Lack of support for a role for RLIP76 (RALBP1) in response to treatment or predisposition to epilepsy

Background: Multidrug transporters are postulated to contribute to antiepileptic drug (AED) resistance. The transporter best studied is P-glycoprotein, an ATP-Binding Cassette (ABC) transporter superfamily member. RLIP76 is suggested to be an energy-dependent non-ABC transporter, reducing AED blood-brain barrier penetration, with a more important role than P-glycoprotein. Knowledge of which transporters may be critical in drug resistance is important for design of potential therapies. We tested the hypothesis that RLIP76 mediates AED resistance using methods complementary to those in the original report. Methods: Double-labeling fluorescent immunohistochemistry localized RLIP76 expression. Population genetics was used to explore association of variation in the RLIP76-encoding gene with drug-response and epilepsy phenotypes. Comparative protein structure modeling and bioinformatic annotation were used to predict RLIP76 structure and features. Results: In normal and epileptogenic brain tissue, immunoreactivity for RLIP76 was cytoplasmic, with colocalization with a neuronal, but not an endothelial, marker. Genotyping of six tagging SNPs, representing common genetic variation in RLIP76, in patients with epilepsy responsive (n = 262) or resistant (n = 107) to AEDs showed no association with phenotype at any level. RLIP76 genotypic and haplotypic frequencies in 783 patients with epilepsy and 359 healthy controls showed no association with epilepsy susceptibility. RLIP76 is not predicted to have transmembrane localization or ATPase activity. Conclusions: No support for RLIP76 itself in directly mediating resistance to AEDs nor in increasing susceptibility to epilepsy was found. More evidence is required before either a role for RLIP76 in drug resistance can be accepted or focus directed away from other transporters, such as P-glycoprotein.