Effects of EPHX1 and CYP3A4*22 genetic polymorphisms on carbamazepine metabolism and drug response among Tunisian epileptic patients.
The aim of this study was to evaluate the impact of polymorphisms in the EPHX1 (c.416A > G, c.337T > C) and CYP3A4*22 genes involved in carbamazepine (CBZ) metabolism and pharmacoresistance among 118 Tunisian patients with epilepsy under maintenance dose of CBZ. These genetic polymorphisms were analyzed by PCR-RFLP. Associations between plasma CBZ concentration, CBZ-E concentration, maintenance doses and metabolic ratio (CBZ-E:CBZ, CBZ-D:CBZ-E) were analyzed with each polymorphism. Both variants of EPHX1 c.416A > G and c.337T > C are significantly associated with higher metabolic ratio CBZ-E:CBZ and seem to decrease the activity of the epoxide hydrolase. The CYP3A4*22 variant allele is significantly associated with lower CBZ-D:CBZ-E ratio and seems also to be associated with less activity of the cytochrome. Our data suggest that certain polymorphisms of metabolizing enzyme genes could influence inter-individual variability of CBZ metabolism.
a Metabolic Biophysics, Professional Toxicology and Applied Environmental Laboratory, Department of Biophysics, Medicine Faculty of Sousse , Sousse University , Sousse , Tunisia ;
Chahra
C
Chbili
b Department of Pharmacovigilance, Faculty of Medicine of Sousse , Sousse University , Sousse , Tunisia ;
Neila
N
Fathallah
a Metabolic Biophysics, Professional Toxicology and Applied Environmental Laboratory, Department of Biophysics, Medicine Faculty of Sousse , Sousse University , Sousse , Tunisia ;
Aicha
A
Laouani
a Metabolic Biophysics, Professional Toxicology and Applied Environmental Laboratory, Department of Biophysics, Medicine Faculty of Sousse , Sousse University , Sousse , Tunisia ;
Manel
M
Nouira
c Neurology Department , Central Hospital University (CHU), Sousse University , Sousse , Tunisia.
Anis
A
Hassine
c Neurology Department , Central Hospital University (CHU), Sousse University , Sousse , Tunisia.
Sana
S
Ben Amor
c Neurology Department , Central Hospital University (CHU), Sousse University , Sousse , Tunisia.
Sofiene
S
Ben Ammou
b Department of Pharmacovigilance, Faculty of Medicine of Sousse , Sousse University , Sousse , Tunisia ;
Chaker
C
Ben Salem
a Metabolic Biophysics, Professional Toxicology and Applied Environmental Laboratory, Department of Biophysics, Medicine Faculty of Sousse , Sousse University , Sousse , Tunisia ;
Saad
S
Saguem
D000328:Adult; D000927:Anticonvulsants / Q000378:metabolism* / Q000627:therapeutic use; D002220:Carbamazepine / Q000378:metabolism* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014416:Tunisia
D000927:Anticonvulsants; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human
CYP3A4*22; EPHX1 gene; drug metabolism