Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 203, Issue 2, Pages 430-439Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2013.03.009
Keywords
P-glycoprotein; Avermectin; Calcium; Chloride; NF-kappa B
Funding
- National Basic Research Program of China [2012CB114103]
- National Natural Science Foundation of China [31272365]
- State Key Laboratory of IPM [ChineseIPM1005]
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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 ([Ca2+](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 Ca2+ channel blocker, and niflumic acid, a chloride channel antagonist, significantly attenuated AVM-induced [Ca2+](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 [Ca2+](i), implying that P-gp and [Ca2+](i) regulate each other. Finally, we found that trifluoperazine, a calmodulin inhibitor, and pyrrolidine dithiocarbamic acid, an NF-kappa B inhibitor, attenuated the AVM-induced expression of P-gp, suggesting that AVM induces P-gp protein expression via the calmodulin/Relish (NF-kappa B) signaling pathway. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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