMed]
  53. Kitagawa, S.; Nabekura, T.; Takahashi, T.; Nakamura, Y.; Sakamoto, H.; Tano, H.; Hirai, M.; Tsukahara, G. Structure-Activity Relationships of the Inhibitory Effects of Flavonoids on P-Glycoprotein-Mediated Transport in KB-C2 Cells. Biol. Pharm. Bull. 2005, 28, 2274–2278. [Google Scholar] [CrossRef] [PubMed]
  54. Kaci, H.; Bodnárová, S.; Fliszár-Nyúl, E.; Lemli, B.; Pelantová, H.; Valentová, K.; Bakos, É.; Özvegy-Laczka, C.; Poór, M. Interaction of luteolin, naringenin, and their sulfate and glucuronide conjugates with human serum albumin, cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) enzymes and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters. Biomed. Pharmacother. 2023, 157, 114078. [Google Scholar] [CrossRef] [PubMed]
  55. Li, C.; Wang, X.; Bi, Y.; Yu, H.; Wei, J.; Zhang, Y.; Han, L.; Zhang, Y. Potent Inhibitors of Organic Anion Transporters 1 and 3 From Natural Compounds and Their Protective Effect on Aristolochic Acid Nephropathy. Toxicol. Sci. 2020, 175, 279–291. [Google Scholar] [CrossRef]
  56. Hong, S.S.; Seo, K.; Lim, S.-C.; Han, H.-K. Interaction characteristics of flavonoids with human organic anion transporter 1 (hOAT1) and 3 (hOAT3). Pharmacol. Res. 2007, 56, 468–473. [Google Scholar] [CrossRef] [PubMed]
  57. Zhang, S.; Morris, M.E. Effects of the Flavonoids Biochanin A, Morin, Phloretin, and Silymarin on P-Glycoprotein-Mediated Transport. J. Pharmacol. Exp. Ther. 2002, 304, 1258–1267. [Google Scholar] [CrossRef]
  58. Wang, M.; Qi, H.; Li, J.; Xu, Y.; Zhang, H. Transmembrane transport of steviol glucuronide and its potential interaction with selected drugs and natural compounds. Food Chem. Toxicol. 2015, 86, 217–224. [Google Scholar] [CrossRef]
  59. Wen, F.; Shi, M.; Bian, J.; Zhang, H.; Gui, C. Identification of natural products as modulators of OATP2B1 using LC-MS/MS to quantify OATP-mediated uptake. Pharm. Biol. 2015, 54, 293–302. [Google Scholar] [CrossRef]
  60. Mohana, S.; Ganesan, M.; Agilan, B.; Karthikeyan, R.; Srithar, G.; Mary, R.B.; Ananthakrishnan, D.; Velmurugan, D.; Prasad, N.R.; Ambudkar, S.V. Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer. Mol. Biosyst. 2016, 12, 2458–2470. [Google Scholar] [CrossRef]
  61. Johnson, E.J.; Won, C.S.; Köck, K.; Paine, M.F. Prioritizing pharmacokinetic drug interaction precipitants in natural products: Application to OATP inhibitors in grapefruit juice. Biopharm. Drug Dispos. 2016, 38, 251–259. [Google Scholar] [CrossRef]
  62. Bajraktari-Sylejmani, G.; Weiss, J. Potential Risk of Food-Drug Interactions: Citrus Polymethoxyflavones and Flavanones as Inhibitors of the Organic Anion Transporting Polypeptides (OATP) 1B1, 1B3, and 2B1. Eur. J. Drug Metab. Pharmacokinet. 2020, 45, 809–815. [Google Scholar] [CrossRef] [PubMed]
  63. Morita, T.; Akiyoshi, T.; Sato, R.; Uekusa, Y.; Katayama, K.; Yajima, K.; Imaoka, A.; Sugimoto, Y.; Kiuchi, F.; Ohtani, H. Citrus Fruit-Derived Flavanone Glycoside Narirutin is a Novel Potent Inhibitor of Organic Anion-Transporting Polypeptides. J. Agric. Food Chem. 2020, 68, 14182–14191. [Google Scholar] [CrossRef]
