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Inhibition of fatty acid amide hydrolase by kaempferol and related naturally occurring flavonoids
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience.
Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
2008 (English)In: British Journal of Pharmacology, ISSN 0007-1188, Vol. 155, no 2, 244-252 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND AND PURPOSE: Recent studies have demonstrated that the naturally occurring isoflavone compounds genistein and daidzein inhibit the hydrolysis of anandamide by fatty acid amide hydrolase (FAAH) in the low micromolar concentration range. The purpose of the present study was to determine whether this property is shared by flavonoids.

EXPERIMENTAL APPROACH:The hydrolysis of anandamide in homogenates and intact cells was measured using the substrate labelled in the ethanolamine part of the molecule.

KEY RESULTS: Twenty compounds were tested. Among the commonly occurring flavonoids, kaempferol was the most potent, inhibiting FAAH in a competitive manner with a K(i) value of 5 microM. Among flavonoids with a more restricted distribution in nature, the two most active toward FAAH were 7-hydroxyflavone (IC(50) value of 0.5-1 microM depending on the solvent used) and 3,7-dihydroxyflavone (IC(50) value 2.2 microM). All three compounds reduced the FAAH-dependent uptake of anandamide and its metabolism by intact RBL2H3 basophilic leukaemia cells.

CONCLUSIONS AND IMPLICATIONS: Inhibition of FAAH is an additional in vitro biochemical property of flavonoids. Kaempferol, 7-hydroxyflavone and 3,7-dihydroxyflavone may be useful as templates for the synthesis of novel compounds, which target several systems that are involved in the control of inflammation and cancer.

Place, publisher, year, edition, pages
2008. Vol. 155, no 2, 244-252 p.
Keyword [en]
anandamide; cannabinoid; fatty acid amide hydrolase; flavonoids; kaempferol; apigenin
URN: urn:nbn:se:umu:diva-10516DOI: 10.1038/bjp.2008.237PubMedID: 18552875OAI: diva2:150187
Available from: 2008-09-23 Created: 2008-09-23 Last updated: 2009-08-12Bibliographically approved
In thesis
1. The cellular processing of the endocannabinoid anandamide and its pharmacological manipulation
Open this publication in new window or tab >>The cellular processing of the endocannabinoid anandamide and its pharmacological manipulation
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Anandamide (arachidonoyl ethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG) exert most of their actions by binding to cannabinoid receptors. The effects of the endocannabinoids are short-lived due to rapid cellular accumulation and metabolism, for AEA, primarily by the enzymes fatty acid amide hydrolase (FAAH). This has led to the hypothesis that by inhibition of the cellular processing of AEA, beneficial effects in conditions such as pain and inflammation can be enhanced. The overall aim of the present thesis has been to examine the mechanisms involved in the cellular processing of AEA and how they can be influenced pharmacologically by both synthetic natural compounds.

Liposomes, artificial membranes, were used in paper I to study the membrane retention of AEA. The AEA retention mimicked the early properties of AEA accumulation, such as temperature-dependency and saturability.

In paper II, FAAH was blocked by a selective inhibitor, URB597, and reduced the accumulation of AEA into RBL2H3 basophilic leukaemia cells by approximately half. Treating intact cells with the tyrosine kinase inhibitor genistein, an isoflavone found in soy plants and known to disrupt caveolae-related endocytosis, reduced the AEA accumulation by half, but in combination with URB597 no further decrease was seen. Further on, the effects of genistein upon uptake were secondary to inhibition of FAAH. The ability to inhibit the accumulation and metabolism of AEA was shared by several flavonoids (shown in paper III). In paper IV, the isoflavone biochanin A and URB597 had effects in vivo, in a model of persistent pain, effects decreased by the cannabinoid receptor 1 antagonist AM251.

In paper VI, the cellular processing of the endocannabinoid metabolites following degradation was examined, a mechanism poorly understood. It was found that nitric oxide (NO) donors significantly increased the retention of tritium in cell membranes following incubation with either tritiated AEA or 2-AG. Further experiments revealed that the effect of NO donors mainly involves the arachidonate part of the molecules. Inhibition of FAAH completely reduced the effect of NO donors in cells with a large FAAH component, indicating that the effects were downstream of the enzyme.

These results suggest that the cellular processing of endocannabinoids can be affected in a manner of different ways by pharmacological manipulation in vitro and that naturally occurring flavonoid compounds can interact with the endocannabinoid system.

Place, publisher, year, edition, pages
Umeå: Farmakologi och klinisk neurovetenskap, 2009. 80 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1247
Endocannabinoid, anandamide, cellular processing, pain, flavonoids, fatty acid amide hydrolase
National Category
Pharmacology and Toxicology
Research subject
Medical Pharmacology
urn:nbn:se:umu:diva-22221 (URN)978-91-7264-732-9 (ISBN)
Farmakologi, 901 87, Umeå
Public defence
2009-05-22, Sal E04, byggnad 6E, Umeå universitetssjukhus, 901 89 Umeå, Umeå, 09:00 (English)
Available from: 2009-04-30 Created: 2009-04-28 Last updated: 2010-01-18Bibliographically approved

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