Publication: Fenitoin tedavisinde genetik polimorfizmin önemi
Abstract
Sitokrom P-450 2C9 (CYP2C9) ve 2C19 (CYP2C19) enzimleri fenitoinin metabolizmasından sorumludurlar. Her bir enzim için aktiviteyi etkileyen iki önemli mutasyon tanımlanmıştır. Bu mutasyonlar; CYP2C9*2 (Arg144Cys; 430C → T 3. ekson), CYP2C9*3 (Ile359Leu; 1075A → T 7. ekson), CYP2C19*2 (681G → 5. ekson) ve CYP2C19*3 (636G → A 4. ekson) mutasyonlarıdır. Bu çalışmanın amacı, epilepsinin tedavisi ve/ veya proflaksisi amacıyla fenitoin kullanan Türk hasta popülasyonunda CYP2C9*2, CYP2C9*3, CYP2C19*2 ve CYP2C19*3 alelik varyant frekanslarını saptamak ve genotip-fenotip ilişkisini göstermektir. Çalışmamızda CYP2C9*2 , CYP2C9*3, CYP2C19*2 ve CYP2C19*3 alel varyantları fenitoin kullanan 102 hastada tanımlandı. Genomik DNA periferik lökositlerden elde edilerek polimeraz zincir reaksiyonu (PCR) ve restriksiyon parça uzunluk polimorfizmi (RFLP) ile alelik varyantlar tanımlandı. Çalışma grubunda CYP2C9 ve CYP2C19 genotip sıklıkları CYP2C9*1/ *1-CYP2C19*1/ *1, CYP2C9*1/ *1-CYP2C19*1/ *2, CYP2C9*1/ *1-CYP2C19*1/ *3, CYP2C9*1/ *1-CYP2C19*2/ *3, CYP2C9*1/ *2-CYP2C19*1/ *1, CYP2C9*1/ *2-CYP2C19*1/ *2, CYP2C9*1/ *2-CYP2C19*1/ *3, CYP2C9*1/ *3-CYP2C19*2/ *3, CYP2C9*1/ *3-CYP2C19*1/ *3, CYP2C9*1/ *1-CYP2C19*2/ *2, CYP2C9*1/ *3-CYP2C19*1/ *1 genotip grupları için sırasıyla % 41.17, % 15.68, % 7.84, % 7.84, % 11.76 , % 1.96, % 0.98, %1.96, % 1.96, % 5.88, % 2.94 olarak, ortalama plazma fenitoin konsantrasyonları ise 7.43 µg/ ml, 9.16 µg/ ml, 7.51 µg/ ml, 10.35 mg/ ml, 8.90 mg/ ml, 14.8 mg/ ml, 16.2 mg/ ml, 27.9 mg/ ml, 10.0 µg/ ml, 9.8 µg/ ml ve 10.47 µg/ ml olarak saptandı. Bulgularımızdan CYP2C9 ve CYP2C19 mutasyonlarının görülme sıklıklarının diğer bazı Avrupa toplumları için bildirilen değerle birebir aynı olmasa da yakın olduğu saptandı. Ayrıca sonuçlarımız bazı CYP2C9 ve CYP2C19 genotipleri ve fenitoin dozu arasında ilişki olduğunu gösterdi. Bu sonuçlar bize genotiplemenin, etkin fenitoin tedavisini sağlamak için ve mutant taşıyıcılarda fenitoinin konsantrasyonuna bağlı toksikasyon riskinin en aza indirilmesi için rutin tedavide kullanılabileceğini düşündürmektedir. THE IMPORTANCE OF GENETIC POLYMORPHISM IN PHENYTOIN THERAPY
The cytocrom P-450 2C9 (CYP2C9) and 2C19 (CYP2C19) enzymes are responsible for the metabolism of phenytoin. Two mutations which were determined to influence the activation of CYP2C9 and CYP2C19 are CYP2C9*2 (Arg144Cys; 430C → T in exon 3), CYP2C9*3 (Ile359Leu; 1075A → T in exon 7), CYP2C19*2 (681G → A in exon 5) and CYP2C19*3 (636G → A in exon 4). The aim of this study was to determine the genetic frequency of the CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 allelic variants in Turkish patients who received phenytoin. The frequency of the CYP2C9*2 , CYP2C9*3, CYP2C19*2 and CYP2C19*3 allelic variants were examined in 102 patients. Allelic variants was carried out using