Effect of MDR1 Haplotype on Risk of Parkinson Disease

Abstract

Background: MDR1, a multidrug transporter, encodes a P-glycoprotein that regulates the bioavailability of xenobiotics and is highly expressed at the blood-brainbarrier. Two single nucleotide polymorphisms (SNPs) (e21/ 2677[G/T/A] and e26/3435[C/T]) in the MDR1 gene can lead to differences in MDR1 expression and function. Specific MDR1 alleles of the 2 SNPs are positively selected among ethnic Chinese but not in the white population.

Absence of P-Glycoprotein Transport in the Pharmacokinetics and Toxicity of the Herbicide Paraquat

“…Several studies have described an association between ABCB1 pharmacogenomics and susceptibility to Parkinson disease (Le Couteur et al, 2001;Furuno et al, 2002;Drozdzik et al, 2003;Lee and Bendayan, 2004;Tan et al, 2004Tan et al, , 2005Kortekaas et al, 2005;Bartels et al, 2008Bartels et al, , 2009Westerlund et al, 2008Westerlund et al, , 2009Vautier and Fernandez, 2009;Dutheil et al, 2010). One mechanism may be that ABCB1 genetic variation decreases P-gp activity at the bloodbrain barrier, leading to increased brain accumulation of neurotoxicants and an increased incidence of Parkinson disease.…”

“…Although P-gp plays an important role in the pharmacokinetics and disposition of drugs from many therapeutic classes, there is less evidence for the role of P-gp in toxicant disposition. P-gp has also been associated with a number of diseases, including Parkinson disease (Le Couteur et al, 2001;Furuno et al, 2002;Drozdzik et al, 2003;Lee and Bendayan, 2004;Tan et al, 2004Tan et al, , 2005Kortekaas et al, 2005;Bartels et al, 2008Bartels et al, , 2009Westerlund et al, 2008Westerlund et al, , 2009Vautier and Fernandez, 2009;Dutheil et al, 2010). Although exposure to neurotoxic xenobiotics is a well-known risk factor in Parkinson disease, it is unknown whether P-gp mediates the transport of these compounds (Langston et al, 1984;Semchuk et al, 1992;Bonnet and Houeto, 1999;Gatto et al, 2009;Wirdefeldt et al, 2011;Kamel, 2013;Mostafalou and Abdollahi, 2013;Pezzoli and Cereda, 2013).…”

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

“…The 1236C>T and 2677G>T/A/C polymorphisms have also been linked to several diseases such as pharmacoresistant epilepsy and Parkinsons disease [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Studies on these polymorphisms have yielded contradictory results, possibly due to small sample sizes and the isolated nature of the study populations.…”

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

“…A role for P-glycoprotein in neurodegenerative diseases has been examined for Alzheimer's disease and to a lesser extent for Parkinson's disease. For the latter, there seem to be positive and negative associations between specific MDR1 haplotypes and disease incidence (Furuno et al, 2002;Droździk et al, 2003;Tan et al, 2004aTan et al, , 2005, although mechanisms underlying these associations are still unclear.…”