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

Nicole Soranzo, Libusha Kelly, Lillian Martinian, Mari Wyn Burley, Maria Thom, Andrej Sali, Deanna L. Kroetz, David B. Goldstein, Sanjay M. Sisodiya

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)674-683
Number of pages10
JournalEpilepsia
Volume48
Issue number4
DOIs
StatePublished - Apr 2007
Externally publishedYes

Fingerprint

Epilepsy
Drug Resistance
P-Glycoprotein
Anticonvulsants
Phenotype
Therapeutics
ATP-Binding Cassette Transporters
Population Genetics
Computational Biology
Blood-Brain Barrier
Single Nucleotide Polymorphism
Adenosine Triphosphatases
Immunohistochemistry
Brain
Pharmaceutical Preparations
Genes
Proteins

Keywords

  • Antiepileptic
  • Drug transporter
  • Genetic association
  • RLIP76
  • Tagging SNPs

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Lack of support for a role for RLIP76 (RALBP1) in response to treatment or predisposition to epilepsy. / Soranzo, Nicole; Kelly, Libusha; Martinian, Lillian; Burley, Mari Wyn; Thom, Maria; Sali, Andrej; Kroetz, Deanna L.; Goldstein, David B.; Sisodiya, Sanjay M.

In: Epilepsia, Vol. 48, No. 4, 04.2007, p. 674-683.

Research output: Contribution to journalArticle

Soranzo, N, Kelly, L, Martinian, L, Burley, MW, Thom, M, Sali, A, Kroetz, DL, Goldstein, DB & Sisodiya, SM 2007, 'Lack of support for a role for RLIP76 (RALBP1) in response to treatment or predisposition to epilepsy', Epilepsia, vol. 48, no. 4, pp. 674-683. https://doi.org/10.1111/j.1528-1167.2007.00926.x
Soranzo, Nicole ; Kelly, Libusha ; Martinian, Lillian ; Burley, Mari Wyn ; Thom, Maria ; Sali, Andrej ; Kroetz, Deanna L. ; Goldstein, David B. ; Sisodiya, Sanjay M. / Lack of support for a role for RLIP76 (RALBP1) in response to treatment or predisposition to epilepsy. In: Epilepsia. 2007 ; Vol. 48, No. 4. pp. 674-683.
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AU - Soranzo, Nicole

AU - Kelly, Libusha

AU - Martinian, Lillian

AU - Burley, Mari Wyn

AU - Thom, Maria

AU - Sali, Andrej

AU - Kroetz, Deanna L.

AU - Goldstein, David B.

AU - Sisodiya, Sanjay M.

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KW - Genetic association

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KW - Tagging SNPs

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