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Östlund, Johanna, 2017. Effect of dietary flavonoids on hepatic CYP2E1 and 3A4 activity : implication for food-drug interactions. Second cycle, A2E. Uppsala: SLU, Dept. of Food Science

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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.

,

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 nedbrytningen
av läkemedel vilket kan orsaka oönskade biverkningar. Interaktionen involverar framförallt
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 inhiberade
CYP3A4 aktivitet som förväntat, men isorhamnetin inhiberade inte CYP3A4. Inhiberingen
var reversibel i alla enzympooler och typen av inhibering var antingen kompetitiv,
okompetitiv eller icke-kompetitiv. Dessa observationer kan relateras till flavonoidernas kemiska
struktur där antalet hydroxylgrupper och dess positioner avgör bindningen till enzymet
och därav graden av inhibering. Den här studien visade dock inga väsentliga skillnader mellan
könen i flavonoidernas förmåga att inhibera cytokrom P450-aktivitet i människor. Det var
stor variation mellan enzympoolerna inom samma kön vilket tyder på interindividuella skillnader
relaterade till genetiska eller andra livsstilsfaktorer snarare än kön.
Resultaten från studien kan bidra till ökad kunskap om cytokrom-P450-reglering i människa
vilket kan stödja forskning inom läkemedelsutveckling.

Main title:Effect of dietary flavonoids on hepatic CYP2E1 and 3A4 activity
Subtitle:implication for food-drug interactions
Authors:Östlund, Johanna
Supervisor:Zamaratskaia, Galia
Examiner:Landberg, Rikard
Series:Publikation / Sveriges lantbruksuniversitet, Institutionen för livsmedelsvetenskap
Volume/Sequential designation:UNSPECIFIED
Year of Publication:2017
Level and depth descriptor:Second cycle, A2E
Student's programme affiliation:NY002 Agricultural Programme - Food Science 270 HEC
Department:(NL, NJ) > Dept. of Food Science
Keywords:cytochrome P450, CYP2E1, CYP3A4, flavonoids, quercetin, myricetin, isorhamnetin, food-drug interactions
URN:NBN:urn:nbn:se:slu:epsilon-s-6308
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-s-6308
Subjects:Food science and technology
Language:English
Deposited On:11 Apr 2017 09:23
Metadata Last Modified:22 Aug 2017 11:55

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