Balkan Journal of Medical Genetics

RLIP76 GENE VARIANTS ARE NOT ASSOCIATED WITH DRUG RESPONSE IN TURKISH EPILEPSY PATIENTS
Manguoğlu E1,*, Akdeniz S1, Dündar NO2, Duman Ö2, Aktekin B3, Haspolat Ş2, Bilge U4, Özel D4, Lüleci G1
*Corresponding Author: Esra Manguoğlu, Department of Medical Biology and Genetics, Faculty of Medicine, Akdeniz University, Antalya, Turkey; Tel.: +90-242-249-6977; Fax: +90-242-249-6906; E-mail: emanguoglu@akdeniz.edu.tr
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INTRODUCTION

Drug resistance in epilepsy is one of major obstacles in clinical medicine. In a 37-year follow-up study, 67% of 144 patients were reported to be in remission at the end of follow-up, while 14% of the patients relapsed after a period of remission and did not re-enter remission, and remaining 19% of the patients never entered remission during the whole period of follow-up [1]. Optimum doses of anti-epileptic drugs (AEDs), prognosis and treatment outcomes showed considerable variation in the patients and could mostly be attributed to genetic variation between individuals [2]. Genetic variants of some proteins that are responsible for drug absorption, distribution, metabolism and elimination, have been extensively studied [3]. The RalA binding protein 1 (RLIP76 or RALBP1) is a protein that has been proposed to be associated with drug resistance in epilepsy [4]. It binds ras-related v-ral simian leukemia viral oncogene homolog A (RalA) and modulates the Rho pathway through the Ras pathway [5]. It is also involved in the transport of glutathione (GSH) conjugates and xenobiotics and in modulating drug sensitivity in cancer cells [6]. It was shown that RLIP76 is the major ATP-dependent transporter of GSH conjugates as well as doxorubicin in human erythrocytes [7]. More recently, Rossé et al. [8], proposed that RLIP76 is required for Epsin phosphorylation to switch endoyctosis off. RLIP76 was shown to be required as an effector for PKCα that is protein kinase transmitting downstream signals in response to stressors such as chemotherapeutic agents [9]. Moreover, RLIP76 is induced by oxidative stress and has been suggested to play a role in insulin resistance under increased oxidative stress [10]. RLIP76 is expressed in normal human breast, heart, liver, erythrocytes, and, to a lesser extent in colon and brain parenchymal tissues [4]. Blood vessels from refractory and non refractory epileptic brain tissues showed higher levels of expression, predominantly in the endothelium. It was also demonstrated that RLIP76 is an important carbamazepine and phenytoin transporter in human epileptic brain tissue. As a result, investigators proposed that RLIP76 might be involved in a drug-resistant epilepsy mechanism [4]. On the contrary, immunohistochemical analysis revealed that RLIP76 was co-localized with a neuronal, but not epithelial marker, in normal and epileptic brain tissues. In addition, no association was found between six common single nucleotide polymorphisms (SNPs) of the RLIP76 gene and 262 drug-responsive and 107 drug-resistant patients. Also, no correlation was found for susceptibility for epilepsy in 783 epilepsy patient and 359 healthy controls [11]. Moreover, a separate study failed to show any association between 13 common RLIP76 polymorphisms and drug-response in epilepsy in a prospective cohort of 503 epilepsy patients [12]. In this study, to further investigate the association between RLIP76 and drug response in epilepsy, we performed genotype analysis for the RLIP76 gene and statistical analyses for any association in refractory and drug-responsive groups.

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