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Effect of Dietary Flavonoids on Hepatic CYP2E1 and 3A4 Activity

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Effect of Dietary Flavonoids on Hepatic CYP2E1 and 3A4 Activity Effect of dietary flavonoids on hepatic CYP2E1 and 3A4 activity – Implication for food-drug interactions Flavonoiders effekt på hepatisk CYP2E1 och 3A4 aktivitet - Implikation för interaktioner mellan mat och läkemedel Johanna Östlund Faculty of Natural Resources and Agricultural Sciences Department of Food Science Effect of dietary flavonoids on hepatic CYP2E1 and 3A4 activity Johanna Östlund Supervisor: Galia Zamaratskaia, Department of Food Science, SLU Examiner: Rikard Landberg, Department of Food Science, SLU Credits: 30 hec Level: Second cycle, A2E Course title: Independent project in Food Science Course code: EX025 Programme/education: Agriculture Programme - Food Science Place of publication: Uppsala Year of publication: 2017 Title of series: Examensarbete/Sveriges lantbruksuniversitet, Institutionen för Livsmedelsvetenskap Number of part of series: ISSN: Online publication: http://stud.epsilon.slu.se Keywords: Cytochrome P450, CYP2E1, CYP3A4, Flavonoids, Quercetin, Myricetin, Isorhamnetin, food-drug interactions Sveriges Lantbruksuniversitet Swedish University of Agricultural Sciences Faculty of Natural Resources and Agricultural Sciences Department of Food Science Abstract Flavonoids are a group of phytochemicals ubiquitously present in vegetables, fruits, berries and herbs. It is suggested that they contribute to protection against several lifestyle diseases including cancer. Nevertheless, herbal extracts and foods rich in certain flavonoids have been shown to interact with the metabolism of drugs that may cause adverse effects. The interac- tions are often due to modulation of drug metabolising cytochrome P450 enzymes in the liver. The present study examined inhibitory effects of the flavonoid quercetin on the cyto- chrome P450 isoform CYP2E1. Quercetin, myricetin and isorhamentin were flavonoids inves- tigated for inhibitory effects on the isoform CYP3A4. The metabolising function of those spe- cific cytochrome P450 isoforms is crucial for detoxification and/or bioactivation of foreign compounds. Catalytic activity was measured in vitro using human liver microsomes separated in male and female pools. Reversibility of enzyme inhibition was investigated and kinetic measurements were performed in order to determine inhibition mechanism. Based on results from animal experiments, the hypothesis was that the selected flavonoids inhibit enzyme ac- tivity and that the degree of inhibition differed between genders. Quercetin inhibited CYP2E1 activity and quercetin and myricetin inhibited CYP3A4 activ- ity as expected, but isorhamnetin had no inhibitory effects on CYP3A4. Inhibition was re- versible in all enzyme pools, but the mechanism varied between competitive, uncompetitive and non-competitive inhibition. These observations are related to the flavonoid structure where the number and position of hydroxyl-groups determine the binding mechanism to the enzyme and thereby the level and mode of inhibition. Surprisingly, this study revealed no sub- stantial gender disparities of flavonoid inhibition in human cytochrome P450 activity. Large variations between enzyme pools were observed within the same gender, suggesting inter-in- dividual differences attributable to genetic and/or other lifestyle factors rather than gender. This study provided gained insight in human cytochrome 450 regulation in presence of fla- vonoids and the results can contribute to research in drug development. Keywords: Cytochrome P450, CYP450, CYP2E1, CYP3A4, Flavonoid, Quercetin, Myricetin, Isorhamnetin, food- drug interactions, FDI 3 Sammanfattning Flavonoider är en grupp fytokemikalier som finns i de flesta grönsaker, frukt bär och örter. De har visat sig bidra till ett skydd mot flera livsstilssjukdomar, till exempel cancer. Örtextrakt och livsmedel med högt innehåll av vissa flavonoider har dock visat sig påverka nedbryt- ningen av läkemedel vilket kan orsaka oönskade biverkningar. Interaktionen involverar fram- förallt en kemisk modulering av läkemedelsnedbrytande, så kallade cytokrom P450-enzymer i levern. Den här studien undersökte inhibering av flavonoiden quercetin på cytokromisoformen CYP2E1 samt flavonoiderna quercetin, myricetin och isorhamnetin på CYP3A4. Aktiviteten hos dessa cytokrom P450-isoformer utgör en vital funktion i nedbrytningen av främmande ämnen. Katalytisk aktivitet mättes in vitro i levermikrosomer från människor uppdelade i manliga och kvinnliga pooler. Inhiberingens reversibilitet undersöktes och kinetiska analyser utfördes för att ta reda på inhiberingsmekanismen. Hypotesen, baserad på resultat från liknande djurstudier, var att de specifika flavonoiderna inhiberar enzymaktivitet och att inhiberingsgraden varierar mellan könen. Resultaten visade att quercetin inhiberade CYP2E1 aktivitet och quercetin, myricetin inhi- berade CYP3A4 aktivitet som förväntat, men isorhamnetin inhiberade inte CYP3A4. Inhibe- ringen var reversibel i alla enzympooler och typen av inhibering var antingen kompetitiv, okompetitiv eller icke-kompetitiv. Dessa observationer kan relateras till flavonoidernas ke- miska struktur där antalet hydroxylgrupper och dess positioner avgör bindningen till enzymet och därav graden av inhibering. Den här studien visade dock inga väsentliga skillnader mel- lan könen i flavonoidernas förmåga att inhibera cytokrom P450-aktivitet i människor. Det var stor variation mellan enzympoolerna inom samma kön vilket tyder på interindividuella skill- nader relaterade till genetiska eller andra livsstilsfaktorer snarare än kön. Resultaten från studien kan bidra till ökad kunskap om cytokrom-P450-reglering i männi- ska vilket kan stödja forskning inom läkemedelsutveckling. Nyckelord: Cytokrom P450, CYP450, CYP2E1, CYP3A4, Flavonoid, Quercetin, Myricetin, Isorhamnetin, Läke- medelsinteraktioner, FDI 4 Table of contents Abbreviations 6 1 Introduction 7 1.1 Background 7 1.2 Objectives 8 2 Literature review 9 2.1 The Cytochrome P450 system 9 2.1.1 Reaction model 9 2.1.2 CYP450 isoforms 10 2.2 CYP450 in xenobiotic metabolism 10 2.2.1 Enzyme inhibition 11 2.2.2 Michaelis Menten kinetics 12 2.3 Food-drug interactions involving CYP450 13 2.4 Inhibition by dietary flavonoids 13 2.4.1 Quercetin 15 2.4.2 Myricetin 15 2.4.3 Isorhamnetin 15 2.5 Cytochrome 2E1 17 2.6 Cytochrome 3A4 17 2.7 Gender related differences in CYP450 activity 18 3 Material and method 20 3.1 Chemicals 21 3.2 Microsomes 21 3.3 Analysis of CYP2E1 21 3.4 Analysis of CYP3A4 22 3.5 Data analysis 22 4 Results 23 4.1 CYP 2E1 activity 23 4.2 CYP 3A4 activity 27 4.3 Summary of results 31 5 Discussion 32 6 Conclusions 35 7 Acknowledgements 36 References 37 8. Appendix: Popular summary 42 5 Abbreviations CYP450 Cytochrome P450 FDI Food-drug interactions ADE Adverse drug event NADPH β-nicotinamide adenine dinucleotide phosphate PNP p-nitrophenol BR Benzyloxyresorufin BFC 7-benzyloxy-4-trifluoromethylcoumarin HFC 7-hydroxy-7-benzyloxy-triflouromethylcoumarine 6 1 Introduction 1.1 Background Cytochrome P450 enzymes (CYP450s) are the main group of enzymes responsible for the metabolism and detoxification of foreign substances, commonly called xenobiotics. They are also involved in the biosynthesis and metabolism of endogenous compounds such as fatty ac- ids and steroids. CYP450s are highly expressed in the liver, where they catalyse reactions that convert lipophilic compounds into more hydrophilic derivatives. Most drugs undergo this bio- transformation in order to be catabolised and eliminated from the body (Gonzalez, 1988). However, other xenobiotic compounds such as dietary flavonoids can modulate the activity of CYP450 enzymes leading to an enhancement or inhibition of the catalytic activity. Conse- quently, the detoxification or functionality of drugs may be interrupted (Hodek et al., 2002). In the present study, the flavonoids quercetin, myricetin and isorhamnetin were examined for their inhibitory effects on enzyme activity of two CYP450 isoforms. These flavonoids are naturally occurring in a wide range of vegetables in the human diet and known to interact with several CYP450 enzymes (Chen et al., 2009; Guo and Zheng, 2014; Lau and Chang, 2009). Emerging in vitro and in vivo evidence propose health effects of many flavonoids attributable to their anti-oxidative properties (C.f. Bodewes et al., 2011). Accordingly, supplements con- taining high concentrations of flavonoids are commonly consumed to prevent health issues. However, knowledge about the underlying mechanisms are limited. (Hollman, Cassidy et al. 2011). Moreover, when co-administrated with prescription drugs there is a considerable risk for adverse health effect since knowledge about potential food-drug interactions (FDI) is still scarce. Understanding the mechanisms behind FDI with CYP450 enzymes can improve the development of new medicines for animals and humans and minimize the risk for adverse ef- fects of drugs (Wanwimolruk and Prachayasittikul, 2014). Besides diet and other lifestyle factors, the expression and activity of CYP450 enzymes depend on genetic profile, age and gender (Zanger and Schwab, 2013). These inter-individual variations in enzyme activity make it difficult to predict individual drug response. The effect of dietary components on CYP450 activity may also vary between men and women. Gender related differences in the effect of phytochemicals on CYP450 activity has previously been reported in porcine microsomes (Ekstrand et al., 2015) but very few studies have investigated this phenomenon in humans. Therefore, this study on gender related differences in CYP activ- ity in human microsomes
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