polymerase chain reaction (PCR) and restriction fragment lenght polymorphism (RFLP). The frequencies of the CYP2C9 and CYP2C19 genotypes in the study group were found to be % 41.17, % 15.68, % 7.84, % 7.84, % 11.76 , % 1.96, % 0.98, %1.96, % 1.96, %5.88, %2.94 and mean plasma phenytoin concentrations to be 7.43 µg/ ml, 9.16 µg/ ml, 7.51 µg/ ml, 10.35 mg/ ml, 8.90 mg/ ml, 14.8 mg/ ml, 16.2 mg/ ml, 27.9 mg/ ml, 10.0 µg/ ml, 9.8 µg/ ml and 10.47 µg/ ml for CYP2C9*1/ *1-CYP2C19*1/ *1, CYP2C9*1/ *1-CYP2C19*1/ *2, CYP2C9*1/ *1-CYP2C19*1/ *3, CYP2C9*1/ *1-CYP2C19*2/ *3, CYP2C9*1/ *2-CYP2C19*1/ *1, CYP2C9*1/ *2-CYP2C19*1/ *2, CYP2C9*1/ *2-CYP2C19*1/ *3, CYP2C9*1/ *3-CYP2C19*2/ *3, CYP2C9*1/ *3-CYP2C19*1/ *3, CYP2C9*1/ *1-CYP2C19*2/ *2, CYP2C9*1/ *3-CYP2C19*1/ *1 genotype groups respectively. The mutation frequency of the CYP2C9 and CYP2C19 does not differ from that of some Europan communities. The results show that there is a correlation between some CYP2C9 and CYP2C19 genotypes and phenytoin dose requirement. It is suggested that genotyping can be used routinely to obtain efficient phenytoin therapy.
The cytocrom P-450 2C9 (CYP2C9) and 2C19 (CYP2C19) enzymes are responsible for the metabolism of phenytoin. Two mutations which were determined to influence the activation of CYP2C9 and CYP2C19 are CYP2C9*2 (Arg144Cys; 430C → T in exon 3), CYP2C9*3 (Ile359Leu; 1075A → T in exon 7), CYP2C19*2 (681G → A in exon 5) and CYP2C19*3 (636G → A in exon 4). The aim of this study was to determine the genetic frequency of the CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 allelic variants in Turkish patients who received phenytoin. The frequency of the CYP2C9*2 , CYP2C9*3, CYP2C19*2 and CYP2C19*3 allelic variants were examined in 102 patients. Allelic variants was carried out using polymerase chain reaction (PCR) and restriction fragment lenght polymorphism (RFLP). The frequencies of the CYP2C9 and CYP2C19 genotypes in the study group were found to be % 41.17, % 15.68, % 7.84, % 7.84, % 11.76 , % 1.96, % 0.98, %1.96, % 1.96, %5.88, %2.94 and mean plasma phenytoin concentrations to be 7.43 µg/ ml, 9.16 µg/ ml, 7.51 µg/ ml, 10.35 mg/ ml, 8.90 mg/ ml, 14.8 mg/ ml, 16.2 mg/ ml, 27.9 mg/ ml, 10.0 µg/ ml, 9.8 µg/ ml and 10.47 µg/ ml for CYP2C9*1/ *1-CYP2C19*1/ *1, CYP2C9*1/ *1-CYP2C19*1/ *2, CYP2C9*1/ *1-CYP2C19*1/ *3, CYP2C9*1/ *1-CYP2C19*2/ *3, CYP2C9*1/ *2-CYP2C19*1/ *1, CYP2C9*1/ *2-CYP2C19*1/ *2, CYP2C9*1/ *2-CYP2C19*1/ *3, CYP2C9*1/ *3-CYP2C19*2/ *3, CYP2C9*1/ *3-CYP2C19*1/ *3, CYP2C9*1/ *1-CYP2C19*2/ *2, CYP2C9*1/ *3-CYP2C19*1/ *1 genotype groups respectively. The mutation frequency of the CYP2C9 and CYP2C19 does not differ from that of some Europan communities. The results show that there is a correlation between some CYP2C9 and CYP2C19 genotypes and phenytoin dose requirement. It is suggested that genotyping can be used routinely to obtain efficient phenytoin therapy.