Polymorphism in the P-glycoprotein drug transporter MDR1 gene

Abstract

P-glycoprotein is a membrane protein encoded by theMDR1gene, which demonstrates functional polymorphism. It is present in endothelial cells of the blood-brain barrier, thus limiting accumulation of its substrates in the central nervous system. Many epidemiological studies suggest an association between pesticides, which are substrates for P-glycoprotein, and Parkinson's disease. It was hypothesized that polymorphism of theMDR1gene could modulate interindividual susceptibility for the disease in subjects exposed to pesticides. In a pilot case-control study involving 107 Parkinson's disease patients (30 early onset and 77 late onset patients; 59 exposed to pesticides and 48 non-exposed) and 103 controls, C3435T polymorphism of the gene was analysed. No statistically significant correlation betweenMDR1gene polymorphism and Parkinson's disease was found. The 3435TT genotype was noted more frequently, but not significantly, in patients with early onset compared to late onset disease (23.3% versus 10.4%, respectively). A significant association between patients with parkinsonism exposed to pesticides and C3435T polymorphism of theMDR1gene was found. Comparing the exposed and non-exposed patients, a statistically higher frequency of heterozygous subjects was observed (72.9% versus 47.9%, respectively). This genotype was associated with a significant, almost three-fold increased risk of disease. Similarly, a higher frequency of 3435TT subjects was revealed in exposed subjects (15.5%) compared to non-exposed patients (12.5%). In exposed versus non-exposed subjects, patients carrying at least one 3435T allele (i.e. homozygous and heterozygous) had a significant, five-fold higher risk of Parkinson's disease. Thus, it appears that mutation of the MDR1 gene predisposes to damaging effects of pesticides, and possibly other toxic xenobiotics transported by P-glycoprotein, leading to Parkinson's disease.