Effect of MDR1 Haplotype on Risk of Parkinson Disease

Tan, Eng‐King; Chan, Daniel Kam-Yin; Ng, Ping-Wing; Woo, Jean; Teo, Yik-Ying; Tang, Kun; Wong, Li-Peng; Chong, Samuel S.; Tan, Celia Ia Choo; Shen, Hui; Zhao, Yongxiang; Lee, Caroline

doi:10.1001/archneur.62.3.460

Cited by 63 publications

(47 citation statements)

References 27 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

Lacher

Gremaud

Skagen

et al. 2013

J Pharmacol Exp Ther

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Genetic variation in the multidrug resistance gene ABCB1, which encodes the efflux transporter P-glycoprotein (P-gp), has been associated with Parkinson disease. Our goal was to investigate P-gp transport of paraquat, a Parkinson-associated neurotoxicant. We used in vitro transport models of ATPase activity, xenobiotic-induced cytotoxicity, transepithelial permeability, and rhodamine-123 inhibition. We also measured paraquat pharmacokinetics and brain distribution in Friend leukemia virus B-type (FVB) wild-type and P-gp-deficient (mdr1a 2/2 / mdr1b 2/2 ) mice following 10, 25, 50, and 100 mg/kg oral doses. In vitro data showed that: 1) paraquat failed to stimulate ATPase activity; 2) resistance to paraquat-induced cytotoxicity was unchanged in P-gp-expressing cells in the absence or presence of P-gp inhibitors GF120918 [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] and verapamil-37.0 [95% confidence interval (CI): 33.2-41.4], 46.2 (42.5-50.2), and 34.1 mM (31.2-37.2)-respectively; 3) transepithelial permeability ratios of paraquat were the same in P-gp-expressing and nonexpressing cells (1.55 6 0.39 and 1.39 6 0.43, respectively); and 4) paraquat did not inhibit rhodamine-123 transport. Population pharmacokinetic modeling revealed minor differences between FVB wild-type and mdr1a 2/2 /mdr1b 2/2 mice: clearances of 0.47 [95% confidence interval (CI): 0.42-0.52] and 0.78 l/h (0.58-0.98), respectively, and volume of distributions of 1.77 (95% CI: 1.50-2.04) and 3.36 liters (2.39-4.33), respectively; however, the change in clearance was in the opposite direction of what would be expected. It is noteworthy that paraquat brain-to-plasma partitioning ratios and total brain accumulation were the same across doses between FVB wildtype and mdr1a 2/2 /mdr1b 2/2 mice. These studies indicate that paraquat is not a P-gp substrate. Therefore, the association between ABCB1 pharmacogenomics and Parkinson disease is not attributed to alterations in paraquat transport.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Lacher

Gremaud

Skagen

et al. 2013

J Pharmacol Exp Ther

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

et al. 2006

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Introduction-The human multi-drug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anti-cancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene which may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C>T, 2677G>T, and 3435C>T have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related.

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“…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.…”

Section: P-glycoprotein At the Blood-brain Barrier 203mentioning

confidence: 99%