Basic Silvio, Hajnsek Sanja, Bozina Nada, Filipcic Igor, Sporis Davor, Mislov Damir, Posavec Ana
Department of Neurology, Zagreb University Hospital Center, Kispatićeva 12, 10 000 Zagreb, Croatia.
Seizure. 2008 Sep;17(6):524-30. doi: 10.1016/j.seizure.2008.01.003. Epub 2008 Mar 7.
Epilepsy is refractory to medical treatment in about one-third of the patients. The exact pathological mechanism of epilepsy pharmacoresistance is still unclear, but a decreased antiepileptic drug (AED) uptake into the brain is suspected to play a role. P-glycoprotein (Pgp), a transmembrane transporter encoded by ABCB1 gene and located at the endothelial cells of the blood-brain barrier (BBB), has been associated with epilepsy pharmacoresistance.
To analyze the effect of two ABCB1 gene polymorphisms, C3435T and G2677T/A, on phenobarbital (PB) concentrations in the cerebrospinal fluid (CSF) and serum (S) and to assess the relationship of ABCB1 polymorphisms to phenobarbital penetration across BBB in vivo and seizure frequency.
CSF PB and S PB concentrations were measured in 60 patients with idiopathic primary generalized epilepsy receiving phenobarbital monotherapy. CSF/S PB concentration ratio was calculated as an index of phenobarbital penetration across BBB. The patients were genotyped for the ABCB1 gene C3435T and G2677T/A polymorphisms. Seizure frequency was recorded during the 6-month phenobarbital monotherapy.
Patients with different C3435T polymorphism had significantly different CSF PB concentrations and CSF/S PB concentration ratio. In comparison with CT heterozygotes and TT homozygotes, CC homozygotes had a significantly lower CSF PB concentration (p=0.006) and CSF/PB concentration ratio (p<0.001). G2677T/A polymorphism showed no such effect (p=0.466). CC genotype and low CSF/S PB concentration ratio correlated with increased seizure frequency.
C3435T polymorphism of ABCB1 gene was demonstrated in vivo to significantly influence the CSF/S PB concentration ratio and seizure frequency.
约三分之一的癫痫患者药物治疗效果不佳。癫痫药物抵抗的确切病理机制尚不清楚，但怀疑脑内抗癫痫药物（AED）摄取减少起了一定作用。P-糖蛋白（Pgp）是一种由ABCB1基因编码、位于血脑屏障（BBB）内皮细胞的跨膜转运蛋白，与癫痫药物抵抗有关。
分析ABCB1基因的两种多态性C3435T和G2677T/A对脑脊液（CSF）和血清（S）中苯巴比妥（PB）浓度的影响，并评估ABCB1基因多态性与体内苯巴比妥透过血脑屏障的情况及癫痫发作频率之间的关系。
对60例接受苯巴比妥单药治疗的特发性原发性全身性癫痫患者测定其脑脊液PB浓度和血清PB浓度。计算脑脊液/血清PB浓度比值作为苯巴比妥透过血脑屏障的指标。对患者进行ABCB1基因C3435T和G2677T/A多态性的基因分型。在6个月的苯巴比妥单药治疗期间记录癫痫发作频率。
具有不同C3435T多态性的患者脑脊液PB浓度和脑脊液/血清PB浓度比值有显著差异。与CT杂合子和TT纯合子相比，CC纯合子的脑脊液PB浓度显著降低（p = 0.006），脑脊液/血清PB浓度比值显著降低（p < 0.001）。G2677T/A多态性未显示出此类影响（p = 0.466）。CC基因型和低脑脊液/血清PB浓度比值与癫痫发作频率增加相关。
体内研究表明ABCB1基因的C3435T多态性显著影响脑脊液/血清PB浓度比值和癫痫发作频率。
