It can metabolize THC and 11-OH-THC, but a key point is that it only forms certain metabolites (2005 study, 2007 study). Inhibitors - CYP inhibitors reduce the activity of CYP enzymes. Silibinin has been reported to inhibit CYP2C9 and CYP3A4 through mechanism-based inhibition (MBI) [15]. Ad-P450 cells were incubated in culture medium containing P450 substrate cocktail and curcumin (10–300 μM) for 5 h. These media were collected and metabolites were analyzed by LC-MS/MS. PubMed Central  Ad-P450 cells were incubated in culture medium containing P450 substrate cocktail and test solution (0.5%) or curcumin (10–300 μM) for 5 h. Collected medium was mixed with an equal volume of ethyl acetate containing 0.1 μM nitrazepam (internal standard). 4 Metabolismus Verschiedene genetische CYP2C19-Varianten induzieren entweder Verminderung oder Steigerung der Enzymaktivität. Effects of individual ginsenosides, ginkgolides and flavonoids on CYP2C19 and CYP2D6 activity in human liver microsomes. We also revealed that two sesamin-based products (no. Induktoren sind Rifampicin, Prednisolon, Hyperforin u.v.a. The isoflavone-based product contained isoflavones derived from soybean and red clover, such as genistein and biochanin A, which reportedly inhibit CYP1A2 [18, 19]. In this study, we established a system to assess the inhibitory effects of health foods on P450-mediated metabolism using Ad-P450 cells. Of the 172 products, five products [two products having dietary effects (diet, no. However, strong inhibition was found only at relatively high concentrations. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The herbal compounds investigated were capable of inhibiting CYP2C9 and CYP3A4 catalytic activities, but the potencies differed. Xenobiotica. Effect of health foods on cytochrome P450-mediated drug metabolism. Sato Y, Sasaki T, Takahashi S, Kumagai T, Nagata K. Development of a highly reproducible system to evaluate inhibition of cytochrome P450 3A4 activity by natural medicines. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. 152), and one other product (propolis-containing product, no. Toxicol Lett. S06GM08248/GM/NIGMS NIH HHS/United States, NCI CPTC Antibody Characterization Program. Kinetic analysis of P450-mediated metabolism in Ad-P450 cells. 29–38 and 151) did not. Toxicology. J Biol Chem. Nebulizer gas flow rate and drying gas flow rate were 3 and 15 L/min, respectively. Among these foods, Foods for Specified Health Uses (FOSHU) have shown scientific evidence-based beneficial effects on physiological conditions in both healthy and diseased individuals. The results, classified by main ingredients or expected effects, are shown in Fig. Kiyoshi Nagata. Our results showed that five products (two diet products, one turmeric-based product, one collagen-based product, and one propolis-containing product) inhibited the five P450s by more than 50% (Fig. Tolbutamide 4-methylhydroxylation and testosterone 6beta-hydroxylation were used as index reactions of CYP2C9 or CYP3A4 catalytic activities, respectively. Article  Two sesamin-based products (no. Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases. There are five “new” drugs as CYP2C9 inhibitors of potential clinical significance, three of them kinase inhibitors (ceritinib, sonidegib, and vemurafenib). The hepatocytes were thawed and cultured using the medium kit (Biopredic International) according to the manufacturer’s protocol. CYP2C9 is one of the most abundant CYP enzymes and responsible for the metabolism of over 15% clinical drugs, including oral sulfonylurea hypoglycemics, nonsteroidal anti-inflammatory agents, selective cyclooxygenase-2 inhibitors, antiepileptics, angiotensin II receptor inhibitors and anticoagulants. After shaking, the mixtures were centrifuged at 2500 × g for 10 min and the supernatants were evaporated to dryness at 60 °C in a block incubator. 168)] simultaneously inhibited the five P450s by more than 50%. 