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Title: The importance of efflux transporters in CNS exposure to avermectin insecticides
Author: Dalzell, Abigail Mary
ISNI:       0000 0004 2730 870X
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2012
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Avermectins are macrocyclic lactones insecticides, used as antihelminthics in humans and animals, since they have low human toxicity. There is a clear role for the efflux transporter mdr1 controlling CNS exposure to avermectins in polymorphic animal models, but the role of MDR1 in limiting human avermectin exposure is less well defined, although no such knockout MDR1 polymorphisms have been identified to date. The aim of this study was to characterise the kinetics of avermectin interactions with efflux transporters in the human SHSY5Y neuroblastoma cell line, and compare them with mouse isoforms expressed in N2a cells to determine the relevance of mouse data to human avermectin exposure. Protein and mRNA expression of human MDR1, MRP and mouse mdr1a were identified in the cell lines, similar to the blood-brain barrier except BCRP and bcrp were absent. Ki values for inhibition of MDR1 or MRP substrate efflux by avermectins did not differ significantly between human and mouse cells (P > 0.05); abamectin (MDR1 Ki = 0.95 ± 0.08μM; mdr1a Ki = 0.77 ± 0.25μM), emamectin benzoate (MDR1 Ki = 0.60 ± 0.07μM; mdr1a Ki = 0.56 ± 0.02μM) and ivermectin (MDR1 Ki = 0.24 ± 0.08μM; mdr1a Ki = 0.18 ± 0.02μM), but ivermectin has the highest affinity for inhibition of MDR1- and mdr1a-substrate efflux. Cytotoxicity was apparent for emamectin benzoate above 6μM, which is 100-fold higher than peak exposure concentrations, but not for abamectin or ivermectin. Expression levels of the chemokine genes SDF-2, AIMP1 and BDNF are candidates for biomarkers of avermectin exposure. These data show that SH-SY5Y cells are a good model in which to investigate avermectin exposure and to compare to mouse cells and have confirmed the involvement of MDR1 and MRP transporters. Avermectins are of global importance, so a greater understanding of mechanisms of human exposure is pertinent.
Supervisor: Not available Sponsor: Syngenta
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available