DOCSLIB.ORG

Download/Index.Php), and Onekp (

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Download/Index.Php), and Onekp ( bioRxiv preprint doi: https://doi.org/10.1101/2020.07.07.192757; this version posted July 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 2 Parallel evolution of UbiA superfamily proteins into aromatic O- 3 prenyltransferases in plants 4 5 Authors 6 Ryosuke Munakata1,2, Alexandre Olry2, Tomoya Takemura1, Kanade Tatsumi1, Takuji Ichino1, Cloé 7 Villard2, Joji Kageyama1, Tetsuya Kurata3, Masaru Nakayasu1, Florence Jacob4, Takao Koeduka5 8 Hirobumi Yamamoto6, Eiko Moriyoshi1, Tetsuya Matsukawa7,8, Jeremy Grosjean2, Célia Krieger2 1 9 10 2* 1* 9 Akifumi Sugiyama , Masaharu Mizutani , Frédéric Bourgaud , Alain Hehn , and Kazufumi Yazaki 10 11 *Author for correspondence 12 Kazufumi Yazaki 13 Tel: +81 774 38 3621 14 Email: [email protected] 15 16 Alain Hehn 17 Tel: +33 3 72 74 40 77 18 Email: [email protected] 19 20 Affiliation 21 1 Laboratory of Plant Gene Expression, Research Institute for Sustainable Humanosphere, Kyoto 22 University, Uji, Kyoto, 611–0011, Japan 23 2 Université de Lorraine, INRA, LAE, F54000, Nancy, France 24 3 EditForce Inc., Fukuoka 810-0001, Japan bioRxiv preprint doi: https://doi.org/10.1101/2020.07.07.192757; this version posted July 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 25 4 PalmElit SAS, Montferrier sur Lez 34980, France 26 5 Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Yamaguchi 27 753-8515, Japan 28 6 Department of Applied Biosciences, Faculty of Life Sciences, Toyo University, Izumino 1–1-1, 29 Itakura-machi, Ora-gun, Gunma 374-0193, Japan 30 7 The Experimental Farm, Kindai University, Wakayama, Japan 31 8 Faculty of Biology-Oriented Science and Technology, Kindai University, 32 Wakayama, Japan 33 9 Functional Phytochemistry, Graduate School of Agricultural Science, Kobe University, Kobe, 34 Japan. 35 10 Plant Advanced Technologies – PAT, 19 Avenue de la forêt de Haye, 54500 Vandoeuvre, France 36 37 ORCID 38 Ryosuke Munakata: 0000-0002-7888-6281 39 Alexandre Olry: 0000-0002-2008-9845 40 Kanade Tatsumi : 0000-0002-9810-9367 41 Takuji Ichino : 0000-0001-9058-5660 42 Cloé Villard: 0000-0001-6683-8541 43 Tetsuya Kurata : 0000-0002-7918-3027 44 Masaru Nakayasu : 0000-0002-6980-7238 45 Florence Jacob: 0000-0002-0454-1037 46 Takao Koeduka: 0000-0002-0786-3242 47 Hirobumi Yamamoto: 0000-0002-4958-4698 48 Eiko Moriyoshi: 0000-0002-8339-3529 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.07.192757; this version posted July 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 49 Tetsuya Matsukawa: 0000-0003-3495-9634 50 Jeremy Grosjean: 0000-0002-1972-2180 51 Akifumi Sugiyama: 0000-0002-9643-6639 52 Masaharu Mizutani : 0000-0002-4321-0644 53 Frédéric Bourgaud: 0000-0002-9898-2625 54 Alain Hehn: 0000-0003-4507-8031 55 Kazufumi Yazaki: 0000-0003-2523-6418 56 57 Abstract 58 Plants produce approximately 300 aromatic molecules enzymatically linked to prenyl side 59 chains via C-O bonds. These O-prenylated aromatics have been found in taxonomically distant plant 60 taxa as compounds beneficial or detrimental to human health, with O-prenyl moieties often playing 61 crucial roles in their biological activities. To date, however, no plant gene encoding an aromatic O- 62 prenyltransferase (O-PT) has been described. This study describes the isolation of an aromatic O-PT 63 gene, CpPT1, belonging to the UbiA superfamily, from grapefruit (Citrus × paradisi, Rutaceae). This 64 gene is responsible for the biosynthesis of O-prenylated coumarin derivatives that alter drug 65 pharmacokinetics in the human body. Another coumarin O-PT gene of the same protein family was 66 identified in Angelica keiskei, an apiaceous medicinal plant containing pharmaceutically active O- 67 prenylated coumarins. Phylogenetic analysis of these O-PTs suggested that aromatic O-prenylation 68 activity evolved independently from the same ancestral gene in these distant plant taxa. These findings 69 shed light on understanding the evolution of plant secondary metabolites via the UbiA superfamily. 70 71 Introduction 72 Plants produce many O-prenylated aromatic molecules possessing prenyl side chains bioRxiv preprint doi: https://doi.org/10.1101/2020.07.07.192757; this version posted July 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 73 attached to the aromatic cores via C-O bonds. These aromatic core structures include flavonoids, 74 coumarins, xanthones, and aromatic alkaloids, with roughly half of them (ca. 150 structures) being 75 classified as coumarins1,2. Some O-prenylated aromatics have pharmaceutical activities, whereas 76 others are deleterious to human health1,2. These beneficial/detrimental activities are often due to or 77 enhanced by O-prenyl moieties3–6. 78 Native coumarin O-prenyltransferases (O-PT) of Rutaceae and Apiaceae, plants that 79 accumulate large amounts of O-prenylated coumarins, have been characterized biochemically, with 80 members of the membrane-bound UbiA superfamily of proteins found to be involved in coumarin O- 81 prenylation7,8. To date, approximately 50 UbiA superfamily genes have been found to encode aromatic 82 C-PTs, which transfer prenyl moieties to aromatic cores via C-C bonds. Although these genes were 83 shown to encode enzymes involved in plant primary and secondary metabolism, no gene encoding an 84 aromatic O-PT has yet been identified in plants. O-Prenylated aromatic compounds have been detected 85 in several distant plant families, including Asteraceae, Boraginaceae, Fabaceae, Hypericaceae, 86 Rutaceae and Apiaceae, but are not ubiquitous throughout the plant kingdom1. The lack of knowledge 87 of aromatic O-PT genes has prevented a determination of the appearance of aromatic O-prenylation 88 activity during plant speciation. 89 Among Rutaceae, Citrus species accumulate large amounts of O-prenylated coumarins, 90 especially in their flavedo (outer pericarp)9–12. Citrus O-prenylated coumarins have shown various 91 pharmaceutical properties2, including anti-cancer4,13, anti-microbial3, and anti-inflammatory14 92 activities, although some of these derivatives have shown undesirable effects in humans. Citrus fruits 93 and juices enhance the bioavailability of orally administrated medications, which can lead to overdoses 94 and increased side effects5,15. The ‘grapefruit-drug interactions’ have been found to alter the 95 pharmacokinetics of more than 85 medications, including statins and calcium channel blockers15. The 96 United States Food and Drug Administration has cautioned consumers not to consume grapefruits or bioRxiv preprint doi: https://doi.org/10.1101/2020.07.07.192757; this version posted July 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 97 grapefruit juice at times close to taking such drugs16. Citrus species are thought to alter drug 98 pharmacokinetics by inactivating CYP3A4, the major xenobiotic-metabolizing enzyme in the 99 intestines and liver5,15. 100 Furanocoumarins (FCs) are tricyclic coumarins containing a furan ring. O-geranylated 101 forms of FCs including bergamottin and its oxidative derivatives (Fig. 1a) are promising candidates 102 causing grapefruit-drug interactions due to their potent inhibition of CYP3A45,15,17. CYP3A4- 103 catalyzed metabolism of their furan rings produces reactive chemicals that inactivate this enzyme 104 itself18, while their O-geranyl side chains contribute to binding to the active site of CYP3A46 toward 105 metabolization of the furan ring. Bergamottin and 6’,7’-dihydroxybergamottin show 7- and 160-fold 106 higher in vitro inhibitory activity, respectively, than the non-geranylated form, bergaptol5. Furthermore, 107 O-geranyl moieties act as linkers to form FC dimers, called paradisins, which are more potent CYP3A4 108 inactivators than monomeric O-geranylated FCs5. These findings suggest that paradisins, along with 109 O-geranylated FC monomers, may be involved in grapefruit-drug interactions. 110 Starting with transcriptome analysis of flavedo tissues, this study describes the isolation of 111 a gene encoding a coumarin O-PT involved in bergamottin biosynthesis in grapefruit and the 112 functional characterization of its gene product. The contribution of O-PT orthologs to coumarin 113 biosynthesis was assessed in various Citrus species. In addition, an aromatic O-PT was isolated from 114 Angelica keiskei, an apiaceous medicinal plant producing O-prenylated coumarins19. The evolutionary 115 development of aromatic O-prenylation activity in plants was assessed by phylogenetic analysis of O- 116 PTs from taxonomically distant families Rutaceae and Apiaceae. 117 118 Results 119 Construction of a transcriptome dataset from grapefruit flavedo tissues 120 Because the native enzymes catalyzing coumarin O-prenylation in lemon flavedo were bioRxiv preprint doi: https://doi.org/10.1101/2020.07.07.192757; this version posted July 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 121 shown
Load more

Recommended publications
  • The Health Benefits of Grapefruit Furanocoumarins1 Yu Wang and Laura Reuss2
    FSHN18-8 The Health Benefits of Grapefruit Furanocoumarins1 Yu Wang and Laura Reuss2 Although not recommended for use with certain medica- tions, grapefruits are known for their numerous health benefits. Both these effects come from, in part, natural chemicals called furanocoumarins. Although these biologically active plant compounds, or phytochemicals, are beneficial to overall health, some compounds have been shown to interact with numerous medications, causing adverse effects known as the “grapefruit juice effect.” Furanocoumarins and flavanones are the major compounds responsible in these drug interactions. Several studies have reported that furanocoumarins present in grapefruit affect absorption of some medications by interfering with a cer- tain liver and intestinal enzyme (Guo et al. 2000). However, numerous studies have shown that compounds in citrus fruits, including furanocoumarins, reduce inflammation and stop cancer cells from multiplying. Furthermore, they Figure 1. Furanocoumarins in grapefruit originate from psoralen and include bergaptol, bergapten, bergamottin, and epoxybergamottin. may also help repair damaged DNA that would otherwise Red, Ruby Red, Ray Red, Star Ruby, Thompson Pink, Marsh contribute to the development of tumors. A variety of White, and Duncan (Girennavar et al. 2008). furanocoumarins can be found in all types of citrus, but those found in grapefruit possess several health-promoting Grapefruits have long been considered a part of a healthy properties that include anti-inflammatory, anti-cancer, diet due to being rich in vitamins, minerals, fiber, and anti-obesity, and bone-building effects (Madrigal-Bujaidar phytochemicals, such as flavonoid and furanocoumarins. It et al. 2013; Mahgoub 2002; Chudnovskiy et al. 2014). is these phytochemicals, in particular the furanocoumarins, that demonstrate anti-inflammatory, anti-cancer, and The furanocoumarins found in grapefruit all originate anti-oxidative effects (Lee et al.