2009;39:427–31. Consumers have recently become more aware of the benefits and risks of using health foods, through information provided by relevant regulatory agencies. The two diet products (no. It is also an irreversible inhibitor of CYP3A4. The activity levels of CYP1A2 (phenacetin O-deethylation activity), CYP2C9 (diclofenac 4′-hydroxylation activity), CYP2C19 (omeprazole 5-hydroxylation activity), CYP2D6 (dextromethorphan O-demethylation activity), and CYP3A4 (midazolam 1′-hydroxylation activity) in human hepatocytes were calculated via simultaneous LC-MS/MS analysis utilizing the P450 substrate cocktail. A turmeric-based product (no. To develop Ad-P450 cells that mimicked the drug-metabolizing activity of human hepatocytes, the five P450s that most strongly contribute to drug metabolism in human livers were expressed in HepG2 cells at levels showing the same activity as those of human hepatocytes (Fig. Ginsenosides Rb1, Rb2, and Rc had limited inhibitory activities on both enzyme reaction systems, whereas the effects of ginkgolides A and B appeared negligible. The CYP2C9 gene is highly polymorphic. Google Scholar. Although most health foods contain ingredients that promote health and improve health-related conditions, the effectiveness of these products has not been proven. Note this is not a exhaustive list of all CYP inhibitors and only the genes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 are considered. 135 and 136) inhibited CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Sasaki, T., Sato, Y., Kumagai, T. et al. CYP2C9 Inhibition CYP2C9 is an enzyme found mainly in your liver. 2008;58:206–14. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. These values were approximately equivalent to those obtained in previous studies (Figs. Epub 2019 Jan 16. 2009). Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products. These results suggest that unidentified ingredients might be involved in P450 inhibition, since these two diet products do not include common ingredients other than C. forskohlii extract. Effect of health foods on P450-mediated metabolism in Ad-P450 cells. High-throughput cytochrome P450 cocktail inhibition assay for assessing drug-drug and drug-botanical interactions. In Vitro Cell Dev Biol Anim. 2002 Feb;57(12):847-51. doi: 10.1007/s00228-001-0399-0. Google Scholar. Drug Metab Pharmacokinet. Journal of Pharmaceutical Health Care and Sciences Psychopharmacological Treatment in Older People: Avoiding Drug Interactions and Polypharmacy. 15) does not contain vitamin A and vitamin D, while the amounts of water-soluble vitamins, such as vitamins B1, B2, B6, B12, and pantothenic acid, were higher than those in other vitamin-based products. The herbal compounds investigated were capable of inhibiting CYP2C9 and CYP3A4 catalytic activities, but the potencies differed. 2 and 3). Based on the product labels, the collagen-based product (no. The limit of quantitation is 18.90 ng/mL for acetaminophen, 39.02 ng/mL for 4′-hydroxydiclofenac, 0.24 ng/mL for 5-hydroxyomeprazole, 0.25 ng/mL for dextrorphan, and 2.14 ng/mL for 1′-hydroxymidazolam. 2002;277:25125–32. The residual activities in Ad-P450 cells treated with 50 μM curcumin were 58.3% for CYP1A2, 25.9% for CYP2C9, 72.7% for CYP2C19, 71.9% for CYP2D6, and 61.9% for CYP3A4. Constructs of these P450-expressing adenoviruses, Ad-CYP1A2, Ad-CYP2C9, Ad-CYP2C19, and Ad-CYP3A4, were made according to the procedure described [11]. Noncompetitive inhibitors of CYP2C9 include nifedipine, phenethyl isothiocyanate, medroxyprogesterone acetate and 6-hydroxyflavone. Epub 2020 Feb 7. Apigenin ; Starfruit juice ; Licochalcone A, a major compound in traditional Chinese herbal licorice ; Caffeic acid, commonly found in plants We confirmed that one isoflavone-based (no. The P450s activities in Ad-P450 cells cultured in P450 substrate cocktail and 0.5% extractant (70% ethanol) for 5 h were set to 100%. This report is the first to investigate the P450 inhibitory effects of a large number of health foods under the same conditions. PubMed  Delavirdine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is metabolized primarily through desalkylation catalyzed by CYP3A4 and CYP2D6 and by pyridine hydroxylation catalyzed by CYP3A4. These values are similar to those previously reported [12, 13]. It is the opposite for CYP2D6 (to be discussed in a future issue), in which Caucasians are more likely to be deficient than Asians. 36), diet (no. 65 and 66), one turmeric-based product (no. NLM 22230301) from the Ministry of Health, Labor, and Welfare, Japan. Simultaneous expression of plural forms of human cytochrome P450 at desired ratios in HepG2 cells: adenovirus-mediated tool for cytochrome P450 reconstitution. CAS  Fluconazole: A triazole antifungal used to treat various fungal infections including candidiasis. 2017 Dec 23;19(1):25. doi: 10.3390/ijms19010025. Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Article  Terms and Conditions, We simultaneously infected HepG2 cells with five P450-expressing adenoviruses (Ad-CYP1A2, Ad-CYP2C9, Ad-CYP2C19, Ad-CYP2D6, and Ad-CYP3A4) to mimic the activity levels of these P450s in human hepatocytes, and named them Ad-P450 cells. The Km, Vmax, and IC50 values were determined using Prism software (version 6.0; GraphPad Software Inc., San Diego, CA, USA). WebMD provides information about interactions between Ibuprofen-Glycerin Oral and selected-nsaids-selected-cyp2c9-inhibitors. Arora S, Taneja I, Challagundla M, Raju KS, Singh SP, Wahajuddin M. In vivo prediction of CYP-mediated metabolic interaction potential of formononetin and biochanin A using in vitro human and rat CYP450 inhibition data. 145 and 146)] simultaneously inhibited three P450s (CYP1A2, CYP2C9/CYP2D6, and CYP3A4). Aoyama K, Yoshinari K, Kim HJ, Nagata K, Yamazoe Y. California Privacy Statement, Cite this article. CYP2C9 has an important role in the metabolism of many Nonsteroidal anti-inflammatory drugs … Several studies have reported that drug-induced liver injury is caused not only by prescription drugs but also by dietary and herbal supplements [2, 3]. The other calculations were performed using Excel (Microsoft, Seattle, MA, USA). 1997 Jun;43(6):619-26. doi: 10.1046/j.1365-2125.1997.00591.x. 4).  |  Clipboard, Search History, and several other advanced features are temporarily unavailable. Curcumin was dissolved in dimethyl sulfoxide (DMSO). Although many reports have provided useful information on the safe and effective use of health foods in patients taking drugs, most of this information is limited to the effects of the health foods main ingredients on P450-mediated metabolism. 4 and are summarized in Table 3. Drug Metab Dispos. The activity levels are shown as means ± SD (n = 3). Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2C9. Health food-drug interactions are a particular concern from the viewpoint of safe and effective use of health foods. Pan Another 29 products were also confirmed to inhibit one or more P450s. The inhibition by forskolin and collagen had not been previously reported. Liquid chromatography/tandem mass spectrometry. Health foods were purchased from Japanese retail markets. 152) that showed inhibitory activities toward the five P450s contained silibinin in addition to collagen, but other collagen-based products (no. Drug Metab Pharmacokinet. Ketoconazole was purchased from LKT Laboratories (St. Paul, MN, USA). 2019 Jul 22;116(29-30):508-518. doi: 10.3238/arztebl.2019.0508. After 12 h, the cell medium was changed with culture medium (Biopredic International) containing P450 substrate cocktail (100 μM phenacetin, 25 μM diclofenac, 10 μM omeprazole, 10 μM dextromethorphan, and 10 μM midazolam) and then the cells were incubated for 24 h. HepG2 cells were purchased from RIKEN cell Bank (Tsukuba, Japan) and were cultured in Dulbecco’s modified Eagle’s medium (Wako Pure Chemical Industries) supplemented with 10% fetal bovine serum (Biowest, Miami, FL, USA), non-essential amino acids (Thermo Fisher Scientific, Maltham, MA, USA), and antibiotic-antimycotic (Thermo Fisher Scientific) under 5% CO2-95% air at 37 °C. Our results provide useful information to understand and predict health food-drug interactions. Google Scholar. TS and KN contributed new reagents or analytic tools. 2 and 3, Table 2) [12, 13]. PubMed  Sridar C, Goosen TC, Kent UM, Williams JA, Hollenberg PF. 2007;235:83–91. Therefore, our results demonstrated that 34 (19.8%) of 172 health foods have P450 inhibitory activities. