Cytochrome P450 gene and pediatric epilepsy: An observational study

Abstract

Background: One of the metabolic processes of sodium valproate (SV) metabolism is cytochrome P450 (CYP)-mediated oxidation. Polymorphism of the genes coding CYP enzymes can cause the changes in steady state SV concentration and clinical outcome. The study's objective was to explore the CYP gene polymorphism patterns in pediatric epileptic patients and its influence on SV concentration and clinical outcome. Methods: Ninety-nine pediatric epileptics aged 2–18 years who were receiving SV monotherapy were included in this cohort study. Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR-RFLP) method was adopted to examine the genetic polymorphism patterns of CYP2C9*2 and CYP3A4*1B. HPLC was used to estimate the serum valproate concentration at the trough level. SPSS 23 was used to examine the relationship between SV concentration and CYP genotypes. Analysis of variance test was utilized, and a P < 0.05 was regarded statistically significant. Results: PCR-RFLP showed homozygous pattern (GG wild type) was observed in 37.3%, whereas heterozygous in 46.6% (mutant GA) and homozygous recessive (AA) in 16.1% patients in CYP3A4*1B (G331A). Homozygous (CC-Wild) and heterozygous (CT) pattern of polymorphism was observed in 90% and 10% patients in CYP2C9*2 (C430T). The mean serum valproate concentration assayed was 105.40 ± 49.9 μg/ml. The associations between the gene polymorphism of CYP3A4*1B (G331A) and CYP2C9*2 (C375T) with SV concentration were insignificant, The SNPs were not in equilibrium. The study findings indicated that patients of homozygous (wild type) CYP2C9*2 had bad clinical outcome compared to other patterns, although statistically insignificant. Conclusions: The association of serum concentration of SV with the different alleles of CYP3A4*1B and CYP2C9*2 was insignificant. SV should be cautiously used in patients with homozygous pattern of CYP2C9*2 due to concern of recurrent seizure episodes. The study may be of great use in personalized therapy in pediatric epilepsy.

Keywords

• allele frequencies
• biotransformation
• pharmacogenetics
• single nucleotide polymorphisms
• sodium valproate