    [Show full text]
  • Bergamot Oil: Botany, Production, Pharmacology
    Entry Bergamot Oil: Botany, Production, Pharmacology Marco Valussi 1,* , Davide Donelli 2 , Fabio Firenzuoli 3 and Michele Antonelli 2 1 Herbal and Traditional Medicine Practitioners Association (EHTPA), Norwich NR3 1HG, UK 2 AUSL-IRCCS Reggio Emilia, 42122 Reggio Emilia RE, Italy; [email protected] (D.D.); [email protected] (M.A.) 3 CERFIT, Careggi University Hospital, 50139 Firenze FI, Italy; fabio.firenzuoli@unifi.it * Correspondence: [email protected] Definition: Bergamot essential oil (BEO) is the result of the mechanical manipulation (cold pressing) of the exocarp (flavedo) of the hesperidium of Citrus limon (L.) Osbeck Bergamot Group (synonym Citrus × bergamia Risso & Poit.), resulting in the bursting of the oil cavities embedded in the flavedo and the release of their contents. It is chemically dominated by monoterpene hydrocarbons (i.e., limonene), but with significant percentages of oxygenated monoterpenes (i.e., linalyl acetate) and of non-volatile oxygen heterocyclic compounds (i.e., bergapten). Keywords: bergamot; citrus; essential oil; production; review 1. Introduction The taxonomy, and consequently the nomenclature, of the genus Citrus, is particularly complicated and has been rapidly changing in recent years (see Table1). For over 400 years, the centre of origin and biodiversity, along with the evolution and phylogeny of the Citrus species, have all been puzzling problems for botanists and the confusing and changing Citation: Valussi, M.; Donelli, D.; nomenclature of this taxon over the years can reflect intrinsic reproductive features of Firenzuoli, F.; Antonelli, M. Bergamot Oil: Botany, Production, the species included in this genus, the cultural and geographical issues, and the rapidly Pharmacology. Encyclopedia 2021, 1, evolving techniques used to clarify its phylogeny [1].
    [Show full text]
  • Identification and Functional Characterization of the First Two
    Identification and functional characterization of the first two aromatic prenyltransferases implicated in the biosynthesis of furanocoumarins and prenylated coumarins in two plant families: Rutaceae and Apiaceae Fazeelat Karamat To cite this version: Fazeelat Karamat. Identification and functional characterization of the first two aromatic prenyl- transferases implicated in the biosynthesis of furanocoumarins and prenylated coumarins in two plant families: Rutaceae and Apiaceae. Agronomy. Université de Lorraine, 2013. English. NNT : 2013LORR0029. tel-01749560 HAL Id: tel-01749560 https://hal.univ-lorraine.fr/tel-01749560 Submitted on 29 Mar 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. AVERTISSEMENT Ce document est le fruit d'un long travail approuvé par le jury de soutenance et mis à disposition de l'ensemble de la communauté universitaire élargie. Il est soumis à la propriété intellectuelle de l'auteur. Ceci implique une obligation de citation et de référencement lors de l’utilisation de ce document. D'autre part, toute contrefaçon, plagiat,
    [Show full text]
  • Distribution of Furanocoumarins in Grapefruit Juice Fractions
    5158 J. Agric. Food Chem. 2005, 53, 5158−5163 Distribution of Furanocoumarins in Grapefruit Juice Fractions JOHN A. MANTHEY* AND BEÄ LA S. BUSLIG Citrus and Subtropical Products Laboratory, Agricultural Research Service, U.S. Department of Agriculture, 600 Avenue S N.W., Winter Haven, Florida 33881 The reported effects of grapefruit (Citrus paradisi Macf.) juice on oral bioavailability of certain prescription drugs have led to the discovery of the inhibition by compounds in grapefruit of cytochrome P450 3A4 (CYP3A4) in the intestinal wall and liver. Recent evidence indicates that furanocoumarins related to bergamottin [5-[(3′,7′-dimethyl-2′,6′-octadienyl)oxy]psoralen] are primarily responsible for the grapefruit effect, yet the exact mechanisms and roles that specific compounds play in this effect are still uncertain. In the current experiments freshly extracted grapefruit juice was separated into four fractions, consisting of raw finished juice (∼5% fine pulp), centrifugal retentate (∼35% fine pulp), centrifuged supernatant (<1% pulp), and coarse finisher pulp. The relative concentrations of furanocoumarins in each of these grapefruit juice fractions were measured by HPLC-MS. These measurements showed that the centrifugal retentate had the highest furanocoumarin content, containing 892 ppm of bergamottin, 628 ppm of 6′,7′-dihydroxybergamottin, 116 ppm of 6′,7′- epoxybergamottin, 105 ppm of 7-geranyloxycoumarin, and ∼467 ppm of furanocoumarin dimers. These high furanocoumarin concentrations make this fraction a useful starting material for preparative- scale isolations of these compounds. MS analysis of this furanocoumarin-enriched fraction provided evidence of additional furanocoumarins in grapefruit juice that remain to be fully characterized and evaluated for their roles in the grapefruit-drug interactions.
