Caruso Antonietta, Bellia Chiara, Pivetti Alessia, Agnello Luisa, Bazza Federica, Scazzone Concetta, Bivona Giulia, Lo Sasso Bruna, Ciaccio Marcello
Department of Biopathology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
Pharmgenomics Pers Med. 2014 Apr 2;7:117-20. doi: 10.2147/PGPM.S55548. eCollection 2014.
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.
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.
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).
Although there is some evidence of involvement of these polymorphisms in enzyme activity in vitro, we found no interference with CBZ metabolism in vivo.
本研究旨在通过评估给药4小时后血清卡马西平（CBZ）10,11 - 环氧化物（CBZ的活性代谢产物）水平的变化，研究EPHX1基因编码区（外显子3和外显子4）的两种基因多态性，即分别为337T>C和416A>G，对CBZ代谢的影响。此外，我们报告了CYP3A4*22（rs 35599367，C>T）变体的基因型频率及其对CBZ代谢的影响。
对50例接受CBZ单药治疗的患者进行分析。使用市售试剂盒从白细胞中提取DNA。采用高效液相色谱法测定血清CBZ 10,11 - 环氧化物水平。使用聚合酶链反应-限制性片段长度多态性进行等位基因鉴别。使用社会科学统计软件包13版软件的Student's t检验对根据基因型划分的CBZ 10,11 - 环氧化物水平平均值差异进行统计分析。
对于EPHX1 337T>C变体，研究组中14%为CC，42%为CT，44%为TT。未鉴定出EPHX1 416A>G变体的GG纯合子；64%为AA，36%为AG。当我们比较给药4小时后的血清CBZ 10,11 - 环氧化物水平时，发现337 CC、CT和TT基因型之间无统计学显著差异。同样，在416A>G的AA和AG之间，血清CBZ 10,11 - 环氧化物水平也无差异。CYP3A4*22（rs 35599367 C>T）等位基因变体的基因型频率为CC占94%，CT占6%，给药4小时后这些基因型之间的血清CBZ 10,11 - 环氧化物水平无统计学显著差异（分别为2.6±1.3μg/μL和2.5±1.2μg/μL）。
尽管有一些证据表明这些多态性在体外参与酶活性，但我们发现在体内对CBZ代谢无干扰。
