Potential impact of ABCB1 (p-glycoprotein) polymorphisms on avermectin toxicity in humans.
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 p-glycoprotein (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 p-glycoprotein 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 p-glycoprotein 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 p-glycoprotein 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.
Macdonald
Neil
N
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ, UK.
Gledhill
Alex
A
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D010575:Pesticides / Q000493:pharmacokinetics / Q000633:toxicity*; D011110:Polymorphism, Genetic
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010575:Pesticides; D007559:Ivermectin; C019264:avermectin