Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 148, Issue 5, Pages 682-687Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjp.0706778
Keywords
HK-2 cells; proximal tubules; kidney; MDR-1; P-glycoprotein; cannabinoid
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1 Endogenous and synthetic cannabinoid molecules have been investigated as possible MDR-1/P-glycoprotein (P-gp) modulators in HK-2-immortalized renal cells, using calcein acetoxymethylester (calcein-AM) as a P-gp substrate. 2 Among the endocannabinoid molecules tested, anandamide ( AEA), but not 2-arachidonoyl-glycerol (2-AG) or palmitoyl-ethanolamide ( PEA), increased the intracellular fluorescence emitted by calcein, a metabolic derivative of the P-gp substrate calcein-AM, indicative of a reduction in transport capacity. 3 All the three synthetic cannabimimetics tested, that is, R-(+)-methanandamide (R(+)-MET), AM 251 and CP55,940 significantly increased calcein accumulation in the cytosol. 4 RT-PCR demonstrated that HK-2 cells do not express CB1 or CB2 cannabinoid receptors. 5 R(+)-MET, AM251 and CP55,940 were also evaluated as modulators of P-gp expression, by Western blot analysis. Only AM251 weakly enhanced the protein levels (by 1.2-fold) after a 4-day-long incubation with the noncytotoxic drug concentration 2 mu M. 6 The present data provide the first evidence that the endocannabinoid AEA and different synthetic cannabinoids may inhibit the P-gp activity in vitro via a cannabinoid receptor-independent mechanism.
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