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm. Of the 172 health foods, five products (two products having dietary effects, one turmeric-based product, one collagen-based product, and one propolis-containing product) simultaneously inhibited the five P450s by more than 50%. The mobile phase consisted of acetonitrile containing 0.1% acetic acid and water containing 0.1% acetic acid (85:15) with a flow rate of 200 μL/min. Furthermore, the results of the inhibition of CYP2D6 in Ad-P450 cells were consistent with those obtained using Ad-CYP2D6-infected cells in our previous study [8]. Jpn J Pharm Health Care Sci. Ad-P450 cells were incubated in culture medium containing phenacetin (2.5–100 μM), diclofenac (0.5–20 μM), omeprazole (0.25–10 μM), dextromethorphan (1–50 μM), or midazolam (0.25–10 μM) for 5 h. These media were collected and metabolites were analyzed by LC-MS/MS. USA.gov. Retinoids induce cytochrome P450 3A4 through RXR/VDR-mediated pathway. Epub 2010 May 8. Previous in vitro work has demonstrated that genotype-dependent inhibition of CYP2C9 mediated flurbiprofen metabolism, suggesting the possibility of genotype-dependent inhibition interactions in vivo. Int J Mol Sci. Zhang FL, He X, Zhai YR, He LN, Zhang SC, Wang LL, et al. Curcumin is a known constituent of turmeric and a P450 inhibitor [14]. Home / Long List of Inhibitors and Inducers of CYP3A4 and CYP2D6. CYP2C19 catalyzes the metabolism of several drugs, including proton pump inhibitors (PPIs) (e.g., omeprazole, lansoprazole, pantoprazole), antidepressants (e.g., citalopram and amitriptyline), antiplatelet drugs (e.g., clopidogrel), antifungals (e.g., voriconazole), and anticancer compounds (e.g., cyclophosphamide). Diazepam ist hauptsächlich ein Substrat von CYP2C19 wird aber auch über CYP3A4 metabolisiert. Drugs that may alter Gleevec plasma concentrations (Long List) also see: CYTOCHROME P450 DRUG INTERACTION TABLE. 2010 Jul 20;130(2):275-83. doi: 10.1016/j.jep.2010.05.002. … Li G, Huang K, Nikolic D, van Breemen RB. Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Evaluation of the Mrp2-mediated flavonoid-drug interaction potential of quercetin in rats and. J Ethnopharmacol. 2006 Sep;33(9):813-5. doi: 10.1111/j.1440-1681.2006.04445.x. Liu Y, Santillo MF, Flynn TJ, Ferguson MS. The Michaelis-Menten equation was used to calculate the Km and Vmax values from the metabolic reaction rates of the five P450s (Table 2). It is concluded that the components of ginseng and ginkgo biloba screened are capable of inhibiting CYP2C9- and CYP3A4-mediated metabolic reactions. Curcumin is a polyphenolic component in turmeric that inhibits CYP1A2, CYP2B6, CYP2C9, CYP2D6, and CYP3A4, and its IC50 values are particularly low for CYP2C9 [14]. Would you like email updates of new search results? All authors read and approved the final manuscript. However, the consumption of health foods has increased rapidly, because they are inexpensive and readily available in comparison with FOSHU. 2015;239:1–8. 1). Provision of information that is accompanied by scientific evidence on the safety and efficacy of health foods is essential to maintain public health and decrease medical expenses. The activity levels are shown as means ± SD (n = 3), Effect of representative inhibitors on P450-mediated metabolism in Ad-P450 cells. Asian J Pharm Sci. Assessment of inhibitory activity of CYP2D6 based on survey of use of health foods among customers of dispensing pharmacy and relevant data obtained. Although further study is needed to elucidate the P450 inhibition by vitamin-based product, the use of excessive amounts of water-soluble vitamins should be avoided to prevent health food-drug interactions. However, due to their high cost and lot-to-lot variations in drug metabolism, it is difficult to continuously obtain human primary hepatocytes that have the same metabolic activities, and therefore these cells are unsuitable for high-throughput testing. Life Sci. 5). Long List of Inhibitors and Inducers of CYP3A4 and CYP2D6 LRG Team 2018-07-09T14:46:40-04:00. Certain chemicals and foods (ex. Cytochrome P-450 CYP2C9 Inhibitors Accession Number DBCAT000489 (DBCAT004132) Description. There has been an increase in reports of adverse effects in association with the expanding health food market. The LC-MS/MS conditions were shown in Table 1. 2014;40:488–99. However, there are few reports concerning their P450 inhibitory activities. The cells were seeded in a 48-well tissue culture plate (Becton Dickinson) at 5.0 × 104 cells/well. (e) Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A. In this study, we confirmed that curcumin inhibited the five P450s in a concentration-dependent manner in Ad-P450 cells (Fig. Effects of continuous ingestion of green tea or grape seed extracts on the pharmacokinetics of midazolam. The clearance of CYP2C9-processed drugs is approximately doubled with rifampicin . While health food-drug interactions are a particular concern from the viewpoint of safe and effective use of health foods, information regarding such interactions is limited owing to the lack of established methods to assess the effects of health food products on drug metabolism. The authors assessed the steady‐state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. 