Authors: Neil Macdonald Alex Gledhill
Publish Date: 2007/03/13
Volume: 81, Issue: 8, Pages: 553-563
Abstract
Several members of the ATP binding cassette ABC transporter protein superfamily perform xenobiotic efflux functions in mammals limiting gut absorption mediating excretion and controlling entry of a wide range of chemicals to sensitive compartments such as brain testes and foetus Perhaps the best characterised of these is pglycoprotein gene name ABCB1/MDR1 a barrier epithelia expressed protein with structurally diverse substrates including the avermectin pesticides In specific mouse and dog strains ABCB1 mutations have been identified that result in loss of pglycoprotein function in the blood brain barrier BBB and increased susceptibility to avermectin neurotoxicity As yet no large rearrangements of the human ABCB1 gene analogous to those in the mouse and dog have been identified However numerous human ABCB1 single nucleotide polymorphisms SNPs have been identified the allelic frequencies of which vary with ethnicity There is no clear consensus on whether or not SNPs or combinations of SNPs reduce human pglycoprotein functionality However recent in vivo human data indicate that the two commonest ABCB1 haplotypes both exhibit full BBB functionality We discuss here the role of pglycoprotein in limiting brain absorption of avermectin pesticides as well as the potential impact of the reported functional effects and population frequencies of known ABCB1 polymorphisms on avermectin pesticide risk assessments
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