[The effect of MDR1 gene polymorphism in the pathogenesis and the treatment of drug-resistant epilepsy].
Recent data indicate the possibility of P-glycoprotein involvement in drug resistance in patients diagnosed with epilepsia. It was demonstrated that P-glycoprotein is expressed in the endothelial cells of the blood-brain barrier, and in neurons and glial cells isolated from the epileptogenic brain tissue. The glycoprotein functions as an efflux pump, thus limiting penetration of antiepileptic drugs (phenytoin, carbamazepine, phenobarbital, gabapentin, felbamate, topiramate, lamotrigine) to the site of action. A naturally occurring MDR1 polymorphism has been described and correlated with potential clinical effects. The C3435T polymorphism was found to significantly correlate with the function of MDR1 and the expression of P-glycoprotein. This polymorphism consists of a C-to-T exchange at position 3435 in exon 26 of the MDR1 gene. Individuals with the TT genotype had significantly lower P-glycoprotein expression than those with the CC and CT genotype. Because C3435T does not change the amino acid sequence and is not located at a promotor position in the MDR1 gene, it is unlikely that this polymorphism directly influences P-glycoprotein expression. However, a strong association between the C3435T and G2677 (A, T) allele was revealed. Since G2677 (A, T) in exon 21 is a missense mutation, it is likely to be causative for differences in P-glycoprotein expression. Finding out the relationship between MDR-1 gen polymorphism and drug-resistant epilepsia may lead to the effective treatment of epilepsia by application of P-glycoprotein inhibitors.
Białecka
Monika
M
Zakład Farmakologii Doświadczalnej i Klinicznej, Katedra Farmakologii, Pomorska Akademia Medyczna, ul. Powstańców Wlkp. 72, 70-111 Szczecin. pbialecki@byss.pl
Hnatyszyn
Grazyna
G
Bielicka-Cymerman
Jolanta
J
Droździk
Marek
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism / Q000493:pharmacokinetics; D000927:Anticonvulsants / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D011110:Polymorphism, Genetic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants