title: Effects of EPHX1 and CYP3A4 polymorphisms on carbamazepine metabolism in epileptic patients.
abstract: BACKGROUND
  The aim of this study was to investigate the effect of two genetic polymorphisms in the coding regions (exon 3 and exon 4) of the EPHX1 gene, ie, 337T>C and 416A>G, respectively, on the metabolism of carbamazepine (CBZ) 10,11-epoxide (the active metabolite of CBZ) by evaluating the variation in serum CBZ 10,11-epoxide levels 4 hours after administration of the drug. Moreover, we reported the genotype frequencies of the CYP3A4*22 (rs 35599367, C>T) variant and its influence on the metabolism of CBZ.
  
  
  METHODS
  The analysis was performed in 50 patients receiving CBZ as monotherapy. DNA was extracted from leukocytes using a commercially available kit. Serum CBZ 10,11-epoxide levels were measured by high-performance liquid chromatography. Allelic discrimination was performed using polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis of the difference in mean values for CBZ 10,11-epoxide levels according to genotype was performed using the Student's t-test with Statistical Package for the Social Sciences version 13 software.
  
  
  RESULTS
  Fourteen percent of the study group were CC, 42% were CT, and 44% were TT for the EPHX1 337T>C variant. No GG homozygote was identified for the EPHX1 416A>G variant; 64% were AA and 36% were AG. When we compared serum CBZ 10,11-epoxide levels 4 hours after drug administration, we found no statistically significant difference between the 337 CC, CT, and TT genotypes. Similarly, no difference in serum CBZ 10,11-epoxide levels was found between 416A>G AA and AG. Genotype frequencies for the CYP3A4*22 (rs 35599367 C>T) allelic variant were 94% for CC and 6% for CT, with no statistically significant difference in serum CBZ 10,11-epoxide levels between these genotypes 4 hours after administration of the drug (2.6±1.3 μg/μL and 2.5±1.2 μg/μL, respectively).
  
  
  CONCLUSIONS
  Although there is some evidence of involvement of these polymorphisms in enzyme activity in vitro, we found no interference with CBZ metabolism in vivo.
authors.affiliation: Department of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Caruso
authors.affiliation: Department of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bellia
authors.affiliation: Department of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Pivetti
authors.affiliation: Department of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Agnello
authors.affiliation: Department of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Bazza
authors.affiliation: Department of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Scazzone
authors.affiliation: Department of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Bivona
authors.affiliation: Department of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
authors.forename: Bruna
authors.initials: B
authors.lastname: Lo Sasso
authors.affiliation: Department of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Ciaccio
keywords: 11-epoxide; CBZ 10; CYP3A4*22; EPHX1 gene; drug metabolism