CYP2D6、CYP2C9、CYP2C19和CYP3A4基因变异对难治性癫痫患儿抗癫痫药物代谢的影响。
Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy.
作者信息
López-García Miguel A, Feria-Romero Iris A, Serrano Héctor, Rayo-Mares Darío, Fagiolino Pietro, Vázquez Marta, Escamilla-Núñez Consuelo, Grijalva Israel, Escalante-Santiago David, Orozco-Suarez Sandra
机构信息
Programa de Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Unidad-Iztapalapa, Ciudad de México, México; Unidad de Investigación Médica en Enfermedades Neurológicas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.
Unidad de Investigación Médica en Enfermedades Neurológicas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México.
出版信息
Pharmacol Rep. 2017 Jun;69(3):504-511. doi: 10.1016/j.pharep.2017.01.007. Epub 2017 Jan 19.
BACKGROUND
Identified the polymorphisms of CYP2D6, CYP2C9, CYP2C19 and CYP3A4, within a rigorously selected population of pediatric patients with drug-resistant epilepsy.
METHOD
The genomic DNA of 23 drug-resistant epilepsy patients and 7 patients with good responses were analyzed. Ten exons in these four genes were genotyped, and the drug concentrations in saliva and plasma were determined.
RESULTS
The relevant SNPs with pharmacogenomics relations were CYP2D62 (rs16947) decreased your activity and CYP2D64 (rs1065852), CYP2C192 (rs4244285) and CYP3A41B (rs2740574) by association with poor metabolizer. The strongest risk factors were found in the AA genotype and allele of SNP rs3892097 from the CYP2D6 gene, followed by the alleles A and T of SNPs rs2740574 and rs2687116, respectively from CYP3A4. The most important concomitance was between homozygous genotype AA of rs3892097 and genotype AA of rs2740574 with 78.3% in drug-resistant epilepsy patients as compared to 14.3% in control patients.
CONCLUSION
The results demonstrated the important role of the CYP 3A4*1B allelic variant as risk factor for developing drug resistance and CYP2D6, CYP2C19 SNPs and haplotypes may affect the response to antiepileptic drugs.
背景
在经过严格挑选的耐药性癫痫患儿群体中，鉴定CYP2D6、CYP2C9、CYP2C19和CYP3A4的多态性。
方法
分析23例耐药性癫痫患者和7例反应良好患者的基因组DNA。对这四个基因的十个外显子进行基因分型，并测定唾液和血浆中的药物浓度。
结果
与药物基因组学相关的单核苷酸多态性（SNP）有：CYP2D62（rs16947）降低其活性，以及与代谢不良相关的CYP2D64（rs1065852）、CYP2C192（rs4244285）和CYP3A41B（rs2740574）。在CYP2D6基因的SNP rs3892097的AA基因型和等位基因中发现最强的危险因素，其次分别是CYP3A4基因的SNP rs2740574和rs2687116的等位基因A和T。最重要的共存情况是rs3892097的纯合子基因型AA与rs2740574的基因型AA之间，耐药性癫痫患者中的比例为78.3%，而对照患者中为14.3%。
结论
结果表明CYP 3A4*1B等位基因变异作为耐药性发展的危险因素具有重要作用，CYP2D6、CYP2C19的SNP和单倍型可能影响对抗癫痫药物的反应。
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