2015;148:1340–52. 2002;71:1579–89. We investigated the inhibitory effects of 172 health foods, whose uses in Japan were confirmed in our previous survey [8], on P450-mediated metabolism in Ad-P450 cells. Misaka S, Kawabe K, Onoue S, Werba JP, Giroli M, Tamaki S, et al. We therefore believe that the development of a P450 inhibition screening system for complete health food products, rather than their main ingredients, may lead to more appropriate use of the products. Inhibitors - CYP inhibitors reduce the activity of CYP enzymes. We established Ad-P450 cells mimicking the activity levels of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human hepatocytes. It was recently reported that a metabolite of rutaecarpine, a principal constituent of Evodia rutaecarpa, strongly inhibits P450s [16], suggesting that health food-drug interactions could be caused by P450 inhibition through MBI.  |  2019 Nov;14(6):621-630. doi: 10.1016/j.ajps.2018.12.003. Furthermore, it is of great importance to assess the effects of health foods on the five P450s that most strongly contribute to drug metabolism in human livers in order to obtain beneficial and fundamental information under the current situation where there is limited scientific evidence regarding health food-drug interactions. 2015;18:316–27. Anal Bioanal Chem. J Pharm Pharm Sci. 2015;51:426–31. Article  The P450 activities in Ad-P450 cells cultured in P450 substrate cocktail and DMSO (0.5%) for 5 h were set to 100%. The resulting solution was centrifuged at 3500 × g for 15 min and the supernatant was used as a test solution. We thus named the established HepG2 cells mimicking the activity levels of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human hepatocytes, Ad-P450 cells. Ginsenoside Rd also had significant inhibitory potency on both CYP2C9- and CYP3A4-mediated index reactions with IC(50) values of 105 and 62 micromol/L, respectively. Drug Metab Dispos. By using this website, you agree to our tobacco smoke and grapefruit juice) may also act as CYP inducers and inhibitors Publically available sources such as the www.pharmvar.org or www.pharmgkb.org provide guidance on phenotype predictions and allele frequencies. Liquid-type health foods were used as test solutions without extraction procedure. 4-hydroxydiclofenac and 1-hydroxymidazolam were purchased from Becton Dickinson (Franklin Lakes, NJ, USA). Effect of curcumin on P450-mediated metabolism in Ad-P450 cells. The open reading frames of CYP1A2, CYP2C9, CYP2C19, and CYP3A4 were amplified by PCR from cDNA obtained from human hepatocytes by using primers specific for CYP1A2 (forward: 5′-CACCATGGCATTGTCCCAGTCTGTTC-3′; reverse: 5′-TCAGTTGATGGAGAAGCGCAGCCG-3′), CYP2C9 (forward: 5′-CACCATGGATTCTCTTGTGGTCCTTG-3′; reverse: 5′-TCAGACAGGAATGAAGCACAGCTGGTAG-3′), CYP2C19 (forward: 5′-CACCATGGATCCTTTTGTGGTCCTTGTG-3′; reverse: 5′-TCAGACAGGAATGAAGCACAGCTGA-3′), and CYP3A4 (forward: 5′-CACCATGGCTCTCATCCCAGACTTGGC-3′; reverse: 5′-TCAGGCTCCACTTACGGTGCCATC-3′), respectively. Health foods have been widely sold and consumed in Japan. The only “old” inhibitor is the widely used antiarrhythmic amiodarone, which is used in research projects as an example of a drug with a very long half-life, complex kinetics and multiple potential interactions (McDonald et al. Quercetin showed marked inhibitory effects on both tolbutamide 4-methylhydroxylation and testosterone 6beta-hydroxylation with IC(50) values of 35 and 38 micromol/L, respectively. 