Role of MDR1 C3435T and GABRG2 C588T Gene Polymorphisms in Seizure Occurrence and MDR1 Effect on Anti-Epileptic Drug (Phenytoin) Absorption

Shivani Ponnala,Jaydip Ray Chaudhari,Prabhakar Rao Kaipa,Momin Abdul Jaleel,Qurratulain Hasan,Dilnawaz Bhiladvala,Undurti N Das

doi:10.1089/gtmb.2011.0225

Abstract

To assess the role of MDR1 and gamma-aminobutyric acid receptor-gamma 2 sub unit (GABRG2) gene polymorphism in seizure susceptibility in generalized seizure (GS) and febrile seizure (FS) patients and to evaluate MDR1 C3435T gene polymorphism's role in absorption of the anti-epileptic drug, phenytoin (PHT) in a cohort of patients. One hundred twenty-seven cases of seizure (86 GS and 41 FS) patients were analyzed for MDR1 C3435T and GABRG2 C588T gene polymorphisms using restriction fragment length polymorphism-polymerase chain reaction. Serum PHT levels were analyzed. The T allele of MDR1 C3435T and GABRG2 C588T gene polymorphism was higher in GS in the Indian population compared with controls. From the data in GS, CT and TT genotype carriers of the MDR1 gene and TT genotype carriers of the GABRG2 gene had more recurrent seizures compared with others. MDR1 T allele carriers in the seizure reoccurrence (SR) group of GS and FS were high compared with the well-controlled seizure group (with no seizures after treatment). TT genotype carriers in SR group were high in FS (with regard to MDR1 gene polymorphism) and GS (with regard to GABRG2 gene polymorphism) compared with a well-controlled seizure group. MDR1 C3435T gene polymorphism affects serum PHT levels (p<0.015). Association of dose PHT ratio and genotype groups of MDR1 C3435T gene polymorphism showed a significant association (p<0.05). MDR1*CC genotype was more common in cases with low serum PHT levels.In addition, it is evident that CT and TT genotype carriers have a high percentage of SR with elevated serum PHT levels. Our results show that the MDR1 3435T and GABRG2 588T alleles play a role in seizure occurrence. Moreover, the MDR1 3435T allele also affects PHT absorption. We suggest MDR1 C3435T and GABRG2 C588T genotyping would be of value in order to lower the risk of concentration-dependent drug toxicity and for better patient management.

Highlights

Epilepsy is a common chronic neurological condition that is characterized by recurrent unprovoked seizures
41 infants/children with febrile seizures (FS) below the age of 5 years were selected based on the clinical symptoms and electroencephalogram findings
CT genotype carriers were high in FS cases compared with the controls

Summary

Introduction

Epilepsy is a common chronic neurological condition that is characterized by recurrent unprovoked seizures. Two most common seizure types are generalized seizures (GS) affecting adults and febrile seizures (FS) affecting children. MDR1 functions in an energy-dependent manner by exporting substances from the inside of cells to the outside. MDR1 and other transporters form an important class of proteins for regulating pharmacokinetics. MDR1 exports a number of structurally unrelated drugs (Marzolini et al, 2004; Pauli-Magnus and Kroetz, 2004). They play an important role in selective absorption and elimination of endogenous substances and xenobiotics, including drugs (Kim, 2002). Decreased expression of MDR1 due to alteration in the gene is known to affect the response of antiepileptic drugs (AEDs) (Amara and Sonders, 1998)

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