DOCSLIB.ORG

Grapefruit-Drug Interaction: Isolation, Synthesis, And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Grapefruit-Drug Interaction: Isolation, Synthesis, And GRAPEFRUIT-DRUG INTERACTION: ISOLATION, SYNTHESIS, AND BIOLOGICAL ACTIVITIES OF FUROCOUMARINS AND THEIR VARIATION DUE TO PRE- AND POST–HARVEST FACTORS A Dissertation by BASAVARAJ GIRENNAVAR Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY August 2007 Major Subject: Horticulture GRAPEFRUIT-DRUG INTERACTION: ISOLATION, SYNTHESIS, AND BIOLOGICAL ACTIVITIES OF FUROCOUMARINS AND THEIR VARIATION DUE TO PRE- AND POST–HARVEST FACTORS A Dissertation by BASAVARAJ GIRENNAVAR Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved by: Chair of the Committee, Bhimanagouda S. Patil Committee Members, Leonard M. Pike Leonardo Lombardini John L. Jifon Peter S. Murano G. K. Jayaprakasha Head of Department, Tim D. Davis August 2007 Major Subject: Horticulture iii ABSTRACT Grapefruit-Drug Interaction: Isolation, Synthesis and Biological Activities of Furocoumarins and Their Variation due to Pre- and Post–Harvest Factors. (August 2007) Basavaraj Girennavar, B. Sc., University of Agricultural Sciences Dharawad, India; M. Sc., Haryana Agricultural University Hisar, India Chair of the Advisory Committee: Dr. Bhimanagouda S. Patil The health maintaining properties of citrus consumption are attributed to the wide assortment of bioactive compounds. Consumption of grapefruit along with certain medications, however, is posing a risk of drug toxicity and side reactions. The first study involved isolation of bioactive furocoumarins with a combination of chromatographic techniques and synthesis. Five furocoumarins namely, dihydroxybergamottin, paradisin A, bergamottin, bergaptol and geranylcoumarin were isolated from grapefruit and series of furocoumarin monomers and paradisin A were synthesized. The second study involved influence of pre- and post-harvest factors on the levels of furocoumarins in grapefruit juice. Considerable differences were observed in the levels of these compounds in different grapefruit cultivars. Ray Red showed the lowest levels of all three furocoumarins and Duncan contains the highest amount of DHB and bergamottin, where as the highest levels of paradisin A was observed in Star Ruby. The highest levels of DHB and bergamottin were found in Flame cultivar grown in California. The changes in the levels of these furocoumarins during the season in Rio Red and Marsh White grapefruit cultivars were evaluated. iv The third study investigated biological activities of grapefruit juices and furocoumarins. Grapefruit and Pummelo juices were found to be potent inhibitors of cytochrome CYP3A4 and CYP2C9 isoenzymes at 5% concentration while CYP2D6 was less affected. Among the five furocoumarins tested, the inhibitory potency was in the order of paradisin A>dihydroxybergamottin>bergamottin>bergaptol>geranylcoumarin at 0.1 µM to 0.1 mM concentrations. A fourth study investigated the effect of furocoumarins on bacterial auto-inducer signaling, and found that furocoumarins are potent inhibitors of AI-1 and AI-2 activities at 0.01% concentration. In a fifth study, involving synthesized furocoumarin monomers and dimer on anti-proliferative activities on normal and cancer cell lines, furocoumarins found to be non-toxic to normal cells. However, bergamottin showed a significant anti-proliferative activity in HT-29 and MCF-7 cell lines. This dissertation indicates that furocoumarins are bioactive compounds from grapefruit juice with potent inhibitory property of major drug metabolizing cytochrome P450 isoenzymes. Furocoumarins show a considerable variation between varieties, location and season. These results corroborate the involvement of furocoumarins in grapefruit drug interaction. v Dedicated To My Family and Friends for Their Unconditional, Support, Love and Inspiration vi ACKNOWLEDGEMENTS I would like to thank Dr. Bhimanagouda Patil for his support for my project and dissertation work. His passion and enthusiasm for research has made an ineffaceable impression on my career. His several qualities are worth emulating and would be corner stone for success in coming days. Thank you Dr. Patil for pushing me into the Ph.D. lane, when I was reluctant to pursue it. I will always remember the wide spectrum of opportunities I got while working with you. You have been great mentor and friend; your informal comments always lighten up the situation during lab meetings! I would like to thank Dr. Leonard Pike for his ever supporting attitude. His simple presence would levitate the situation and add an inquisitive dimension. It was life time experience to associate with you and learn humility and simple way of managing complex problem. On several occasions I told Aunty Roxy that you are a role model to look at. Cutting “Aggie Maroon” carrots and selling them in the supermarket with you was really fun! I am grateful to Dr. Leo Lombardini for his support, suggestions and encouragement during dissertation work. I would like to extend my thanks and appreciation to Dr. John Jifon for his valuable suggestions, encouragement and support throughout my graduate studies. I thank Dr. Peter Murano for serving on my committee and helping me out amid his busy schedule. Dr. Jay, it was fun working with you. Your presence made me to realize several things in the research projects and immense advancement. I would say, without your help I would not have written so many manuscripts! Your help and encouragement will always be remembered. vii I would like to thank Sara for her titanic help in the project. Your help in preparation of the astronomical number of samples and chromatography was of incredible. Thanks for all the English and art work on manuscripts and dissertation. You also put my project in winning streak by bagging couple of prizes in several competitions. Joe Kumar (Jose Luis Perez), your help and companionship is truly appreciated. Your hard working approaches inspired me and try to exceed the limits of reality. Kumar, you are cool and keep it that way! Thanks to Alex for adding a different dimension and realizing my critical project of synthesizing the furocoumarins. Running some crazy experiments with you was a real good experience. I would like to thank Dr. Murthy and Ms. Jinhee Kim for their help in cell culture studies. I would like to thank Dr. Brian Connell, Dr. Kil Sun Yoo, Dr. Suresh Pillai, Dr. Bhat, Dr. Park, Dr. Nelson Dr. Skaria, Dr. de Graca, Dr. French, Dr. Louzada, Dr. Deyhim for their help in accomplishing my research goals. Thanks to all my colleagues: Shibu, Kranthi, Jasmine, Julian, Sonia, Amit, Deepak, Clark, Michael, Conrad, Haejeen Bae, Kim, Jaiprakash, Ren Yan, Ryan, Justin, Alex, Jairam, Jennifer, Melissa, Palmy, Kranthi, Ram, Martha, Kamlesh, Nick and Tara for their help in project and companionship. I would like to thank Charlotte and Connie for their help and support. Your help is truly appreciated. I sincerely thank Dr. Mike Arnold, Dr. Tim Davis, and Sharon, Laverne and Jennifer for their help. I would like to express my appreciation to the Citrus Center cartel, Sonia del Rio, Mari, Gina, Teri, Marilyn, Ben Franklin (Tacho), Mike, Elias and field crew for all the support and help. Thanks to faculty and staff at TAES and viii USDA ARS Weslaco for help. Thanks to Joe Maxim and Mickey for providing technical help on E-beam irradiation at National Center for E-beam Food Research at TAMU and John at USDA/AHIS Edinburg, TX. I would like to thank the Department of Horticulture Sciences, Vegetable and Fruit Improvement Center. I would like to acknowledge funding and support from various agencies and organizations such as USDA, Texas Citrus Producer’s Board, and the State of Texas for ITPEG grant and NIH. I would like to thank my friends Vivek, Ankur, Ananth, BoBo, Kumaran, Sai and Chaitanya for their friendship and also being instrumental in planning the future and starting the project called “Team India 100”. Time spent with you guys was memorable. Thanks to Adriana, Lupe, Cindy, Hway-Seen, Candace, Madhu, Arlene, Veronica, George, Sonia, Sree, Lavanya, Magnifique, Madhur Babu, Madhavi, Viola, Vilma Ruth, George and Virginia for their wonderful company. I treasure keeping our friendship alive across the miles; you guys are wonderful and always a source of motivation. Thanks to Ramesh, Sharanu, D.K., Vikas, Shashikanth, Ramachandra, Rajshekar, Siddu, Dinesh, Nadaf, Anand, and many more…… I feel a deep sense of gratitude for my family back home. I would like to thank all of them for their unconditional support and love. I would like to thank Manz, Mallikarjun, Sangmesh, Sada and Mangala for their help and support. I would like to extend my appreciation to Mrs. Vidya Patil for providing moral support and encouragement during my studies. I would like to thank my several teachers and professors from elementary school, high school and college for all their academic help and encouragement in realizing my graduate studies. ix TABLE OF CONTENTS Page ABSTRACT………………………………………………………………………….. iii DEDICATION………………………………………………………………………... v ACKNOWLEDGEMENTS………………………………………………………….... vi TABLE OF CONTENTS……………………………………………………………... ix LIST OF FIGURES…………………………………………………………………… xiv LIST OF TABLES……………………………………………………………………. xvii CHAPTER I INTRODUCTION…………………………………………………........... 1 Background……………………………………………................... 1 Citrus and Bioactive Compounds…………………………………. 2 Furocoumarins and Their Biosynthesis…………………………… 3 Mechanism of Grapefruit-Drug Interaction……………………….
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]
  • 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.
    [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]