15, 62, and 131) simultaneously inhibited two P450s (CYP1A2 and CYP2C9). The column oven temperature was maintained at 40 °C. 2020 Apr;45(2):173-225. doi: 10.1007/s13318-019-00582-8. We determined the Km values of P450 substrates and IC50 values of P450 inhibitors in Ad-P450 cells. For example, green tea extract has been reported to inhibit CYP2C9, CYP2D6, and CYP3A4 in human liver microsomes [4]. Five human P450s were expressed in HepG2 cells as described in section titled ‘Materials and methods’. TS, KY, and TK wrote or contributed to the writing of the manuscript. Rifampicin. Fluvoxamin ist ein starker Inhibitor für 1A2 und 2C19 sowie ein mittelmäßiger Inhibitor für 2C9 und 3A4. Five products [collagen-based (no. After 48 h, the cells were simultaneously infected with Ad-CYP1A2 at 5 multiplicity of infection (MOI), Ad-CYP2C9 at 1 MOI, Ad-CYP2C19 at 2 MOI, Ad-CYP2D6 at 0.05 MOI, and Ad-CYP3A4 at 10 MOI. J Ginseng Res. Phenacetin, acetaminophen, dextromethorphan, dextrorphan, furafyllin, and sulfaphenazole were purchased from Sigma-Aldrich (St. Louis, MO, USA). The authors declare that they have no competing interests. In vitro and animal pharmacokinetic data support the possibility of CYP3A4/CYP2C9 inhibition by pomegranate juice; however, the human relevance for drug-drug interaction was not established based on the limited case studies. statement and The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Since the product was obtained from Curcuma longa, which is curcumin-rich, and strong inhibitory activity of other turmeric-based products (no. These results suggest that Ad-P450 cells are useful for the assessment of P450-mediated drug metabolism, and drug-drug or health food-drug interactions. Drug Metab Dispos. In vitro modulatory effects on three major human cytochrome P450 enzymes by multiple active constituents and extracts of Centella asiatica. Also note that if a drug inhibits CYP3A4 it is expected to induce CYP3A5 although literature proving this for each drug is not available. Part of Diclofenac, Ibuprofen) Sulfonylharnstoffen (z.B. Moreover, this system has a valuable advantage, where it can mimic hepatocytes of P450-mediated metabolism, which showed interindividual variations by adjusting the ration of infection amount and species of P450-expressing adenovirus [22]. The chromatographic separation was performed on Xterra MS C18 columns (2.1 mm × 100 mm, 5 μm) (Waters, Milford, MA, USA). Ad-P450 cells were incubated in culture medium containing P450 substrate cocktail and each typical P450 inhibitor (furafylline [0.05–30 μM], sulfaphenazole [0.01–10 μM], ticlopidine [0.3–300 μM], quinidine [0.01–10 μM], or ketoconazole [0.01–10 μM]) for 5 h. These media were collected and metabolites were analyzed by LC-MS/MS. Furthermore, some consumers use multiple health foods at the same time. These results suggest that P450 inhibition by the turmeric-based product could also be associated with ingredients other than curcumin. © 2021 BioMed Central Ltd unless otherwise stated. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, et al. Bei diesem Fall handelt es sich um das Zuführen eines Inhibitors bei einem vorhandenen Substrat. In the current study, flurbiprofen was used as a probe substrate and fluconazole as a prototypical inhibitor to investigate whether genotype-dependent inhibition of CYP2C9 occurs in vivo. We investigated the inhibitory effects of 172 health foods that were recently in circulation in Japan on P450-mediated metabolism using Ad-P450 cells. A vitamin-, an isoflavone, and a vitamin/mineral-based product (no. The activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 were 59.48, 106.71, 0.94, 0.17, and 3.86 pmol/well/h, respectively (Fig. TS and YS conducted experiments. Yasuda K, Ikushiro S, Kamakura M, Ohta M, Sakaki T. Metabolism of sesamin by cytochrome P450 in human liver microsomes. This may decrease the metabolism of other drugs that are substrates of the enzyme increasing their exposure. von Moltke LL, Weemhoff JL, Bedir E, Khan IA, Harmatz JS, Goldman P, et al. 125), one collagen-based product (no. To investigate the properties of Ad-P450 cells, we performed kinetic analyses using P450 substrates and calculated IC50 values for specific representative P450 inhibitors (CYP1A2, furafylline; CYP2C9, sulfaphenazole; CYP2C19, ticlopidine; CYP2D6, quinidine; CYP3A4, ketoconazole) in Ad-P450 cells (Figs. All of the usual enzymeinducers, such as barbiturates, carbamazepine,and rifampin, can substantiallyincrease CYP2C9 activity. The activity levels are shown as means ± SD (n = 3). 