ABCMdb

PMID: 16386926

Kim YO, Kim MK, Woo YJ, Lee MC, Kim JH, Park KW, Kim EY, Roh YI, Kim CJ
Single nucleotide polymorphisms in the multidrug resistance 1 gene in Korean epileptics.
Seizure. 2006 Jan;15(1):67-72., [PubMed]

Sentences

No. Mutations Sentence Comment

16 ABCB1 p.Thr1236Cys Among these proteins, P-glycoprotein 170, which is the product of the ATP-binding cassette subfamily b member 1 (ABCB1), also known as the multidrug resistance 1 (MDR1) gene, is the most extensively studied.4 P-glycoprotein 170 is an energy-dependent efflux pump that exports several antiepileptic drugs,4,6 including carbamazepine,7 phenytoin,8 phenobarbital, lamotrigine, and felbamate.9 Single nucleotide polymorphisms (SNPs) in the MDR1 gene have been described, including T1236C in exon 12, G2677T/A in exon 21, and C3435T in exon 26. Login to comment 62 ABCB1 p.Thr1236Cys But the BBB represents a serous obstacle in achieving appropriate drug concentrations in the CNS.19 The P-glycoprotein of an efflux transporter in the BBB is a 170-kDa transmembrane phosphoglycoprotein that is encoded by the MDR1 gene, which is located on chromosome 7 and consists of 28 exons.6,20 The P-glycoprotein expression levels in different tissues are not constant, but rather change in response to various agents and environmental factors.20 In epileptics, P-glycoprotein is overexpressed in endothelial cells of the BBB and is expressed at sites at which P-glycoprotein is not expressed in normal subjects, e.g., in astrocytes and neurons.21-23 Mutations in MDR1 influence the expression or function of P-glycoprotein in normal tissues.24 Approximately 28 SNPs have been identified in MDR1, among which the SNPs of T1236C in exon 12, G2677A/T in exon 21, and C3425T in exon 26 are the most commonly reported in normal subjects 70 Y.O. Kim et al. Table 3 Genotype frequencies at nucleotide site 2677 in exon 21 of MDR1 Genotype Genotype frequency, N (%) P value Odds ratio 95% C.I. RS [N, 99] RP [N, 107] GG 19 (19.2) 17 (15.9) 0.66 1.26 0.61-2.58 GT 33 (33.3) 40 (37.4) 0.64 0.84 0.47-1.48 GA 22 (22.2) 21 (19.6) 0.77 1.17 0.60-2.29 TA 12 (12.1) 15 (14.0) 0.84 0.85 0.37-1.91 TT 11 (11.1) 9 (8.4) 0.68 1.36 0.54-3.44 AA 2 (2.0) 5 (4.7) 0.49 0.42 0.08-2.22 N, total number; RS, patients with drug-resistant epilepsy; RP, patients with drug-responsive epilepsy. Login to comment 65 ABCB1 p.Thr1236Cys from different ethnic groups.15-17 The G2677A/T SNP in exon 21 is usually associated with an amino acid conversion from Ala to Thr and to Ser, respectively.15 On the other hand, the T1236C SNP in exon 12 is located in non-coding regions and the C3435T SNP in exon 26 does not lead to a change in the amino acid sequence.15 Nevertheless, silent SNPs may play important roles in drug resistance, since they may be in linkage disequilibrium with non-silent SNPs.3,15,25 The mutation at nucleotide position 3435 in exon 26 of MDR1 is the most frequently studied polymorphism in relation to multidrug resistance.3,10-12 Siddiqui et al.3 have reported an association between multidrug resistance in epileptics and the C3435T polymorphism in the drug transporter gene ABCB1. Login to comment 74 ABCB1 p.Thr1236Cys Moreover, MDR1 mutations may reveal the characteristics of specific MDR1 variants, which could lead to the development of inhibitors that are specific for individual variants.12 Single nucleotide polymorphisms 71 Table 5 Haplotype frequencies of three single nucleotide polymorphisms in the MDR1 gene Haplotype Haplotype frequency (%) P value Odds ratio 95% C.I. T1236C G2677T/A C3435T RS [N, 97] RP [N, 99] T G C 20.78 19.49 0.96 1.09 0.54-2.21 T G T 1.07 4.68 0.28 0.20 0.02-1.71 T T C 10.40 9.13 0.95 1.15 0.45-2.96 T T T 17.12 15.74 0.95 1.10 0.52-2.33 T A C 1.06 0.59 0.67 1.02 0.06-16.56 T A T 10.40 8.95 0.92 1.15 0.45-2.96 C G C 19.91 17.24 0.77 1.18 0.57-2.42 C G T 0.00 0.00 C T C 16.54 16.12 0.91 1.02 0.48-2.19 C T T 0.79 1.44 0.80 1.02 0.06-16.56 C A C 1.94 6.62 0.21 0.28 0.06-1.37 C A T 0.00 0.00 N, total number; RS, patients with drug-resistant epilepsy; RP, patients with drug-responsive epilepsy. Login to comment