  64. Shirasaka, Y.; Li, Y.; Shibue, Y.; Kuraoka, E.; Spahn-Langguth, H.; Kato, Y.; Langguth, P.; Tamai, I. Concentration-Dependent Effect of Naringin on Intestinal Absorption of β1-Adrenoceptor Antagonist Talinolol Mediated by P-Glycoprotein and Organic Anion Transporting Polypeptide (Oatp). Pharm. Res. 2008, 26, 560–567. [Google Scholar] [CrossRef]
  65. Roth, M.; Timmermann, B.N.; Hagenbuch, B. Interactions of Green Tea Catechins with Organic Anion-Transporting Polypeptides. Drug Metab. Dispos. 2011, 39, 920–926. [Google Scholar] [CrossRef]
  66. Fuchikami, H.; Satoh, H.; Tsujimoto, M.; Ohdo, S.; Ohtani, H.; Sawada, Y. Effects of herbal extracts on the function of human organic anion-transporting polypeptide OATP-B. Drug Metab. Dispos. 2006, 34, 577–582. [Google Scholar] [CrossRef] [PubMed]
  67. Kawasaki, T.; Kondo, M.; Hiramatsu, R.; Nabekura, T. (−)-Epigallocatechin-3-gallate Inhibits Human and Rat Renal Organic Anion Transporters. ACS Omega 2021, 6, 4347–4354. [Google Scholar] [CrossRef] [PubMed]
  68. Wong, C.C.; Barron, D.; Orfila, C.; Dionisi, F.; Krajcsi, P.; Williamson, G. Interaction of hydroxycinnamic acids and their conjugates with organic anion transporters and ATP-binding cassette transporters. Mol. Nutr. Food Res. 2011, 55, 979–988. [Google Scholar] [CrossRef]
  69. Uwai, Y.; Ozeki, Y.; Isaka, T.; Honjo, H.; Iwamoto, K. Inhibitory Effect of Caffeic Acid on Human Organic Anion Transporters hOAT1 and hOAT3: A Novel Candidate for Food–Drug Interaction. Drug Metab. Pharmacokinet. 2011, 26, 486–493. [Google Scholar] [CrossRef]
  70. Teng, Y.-N.; Wang, C.C.N.; Liao, W.-C.; Lan, Y.-H.; Hung, C.-C. Caffeic Acid Attenuates Multi-Drug Resistance in Cancer Cells by Inhibiting Efflux Function of Human P-Glycoprotein. Molecules 2020, 25, 247. [Google Scholar] [CrossRef]
  71. Wang, L.; Sweet, D.H. Potential for food-drug interactions by dietary phenolic acids on human organic anion transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11). Biochem. Pharmacol. 2012, 84, 1088–1095. [Google Scholar] [CrossRef] [PubMed]
  72. Muthusamy, G.; Balupillai, A.; Ramasamy, K.; Shanmugam, M.; Gunaseelan, S.; Mary, B.; Prasad, N.R. Ferulic acid reverses ABCB1-mediated paclitaxel resistance in MDR cell lines. Eur. J. Pharmacol. 2016, 786, 194–203. [Google Scholar] [CrossRef] [PubMed]
  73. Hou, X.-L.; Takahashi, K.; Tanaka, K.; Tougou, K.; Qiu, F.; Komatsu, K.; Takahashi, K.; Azuma, J. Curcuma drugs and curcumin regulate the expression and function of P-gp in Caco-2 cells in completely opposite ways. Int. J. Pharm. 2008, 358, 224–229. [Google Scholar] [CrossRef]
  74. Li, Z.; Wang, K.; Zheng, J.; Cheung, F.S.G.; Chan, T.; Zhu, L.; Zhou, F. Interactions of the active components of Punica granatum(pomegranate) with the essential renal and hepatic human Solute Carrier transporters. Pharm. Biol. 2014, 52, 1510–1517. [Google Scholar] [CrossRef] [PubMed]