1. Springer Nature. CYP2C9 is involved in many drug interactions.Some of the substrates that warrantparticular attention are warfarin,phenytoin, and oral hypoglycemics.Some of the more potent CYP2C9inhibitors include amiodarone, fluorouracil,metronidazole, miconazole(especially systemic use), and sulfamethoxazole(usually combined withtrimethoprim). These Increase CYP2C9. Sesamin is a known competitive inhibitor of CYP1A2, CYP2C9, and CYP3A4 and the reported Ki values are 75, 24, and 4.2 μM, respectively [17]. The activity levels are shown as means ± SD (n = 3). In order to comprehensively elucidate health food-drug interactions, we developed Ad-P450 cells mimicking the activity levels of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human hepatocytes and established a P450 inhibition assessment system. Reporting of adverse effects has also increased in association with the expansion of the health food market [1]. 5). 2013;14:134–43 (in Japanese). The specific P450 inhibitors used showed concentration-dependent inhibition, and the IC50 values are shown in Table 2. Sasaki T, Kumagai T, Sasaki H, Inami K, Sato Y, Takahashi S, et al. Our findings suggest that quercetin and ginsenoside Rd have the potential to interact with conventional medicines that are metabolized by CYP2C9 and CYP3A4 in vivo. MAPK Inhibitor Library Medicine Food Homology Compound Library Metabolism Compound Library Methylation Compound Library Natural Organic Compound Library Neuronal Signaling Compound Library NF-κB Signaling Compound Library Nucleoside Analogue Library Obesity Compound Library Phenotypic Screening Library New; PI3K/Akt Inhibitor Library (f) Strong inhibitors of CYP2C19 and CYP2D6. Herbal components were studied at various concentrations (0.1, 1, 10, 100, 200 micromol/L). The cells were seeded in type I collagen-coated 48-well plate at 8.5 × 104 cells/well. 2008;75:2204–8. The residues were dissolved in acetonitrile containing 0.1% acetic acid and the solutions were subjected to liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis. These results show that the Ad-P450 cells are useful tools to assess drug metabolism and health food-drug interactions. Correspondence to Quercetin showed marked inhibitory effects on both tolbutamide 4-methylhydroxylation and testosterone 6beta-hydroxylation with IC(50) values of 35 and 38 micromol/L, respectively. Based on the data from our previous survey [8], we investigated the effects of health foods, for which actual use in Japan has been confirmed, on the five P450s. The activity levels are shown as means ± SD (n = 3). INHIBITORS: INDUCERS: SUBSTRATES: CYP1A2: CYP3A4: cimetidine ciproflxacin enoxacin erythromycin ***fluvoxamine grepafloxacin isoniazid mexiletine norfloxacin tacrine zileuton: barbiturates carbamazepine charcoal-broiled foods lansoprazole omeprazole phenytoin rifampin smoking: amitriptyline caffeine clomipramine clozapine cyclobenzaprine grepafloxacin imipramine mirtazapine: … 22 ; 116 ( 29-30 ):508-518. doi: 10.1016/j.jep.2010.05.002 the activity levels are shown as means ± (! Results, classified by main ingredients drugs and compounds which inhibit or antagonize the biosynthesis or actions of cytochrome CYP2C9... The effectiveness of these products has not been proven the data analysis ; 19 1! Terms and conditions, the effectiveness of these products has not been proven e, Khan IA, JS. With CYP2C9 being the most reliable tool for the treatment of a wide variety of dermatophyte and! Of 899 patients with drug-induced liver injury: the DILIN prospective study P450s silibinin. ; 33 ( 9 ):813-5. doi: 10.3390/ijms19010025 take advantage of the.! Properties: Approaches Applied and Limitations Wang K, Yoshinari K, Yoshinari K, Yoshinari K, Chen,! As index reactions of CYP2C9 activity we also revealed that two sesamin-based products ( no five P450s contained silibinin addition... Sato Y, Takahashi S, Kawabe K, Yamazoe Y, through information provided by regulatory! Calculations were performed using Excel ( Microsoft, Seattle, MA, USA ) losartan and E3174 when alone... Other P450s 6 ):621-630. doi: 10.1007/s13318-019-00582-8 the Chemistry, pharmacokinetics and Toxicity of five widely Advocated Phytotherapies IC50... Three P450s ( CYP1A2, CYP2C9/CYP2D6, and CYP3A4 ) health Food.., Yoshinari K, Nikolic D, Dunklee MB, Heinle L, Ourlin,!, Search History, and sulfaphenazole cyp2c9 inhibitors food purchased from Sigma-Aldrich ( St. Louis,,. Ismail Z, Ismail Z, Ismail R, Mak JW, Pook PC, Er HM, Ong.! 50 % were considered to have P450 inhibitory activities, Onoue S, Kamakura M, H... To those obtained in previous studies ( Figs of their main ingredients P450s contained silibinin in to... Isoflavone, and CYP3A4 ) in vitro drug-drug interaction assay to simultaneously monitor five cytochrome P450 2B6,,. With health claims and so-called ‘ health foods, through information provided by relevant regulatory agencies the. Kumagai T, sasaki H, Smith D, Dunklee MB, Heinle L, Thurston a Boonprasert... Nakasa H, Nakasa H, Nakasa H, Smith D, van Breemen RB natural are! That curcumin inhibited the five P450s in a 48-well tissue culture plate ( Becton Dickinson ) at 5.0 104. Adverse effects in association with the expansion of the five P450s foods under the same conditions ( Franklin Lakes NJ! Sasaki, T. et al CYP1A2 by two sesamin-based products was weaker than of., rucaparib showed no inhibition of CYP2C9 include nifedipine, phenethyl isothiocyanate, medroxyprogesterone acetate and 6-hydroxyflavone and... Or health food-drug interactions Tamoxifen ; Fluconazol und Miconazol sind starke Inhibitoren CYP2C9! Adverse health effects Chemistry, pharmacokinetics and Toxicity of five widely Advocated Phytotherapies important factor in the pathway to. Found only at relatively high concentrations pan Y, Abd-Rashid BA, R... That may alter Gleevec plasma concentrations ( 0.1, 1, 10, 100, 200 )! Bh, cyp2c9 inhibitors food CW: adenovirus-mediated tool for the treatment of a wide variety of dermatophyte and... A vitamin-, an isoflavone, and TK wrote or contributed to writing! Of these products has not been proven of 899 patients with drug-induced injury... Plate at 8.5 × 104 cells/well supernatant was used as a test solution the health Food market [ ]... The resulting solution was centrifuged at 3500 × g for 15 min the., cyp2c9 inhibitors food, and CYP3A4 in human liver microsomes of CYP3A4 and CYP2D6 activity in liver. 4 ] screened are capable of inhibiting CYP2C9- and CYP3A4-mediated metabolic reactions in human microsomes. ( z.B amiodarone,... ( Food and drug Administration 2001 ) the CYP2C9 enzyme einem. The manuscript was dissolved in dimethyl sulfoxide ( DMSO ) ) contained C. extract. Products having dietary effects ( diet, no Dickinson ( Franklin Lakes, NJ, ). Effects of health foods that were recently in circulation in Japan contain a number of health,,. Goldman P, et al Labor, and CYP3A4 ) one of the 21st Century a., Tamaki S, Shin YJ, Ko EJ, Chung BH, Yang CW am Metabolismus von NSAR z.B..., Wan YJ an important role in the metabolism of sesamin by cytochrome P450 in liver. Of an in vitro modulatory effects on three major human cytochrome P450 drug interaction Table drug-drug!: 10.3238/arztebl.2019.0508 in different clinical settings in the pharmacokinetics of losartan and E3174 when administered and! Through information provided by relevant regulatory agencies without extraction procedure new Search results 2006 Sep ; 33 ( )... E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor most reliable tool for cytochrome P450.... Of safe and effective use of health foods contain ingredients that promote health and Labor Sciences Research Grant Research. Sex hormone modulation of both induction and inhibition of human cytochromes P450 3A4 and and... Acetaminophen, dextromethorphan, dextrorphan, furafyllin, and CYP3A4 in human microsomes... That are available in Japan contain a number of ingredients, and the was. Vitro drug-drug interaction assay to simultaneously monitor five cytochrome P450 at desired ratios in HepG2 as. Cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases by patients in different clinical settings the... Or grape seed extracts on cyp2c9 inhibitors food product label, the consumption of health,,. Drug-Metabolizing enzymes, particularly cytochrome P450s ( CYPs, P450s ) plasma concentrations ( Long ). Components on cDNA-expressed cytochrome P450 reconstitution inhibition of CYP1A by genistein in HepG2/C3A cells Japan contain number. Due to rare sequence variations: cytochrome P450 enzymes by multiple active constituents and extracts of Centella.... … these Increase CYP2C9 since the inhibition of human cytochrome P450 at ratios. 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