    [Show full text]
  • The Fascinating History of Bergamot (Citrus Bergamia Risso & Poiteau
    Journal of Environmental Science and Engineering A 6 (2017) 22-30 doi:10.17265/2162-5298/2017.01.003 D DAVID PUBLISHING The Fascinating History of Bergamot (Citrus Bergamia Risso & Poiteau), the Exclusive Essence of Calabria: A Review Gina Maruca1, Gaetano Laghetti1, Rocco Mafrica2, Domenico Turiano3 and Karl Hammer4 1. Institute of Bioscience and Bioresouces, National Council of Research, Bari 70126, Italy 2. Institute of Agronomy, Department of Agrarian, Mediterranean University of Reggio Calabria, Reggio Calabria 89122, Italy 3. Sperimental Demonstrative Centre of the Straits of Messina, Regional Administration for the Development of the Calabrian Agriculture, Reggio Calabria 89100, Italy 4. Former Agrobiodiversity, University of Kassel, Witzenhausen D-37213, Germany Abstract: The bergamot (Citrus bergamia Risso et Poiteau), a citrus fruit growing almost exclusively in the South Italy, is considered the “prince of citrus” for its storical role in the perfume industry due to its essential oil, a product in great demand of a pleasant and refreshing scent. Recently, analgesic, anxiolytic, neuroprotective consistent effects have been ascribed to bergamot essential oil when it is used in aromatherapy, for the relief of pain and symptoms associated with stress-induced anxiety and depression. Moreover, today, bergamot fruit due to a considerable abundance and variety of nutraceutical compounds which are present in its juice, is becoming increasingly important also in the food, pharmaceutical and confectionery industries. In this review, it is discussed that the literature on C. bergamia, focusing on the several studies performed with the experimental data, and recently accumulated, may form the rational basis for further development. Key words: Bergamot (Citrus bergamia Risso & Poiteau), essential oil.
    [Show full text]
  • White and Colored Grapefruit Juice Produce Similar Pharmacokinetic Interactions
    ORIGINAL ARTICLES Clinical Pharmaceutics Laboratory, Department of Pharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan White and colored grapefruit juice produce similar pharmacokinetic interactions Y. Uesawa, M. Abe, K. Mohri Received March 4, 2008, accepted March 28, 2008 Dr. Yoshihiro Uesawa, Clinical Pharmaceutics Laboratory, Department of Pharmaceutics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan [email protected] Pharmazie 63: 598–600 (2008) doi: 10.1691/ph.2008.8550 Colored (pink and red) grapefruit pulp contains lower amounts of the furanocoumarin derivatives that cause pharmacokinetic interactions than white grapefruit pulp. However, few studies have ex- amined interactions with colored juice products. Therefore, we examined the potential interactions of both white and colored grapefruit products by measuring the concentrations of furanocoumarin derivatives and inhibition of the metabolizing cytochrome P450 (CYP) 3A enzymes, the target of the furanocoumarins. We measured concentrations of three major furanocoumarin derivatives, ber- gaptol, bergamottin, and 60,70-dihydroxybergamottin, with high-performance liquid chromatography in 21 brands of grapefruit juice sold in Japan, including 14 white and 7 colored brands. The mean difference in bergaptol, bergamottin, and 60,70-dihydroxybergamottin concentrations in white grape- fruit juice samples was 1.59, 0.902, and 1.03 times, respectively, the amounts in colored samples. White samples inhibited CYP3A-mediated testosterone-6b oxidation in human liver microsomes by 1.04 and 0.922 times (whole juice and furanocoumarin, respectively) the inhibition by colored juice. Thus, colored grapefruit juice may produce drug interactions at the same rate as white grapefruit juice. 1. Introduction 2. Investigations, results and discussion 2.1.
    [Show full text]
  • Clinical Study Protocol an Open-Label, Single
    CLINICAL STUDY PROTOCOL AN OPEN-LABEL, SINGLE SEQUENCE, CROSSOVER STUDY ASSESSING THE EFFECT OF PEXIDARTINIB ON THE PHARMACOKINETICS OF MIDAZOLAM AND S-WARFARIN IN PATIENTS PL3397-A-U126 IND 105521 VERSION 1.0, 28 APRIL 2017 DAIICHI SANKYO INC. 211 MT AIRY ROAD BASKING RIDGE, NJ 07920-2311 CONFIDENTIALITY STATEMENT Information contained in this document is proprietary to Daiichi Sankyo Inc. The information is provided to you in confidence which is requested under an agreed upon and signed Confidentiality and Disclosure Agreement. Do not give this document or any copy of it or reveal any proprietary information contained in it to any third party (other than those in your organization who are assisting you in this work and are bound by the Confidentiality and Disclosure Agreement) without the prior written permission of an authorized representative of Daiichi Sankyo Inc. Proprietary and Confidential Page 1 Protocol PL3397-A-U126 Version 1.0, 28 April 2017 Print Name Signature Title Date (DD MMM YYYY) Proprietary and Confidential Page 3 Protocol PL3397-A-U126 Version 1.0, 28 April 2017 PROTOCOL SYNOPSIS IND Number: 105521 EudraCT: 2017-001687-38 Protocol Number: PL3397-A-U126 Investigational Product: PLX3397 Active Ingredient/INN: Pexidartinib Study Title: An open-label, single sequence, crossover study assessing the effect of pexidartinib on the pharmacokinetics of midazolam and S-warfarin in patients Study Phase: Phase 1, drug-drug interaction (DDI) study Indication Under Investigation: Pexidartinib DDI with midazolam and S-warfarin Safety
    [Show full text]
  • Bergamottin and Its Role As a Drug Inhibitor
    Chemistry 150, Fall 2008 Bergamottin and its Role as a The Citrus bergamia also grows in warmer climates and was initially found in Southeast Asia.1 Citrus bergamia is Drug Inhibitor often found in Earl Grey tea.1 This species is the namesake of bergamottin, and it was in the bergamot orange that the Jennifer Murphy, Fall 2008 compound was first isolated.1 Introduction Bergamottin is a member of the furanocoumarin family and is most commonly found in grapefruit juice. Bergamottin is a known drug inhibitor of cytochrome P450 34A. For this reason, it is often recommended that patients avoid consumption of grapefruit juice if currently prescribed medication such as statins, antihistamines, and drugs in several other classes. This drug interaction is often referred to Figure 3. Citrus bergamia. source as “the grapefruit effect” and can cause the compound to (http://cherylinskintherapy.co.uk/images/bergamot.jpg) remain in the body for a prolonged period of time; which may ultimately lead to health risks in some patients. The II. Biological Activity occurrence of bergamottin, the synthesis and biosynthesis of Bergamottin inhibits the cytochrome P450 34A enzyme.3 the compound will be discussed in the following review. Grapefruit juice was first noticed to cause such an inhibition when it was used as an additive to ease the consumption of the drug felodipine, which was mixed with ethanol and therefore had a very strong taste.4 It was observed that there was in fact a compound in the grapefruit juice that was causing this cytochrome P450 34A enzyme inhibition to be targeted, and an increase in the oral bioavailability was clearly taking place.4 Figure 1.
    [Show full text]
  • NIH Public Access Author Manuscript Pharmacol Ther
    NIH Public Access Author Manuscript Pharmacol Ther. Author manuscript; available in PMC 2013 November 01. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Pharmacol Ther. 2012 November ; 136(2): 186–201. doi:10.1016/j.pharmthera.2012.08.001. Mechanisms Underlying Food-Drug Interactions: Inhibition of Intestinal Metabolism and Transport Christina S. Wona, Nicholas H. Oberliesb, and Mary F. Painea,* aDivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7569 USA bDepartment of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402-6170 USA Abstract Food-drug interaction studies are critical to evaluate appropriate dosing, timing, and formulation of new drug candidates. These interactions often reflect prandial-associated changes in the extent and/or rate of systemic drug exposure. Physiologic and physicochemical mechanisms underlying food effects on drug disposition are well-characterized. However, biochemical mechanisms involving drug metabolizing enzymes and transport proteins remain underexplored. Several plant- derived beverages have been shown to modulate enzymes and transporters in the intestine, leading to altered pharmacokinetic (PK) and potentially negative pharmacodynamic (PD) outcomes. Commonly consumed fruit juices, teas, and alcoholic drinks contain phytochemicals that inhibit intestinal cytochrome P450 and phase II conjugation enzymes, as well as uptake and efflux transport proteins. Whereas myriad phytochemicals have been shown to inhibit these processes in vitro, translation to the clinic has been deemed insignificant or undetermined. An overlooked prerequisite for elucidating food effects on drug PK is thorough knowledge of causative bioactive ingredients.
    [Show full text]
  • Opinion on Furocoumarins in Cosmetic Products ______
    SCCP/0942/05 EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate C - Public Health and Risk Assessment C7 - Risk assessment SCIENTIFIC COMMITTEE ON CONSUMER PRODUCTS SCCP Opinion on Furocoumarins in cosmetic products Adopted by the SCCP during the 6th plenary of 13 December 2005 SCCP/0942/05 Opinion on furocoumarins in cosmetic products ____________________________________________________________________________________________ TABLE OF CONTENTS 1. BACKGROUND ………………………………………………… 3 2. TERMS OF REFERENCE ………………………………………………… 4 3. OPINION ………………………………………………… 4 4. DISCUSSION ………………………………………………… 7 5. CONCLUSION ………………………………………………… 9 6. MINORITY OPINION ………………………………………………… 9 7. REFERENCES ………………………………………………… 9 8. ACKNOWLEDGEMENTS ………………………………………………… 9 2 SCCP/0942/05 Opinion on furocoumarins in cosmetic products ____________________________________________________________________________________________ 1. BACKGROUND Commission Directive 95/34/EC July 10, 1995 adopted an amendment to Annex II, Annex to Cosmetic Directive under reference number 358 as follows: “Furocoumarins (e.g. trioxysalan, 8- methoxypsoralen, 5-methoxypsoralen) except for normal content in natural essences used. In sun protection and in bronzing products, furocoumarins shall be below 1 mg/kg.” The technical adaptation was based on an opinion adopted by the Scientific Committee on Cosmetology (SCC) in 1990. Furocoumarins are recognized to be photomutagenic and photo- carcinogenic. International Agency for Research on cancer (IARC) has classified 5-MOP and 8- MOP plus ultraviolet radiation in group 2A (probably carcinogenic to humans) and in group 1 (carcinogenic to human), respectively. The Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers (SCCNFP) adopted an “Initial List of Perfumery Materials which must not form part of Cosmetic Products except subject to the restrictions and conditions laid down” (SCCNFP/0392/00, final, adopted by the SCCNFP during the 18th Plenary meeting of 25 September 2001).
    [Show full text]
  • Investigating the Chemical Space and Metabolic Bioactivation of Natural Products and Cross-Reactivity of Chemical Inhibitors in Cyp450 Phenotyping
    INVESTIGATING THE CHEMICAL SPACE AND METABOLIC BIOACTIVATION OF NATURAL PRODUCTS AND CROSS-REACTIVITY OF CHEMICAL INHIBITORS IN CYP450 PHENOTYPING Nicholas M. Njuguna Supervisor: Prof. Kelly Chibale Department of Chemistry, University of CapeTown Town Co-supervisor: Dr. Collen Masimirembwa African Institute of Biomedical Science andCape Technology, Harare, Zimbabwe of Thesis presented for the Degree of Doctor of Philosophy In the Department of Chemistry UniversityUNIVERSITY OF CAPE TOWN November 2014 The copyright of this thesis vests in the author. No quotation from it or information derived from it is to be published without full acknowledgement of the source. The thesis is to be used for private study or non- commercial research purposes only. Published by the University of Cape Town (UCT) in terms of the non-exclusive license granted to UCT by the author. Univeristy of Cape Town DECLARATION I, Nicholas Mwaura Njuguna, hereby declare that: (i) This thesis is my own unaided work, both in conception and execution, and that apart from the normal guidance of my supervisors; I have received no assistance apart from that acknowledged; (ii) Neither the substance nor any part of the thesis has been submitted in the past, or is to be submitted for a Degree in the University of Cape Town or any other University. Signed: Date: i DEDICATION To my family: Dad, Mum, Kim, Maureen, Joe and Shi For your enduring love, steadfast support and unshakeable belief that have made my journey into the unknown so much more bearable. ii ACKNOWLEDGEMENTS I wish to convey my heartfelt gratitude to all the people that contributed in every way, great or small, in the conceptualisation, execution and conclusion of this work.
    [Show full text]
  • Chemistry and Health Effects of Furanocoumarins in Grapefruit
    journal of food and drug analysis xxx (2016) 1e13 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.jfda-online.com Review Article Chemistry and health effects of furanocoumarins in grapefruit * Wei-Lun Hung, Joon Hyuk Suh, Yu Wang Citrus Research and Education Center, Department of Food Science and Human Nutrition, University of Florida, Lake Alfred, FL, USA article info abstract Article history: Furanocoumarins are a specific group of secondary metabolites that commonly present in Received 1 September 2016 higher plants, such as citrus plants. The major furanocoumarins found in grapefruits 0 0 Received in revised form (Citrus paradisi) include bergamottin, epoxybergamottin, and 6 ,7 -dihydroxybergamottin. 2 November 2016 During biosynthesis of these furanocoumarins, coumarins undergo biochemical modifi- Accepted 3 November 2016 cations corresponding to a prenylation reaction catalyzed by the cytochrome P450 enzymes Available online xxx with the subsequent formation of furan rings. Because of undesirable interactions with several medications, many studies have developed methods for grapefruit furanocoumarin Keywords: quantification that include high-performance liquid chromatography coupled with UV anticancer activity detector or mass spectrometry. The distribution of furanocoumarins in grapefruits is bergamottin affected by several environmental conditions, such as processing techniques, storage bone health temperature, and packing materials. In the past few years, grapefruit furanocoumarins furanocoumarins have been demonstrated to exhibit several biological activities including antioxidative, grapefruit -inflammatory, and -cancer activities as well as bone health promotion both in vitro and in vivo. Notably, furanocoumarins potently exerted antiproliferative activities against cancer cell growth through modulation of several molecular pathways, such as regulation of the signal transducer and activator of transcription 3, nuclear factor-kB, phosphatidy- linositol-3-kinase/AKT, and mitogen-activated protein kinase expression.
    [Show full text]