  75. Li, Z.; Du, X.; Li, Y.; Wang, R.; Liu, C.; Cao, Y.; Wu, W.; Sun, J.; Wang, B.; Huang, Y. Pharmacokinetics of gallic acid and protocatechuic acid in humans after dosing with Relinqing (RLQ) and the potential for RLQ-perpetrated drug–drug interactions on organic anion transporter (OAT) 1/3. Pharm. Biol. 2021, 59, 757–768. [Google Scholar] [CrossRef] [PubMed]
  76. Athukuri, B.L.; Neerati, P. Enhanced Oral Bioavailability of Diltiazem by the Influence of Gallic Acid and Ellagic Acid in Male Wistar Rats: Involvement of CYP3A and P-gp Inhibition. Phytotherapy Res. 2017, 31, 1441–1448. [Google Scholar] [CrossRef]
  77. Poór, M.; Kaci, H.; Bodnárová, S.; Mohos, V.; Fliszár-Nyúl, E.; Kunsági-Máté, S.; Özvegy-Laczka, C.; Lemli, B. Interactions of resveratrol and its metabolites (resveratrol-3-sulfate, resveratrol-3-glucuronide, and dihydroresveratrol) with serum albumin, cytochrome P450 enzymes, and OATP transporters. Biomed. Pharmacother. 2022, 151, 113136. [Google Scholar] [CrossRef]
  78. Jia, Y.; Liu, Z.; Wang, C.; Meng, Q.; Huo, X.; Liu, Q.; Sun, H.; Sun, P.; Yang, X.; Ma, X.; et al. P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate. Toxicol. Appl. Pharmacol. 2016, 306, 27–35. [Google Scholar] [CrossRef]
  79. El-Readi, M.Z.; Eid, S.; Abdelghany, A.A.; Al-Amoudi, H.S.; Efferth, T.; Wink, M. Resveratrol mediated cancer cell apoptosis, and modulation of multidrug resistance proteins and metabolic enzymes. Phytomedicine 2019, 55, 269–281. [Google Scholar] [CrossRef]
Ijms 25 00991 g001
Figure 1. Chemical structures of the tested food ingredients that have strong and moderate alterations in OATP4C1-mediated transport.
Figure 1. Chemical structures of the tested food ingredients that have strong and moderate alterations in OATP4C1-mediated transport.
Ijms 25 00991 g001
Ijms 25 00991 g002aIjms 25 00991 g002b
Figure 2. Chemical structures of the tested food ingredients that did not exhibit significant alterations in OATP4C1-mediated transport.
Figure 2. Chemical structures of the tested food ingredients that did not exhibit significant alterations in OATP4C1-mediated transport.
Ijms 25 00991 g002aIjms 25 00991 g002b
Ijms 25 00991 g003
Figure 3. Screening of the effect of food ingredients on OATP4C1-mediated transport. Cells were incubated with 1 µM T3 with or without food ingredients for 10 min at 37 °C. The concentration of the compounds was 100 µM, except for theaflavin (50 µM). The amount of OATP4C1-mediated uptake was calculated by subtracting the nonspecific uptake of T3 by mock cells from the total cellular uptake by OATP4C1-expressing cells. Data are presented as the mean ± standard error (SE) (n = 3). * p < 0.05, significantly different from the control by one-way analysis of variance followed by Tukey’s test. Dashed line represents 100% (control uptake in the absence of food ingredient).
Figure 3. Screening of the effect of food ingredients on OATP4C1-mediated transport. Cells were incubated with 1 µM T3 with or without food ingredients for 10 min at 37 °C. The concentration of the compounds was 100 µM, except for theaflavin (50 µM). The amount of OATP4C1-mediated uptake was calculated by subtracting the nonspecific uptake of T3 by mock cells from the total cellular uptake by OATP4C1-expressing cells. Data are presented as the mean ± standard error (SE) (n = 3). * p < 0.05, significantly different from the control by one-way analysis of variance followed by Tukey’s test. Dashed line represents 100% (control uptake in the absence of food ingredient).
Ijms 25 00991 g003
Ijms 25 00991 g004
Figure 4. Inhibitory effects of curcumin on OATP4C1-mediated transport under the presence of AA. (A) Cells were incubated with 1 µM T3 with AA for 10 min at 37 °C. The AA concentrations were 0, 10, 100, and 1000 µM. (B) Cells were incubated with 1 µM T3 and 50 µM curcumin with or without 10, 100, and 1000 µM AA for 10 min at 37 °C. The amount of OATP4C1-mediated uptake was calculated by subtracting the nonspecific uptake of T3 by mock cells from the total cellular uptake by the OATP4C1-expressing cells. Data are shown as the mean ± SE (n = 3). N.S., not significantly different. * p < 0.05, significantly different.
Figure 4. Inhibitory effects of curcumin on OATP4C1-mediated transport under the presence of AA. (A) Cells were incubated with 1 µM T3 with AA for 10 min at 37 °C. The AA concentrations were 0, 10, 100, and 1000 µM. (B) Cells were incubated with 1 µM T3 and 50 µM curcumin with or without 10, 100, and 1000 µM AA for 10 min at 37 °C. The amount of OATP4C1-mediated uptake was calculated by subtracting the nonspecific uptake of T3 by mock cells from the total cellular uptake by the OATP4C1-expressing cells. Data are shown as the mean ± SE (n = 3). N.S., not significantly different. * p < 0.05, significantly different.
Ijms 25 00991 g004
Ijms 25 00991 g005
Figure 5. Concentration-dependent inhibition of OATP4C1-mediated T3 transport by kaempferol (AA(−)) (A), kaempferol (AA(+)) (B), curcumin (AA(−)) (C), and curcumin (AA(+)) (D). Cells were incubated with 1 µM T3 with kaempferol or curcumin with or without 10 µM AA for 10 min at 37 °C. Their concentrations were 0, 1, 3, 10, 30, 50, and 100 µM. The amount of OATP4C1-mediated uptake was calculated by subtracting the nonspecific uptake of T3 by mock cells from the total cellular uptake by OATP4C1-expressing cells. Data are shown as the mean ± SE (n = 3). Dots and bars represent the mean ± SE (n = 3). The dashed lines are the inhibition curves fitted by using the Rodbard model. Double tilde indicates omission between 0 and 1.
Figure 5. Concentration-dependent inhibition of OATP4C1-mediated T3 transport by kaempferol (AA(−)) (A), kaempferol (AA(+)) (B), curcumin (AA(−)) (C), and curcumin (AA(+)) (D). Cells were incubated with 1 µM T3 with kaempferol or curcumin with or without 10 µM AA for 10 min at 37 °C. Their concentrations were 0, 1, 3, 10, 30, 50, and 100 µM. The amount of OATP4C1-mediated uptake was calculated by subtracting the nonspecific uptake of T3 by mock cells from the total cellular uptake by OATP4C1-expressing cells. Data are shown as the mean ± SE (n = 3). Dots and bars represent the mean ± SE (n = 3). The dashed lines are the inhibition curves fitted by using the Rodbard model. Double tilde indicates omission between 0 and 1.
Ijms 25 00991 g005
Ijms 25 00991 g006
Figure 6. Concentration dependence of OATP4C1-mediated T3 uptake in the presence or absence of kaempferol and curcumin. Cells were incubated with 0.3, 1, 3, 5, 10, and 30 µM T3 with or without the inhibitors (kaempferol (30 µM) and curcumin (30 µM)) in the presence of 10 µM AA for 10 min at 37 °C. The amount of OATP4C1-mediated uptake was calculated by subtracting the nonspecific uptake of T3 by mock cells from the total cellular uptake by OATP4C1-expressing cells. Data are shown as the mean ± SE (n = 6). The kinetic curves were fitted to the Michaelis–Menten equation. The black, gray, and white circles were the control, curcumin, and kaempferol, respectively. Each curve represents the fitted line obtained by the kinetic analysis by JMP Pro 16.
