Abstract：
:Avermectin (AVM) is a macrocyclic lactone agent widely used as a nematicide, acaricide and insecticide in veterinary medicine and plant protection. P-glycoprotein (P-gp) is an ATP-dependent drug efflux pump for xenobiotic compounds, and is involved in multidrug resistance. To understand the development of AVM resistance in invertebrates, we investigated the mechanisms by which AVM affected P-gp expression in Drosophila S2 cells. We found that AVM induced upregulation of P-gp protein expression, increased P-gp ATPase activity and enhanced cellular efflux of the P-gp substrate rhodamine 123 from cells. Furthermore, we observed that AVM-induced expression of P-gp was due to elevation of intracellular calcium concentration ([Ca(2+)](i)). This occurred both directly, by activating calcium ion channels, and indirectly, by activating chloride ion channels. These results are supported by our observations that verapamil, a Ca(2+) channel blocker, and niflumic acid, a chloride channel antagonist, significantly attenuated AVM-induced [Ca(2+)](i) elevation, thereby reducing P-gp expression. Inhibition of P-gp with anti-P-gp antibody or cyclosporine A (a P-gp inhibitor) reduced the AVM-induced elevation of [Ca(2+)](i), implying that P-gp and [Ca(2+)](i) regulate each other. Finally, we found that trifluoperazine, a calmodulin inhibitor, and pyrrolidine dithiocarbamic acid, an NF-κB inhibitor, attenuated the AVM-induced expression of P-gp, suggesting that AVM induces P-gp protein expression via the calmodulin/Relish (NF-κB) signaling pathway.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Luo L,Sun YJ,Yang L,Huang S,Wu YJdoi
10.1016/j.cbi.2013.03.009subject
Has Abstractpub_date
2013-04-25 00:00:00pages
430-9issue
2eissn
0009-2797issn
1872-7786pii
S0009-2797(13)00070-7journal_volume
203pub_type
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