title: Role of MDR1 C3435T and GABRG2 C588T gene polymorphisms in seizure occurrence and MDR1 effect on anti-epileptic drug (phenytoin) absorption.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois, USA. sponnala@uic.edu
authors.forename: Shivani
authors.initials: S
authors.lastname: Ponnala
authors.forename: Jaydip Ray
authors.initials: JR
authors.lastname: Chaudhari
authors.forename: Momin Abdul
authors.initials: MA
authors.lastname: Jaleel
authors.forename: Dilnawaz
authors.initials: D
authors.lastname: Bhiladvala
authors.forename: Prabhakar Rao
authors.initials: PR
authors.lastname: Kaipa
authors.forename: Undurti N
authors.initials: UN
authors.lastname: Das
authors.forename: Qurratulain
authors.initials: Q
authors.lastname: Hasan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007194:India / Q000453:epidemiology; D007223:Infant; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D011963:Receptors, GABA-A / Q000235:genetics*; D012640:Seizures / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D003294:Seizures, Febrile / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; C546279:GABRG2 protein, human; D011963:Receptors, GABA-A; D010672:Phenytoin