P-糖蛋白在多药耐药的K562细胞转运苯妥英纳与卡马西平中的作用  

The Role of P-Glycoprotein-mediated Transport of Phenytoin and Carbamazepine in a Multidrug Resistant K562

作　　者：陈英辉[1,2] 赵永波[2] 

机构地区：[1]复旦大学附属金山医院神经内科,上海200540 [2]上海交通大学附属第一人民医院神经科,上海200080

出　　处：《生物化学与生物物理进展》2008年第12期1425-1429,共5页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(30370511;30870880);复旦大学生物医学研究院开放课题2007资助项目.~~

摘　　要：研究证实,多药转运体与难治性癫痫耐药机制密切相关,P-糖蛋白在其中起重要作用.主要研究P-糖蛋白拮抗剂维拉帕米对P-糖蛋白过表达的K562细胞耐药性及细胞内苯妥英纳与卡马西平浓度的影响.首先建立了P-糖蛋白高表达的K562/Dox(阿霉素诱导)耐药细胞株,比较耐药细胞株和P-糖蛋白表达阴性的K562细胞株对苯妥英纳和卡马西平的耐药性,并观察给予维拉帕米后,耐药细胞内抗癫痫药物的浓度变化.结果发现,苯妥英纳和卡马西平对K562/Dox细胞株的半数抑制浓度(IC50)明显高于K562细胞株,加入维拉帕米后,苯妥英纳和卡马西平对K562/Dox细胞的IC50明显下降,逆转倍数分别为2.5和1.5.进一步研究发现,K562/Dox细胞内苯妥英纳和卡马西平的浓度均显著少于其药敏K562细胞,仅分别为正常K562细胞的23.6%和32.2%.当加入维拉帕米后,K562/Dox细胞内抗癫痫药物浓度明显升高(P<0.05).由此证明,高表达的P-糖蛋白参与了细胞的药物转运,在难治性癫痫的耐药机制中扮演重要角色.A series of researches concerning the relationship between multidrug transporters and drug resistance in medically intractable epilepsy have been done. There is accumulating evidence demonstrating that P-glycoprotein （PGP） is a candidate to cause AEDs resistance. The effect of PGP inhibitor-verapamil on the intracellular AEDs accumulation in a MDR（multidrug resistant） K562 was investigated. The multidrug resistant （overexpression of PGP） cell line K562/Dox was established and the intracellular PHT and CBZ accumulation in multidrug resistant cell line and non-multidrug resistant cell line was observed. After PGP inhibitor-verapamil was applied to the two cell lines, the concentration change of PHT and CBZ in MDR cell was observed. The results were found： compared with non-MDR cell line K562, which IC50 was significantly increased in MDR cell line K562/Dox after PHT and CBZ was applied; veraparnil could decrease significantly the level of IC50 in MDR cell line K562/Dox, and the reversal index were 2.5 and 1.5. The concentration of PHT and CBZ in MDR cell line K562/Dox was lower than that in non-MDR cell line K562, and verapamil significantly increased the concentration of PHT and CBZ in MDR cell line K562/Dox（P 〈 0.05）. It is obvious that overexpression of PGP are concerned with drug resistance of medically intractable epilepsy.

关 键 词：难治性癫痫 P-糖蛋白 维拉帕米 多药耐药 

分 类 号：R742.1[医药卫生—神经病学与精神病学] R971.6[医药卫生—临床医学]