Figure 6. Concentration dependence of OATP4C1-mediated T3 uptake in the presence or absence of kaempferol and curcumin. Cells were incubated with 0.3, 1, 3, 5, 10, and 30 µM T3 with or without the inhibitors (kaempferol (30 µM) and curcumin (30 µM)) in the presence of 10 µM AA for 10 min at 37 °C. The amount of OATP4C1-mediated uptake was calculated by subtracting the nonspecific uptake of T3 by mock cells from the total cellular uptake by OATP4C1-expressing cells. Data are shown as the mean ± SE (n = 6). The kinetic curves were fitted to the Michaelis–Menten equation. The black, gray, and white circles were the control, curcumin, and kaempferol, respectively. Each curve represents the fitted line obtained by the kinetic analysis by JMP Pro 16.
Ijms 25 00991 g006
Table 1. IC50 and Ki values of curcumin in the absence or presence of AA.
Table 1. IC50 and Ki values of curcumin in the absence or presence of AA.
IC50
(µM)		Ki
(µM)		Average of Ki
(µM)		SE
(µM)
AA (−)49.442.252.25.1
69.459.3
64.555.2
AA (+)26.522.723.50.5
28.624.5
27.423.4
Table 2. Km, Vmax, and Vmax/Km values of OATP4C1-mediated T3 uptake in the absence or presence of kaempferol and curcumin.
Table 2. Km, Vmax, and Vmax/Km values of OATP4C1-mediated T3 uptake in the absence or presence of kaempferol and curcumin.
Km
(µM)		Vmax
(pmol/mg Protein/10 min)		Vmax/Km
(µL/mg Protein/10 min)
Control6.06 ± 0.83524 ± 18.288.8 ± 8.90
Curcumin20.8 ± 4.89757 ± 76.039.7 ± 6.79
Kaempferol17.6 ± 5.01517 ± 92.631.8 ± 4.16
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Sato, T.; Yagi, A.; Yamauchi, M.; Kumondai, M.; Sato, Y.; Kikuchi, M.; Maekawa, M.; Yamaguchi, H.; Abe, T.; Mano, N. The Use of an Antioxidant Enables Accurate Evaluation of the Interaction of Curcumin on Organic Anion-Transporting Polypeptides 4C1 by Preventing Auto-Oxidation. Int. J. Mol. Sci. 2024, 25, 991. https://doi.org/10.3390/ijms25020991

AMA Style

Sato T, Yagi A, Yamauchi M, Kumondai M, Sato Y, Kikuchi M, Maekawa M, Yamaguchi H, Abe T, Mano N. The Use of an Antioxidant Enables Accurate Evaluation of the Interaction of Curcumin on Organic Anion-Transporting Polypeptides 4C1 by Preventing Auto-Oxidation. International Journal of Molecular Sciences. 2024; 25(2):991. https://doi.org/10.3390/ijms25020991

Chicago/Turabian Style

Sato, Toshihiro, Ayaka Yagi, Minami Yamauchi, Masaki Kumondai, Yu Sato, Masafumi Kikuchi, Masamitsu Maekawa, Hiroaki Yamaguchi, Takaaki Abe, and Nariyasu Mano. 2024. "The Use of an Antioxidant Enables Accurate Evaluation of the Interaction of Curcumin on Organic Anion-Transporting Polypeptides 4C1 by Preventing Auto-Oxidation" International Journal of Molecular Sciences 25, no. 2: 991. https://doi.org/10.3390/ijms25020991

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop