Ketoconazole inhibits the cellular uptake of anandamide via inhibition of FAAH at pharmacologically relevant concentrations.
BACKGROUND
The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA).


RESULTS
The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH) activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 µM, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component) of 34 µM.


CONCLUSIONS
The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer.
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Emmelie
E
Björklund
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Therése N L
TN
Larsson
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Stig O P
SO
Jacobsson
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
Christopher J
CJ
Fowler
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000704:Analysis of Variance; D001095:Arachidonic Acids / Q000378:metabolism* / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000378:metabolism* / Q000493:pharmacokinetics*; D056945:Hep G2 Cells; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000378:metabolism* / Q000493:pharmacokinetics*; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063388:Endocannabinoids; D007654:Ketoconazole; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide