细胞色素酶CYP2C19代谢对沙利度胺体外抗骨髓瘤作用的影响  

Effect of cytochrome CYP2C19 on the antimyeioma activity of thalidomide in vitro

作　　者：李勇华[1] 侯健[1] 姜华[1] 黄红铭[1] 朱蓉[1] 

机构地区：[1]第二军医大学长征医院血液内科,上海200003

出　　处：《中华血液学杂志》2008年第10期654-657,共4页Chinese Journal of Hematology

摘　　要：目的研究人肝微粒体代谢对沙利度胺体外抗骨髓瘤作用的影响，并探讨细胞色素酶CYP2C19在其中的作用。方法以沙利度胺或与人肝微粒体在体外孵育后分别处理多发性骨髓瘤（MM）细胞株U266、NCI—H929、RPMI8226、LP－1和Cz—1细胞，采用MTT法检测细胞活力，流式细胞术测定细胞周期和细胞凋亡。结果沙利度胺对MM细胞活力无明显抑制作用，10、50和100μg/ml沙利度胺处理5株MM细胞后的细胞活力分别为96．2％-103．7％、96．3％～103．7％和97．9％-106．5％，与对照组比较差异无统计学意义（P〉0．05）。但与人肝微粒体孵育后，沙利度胺明显抑制MM细胞活力，且该作用呈剂量依赖性。10、50和100μg/ml沙利度胺与人肝微粒体共孵育后对5株MM细胞活力抑制率分别为12．2％～22．9％、25．9％～36．4％和34．9％～46．3％，与对照组比较差异均具有统计学意义（P〈0．05）。100μg/ml沙利度胺与人肝微粒体孵育后，5株MM细胞凋亡的比例增加达18．5％～32．5％。在孵育体系中加入CYP2C19特异性抑制剂奥美拉唑后，沙利度胺与人肝微粒体孵育后对MM细胞活力的抑制作用减弱，5μmol／L和10μmol／L奥美拉唑对100μg/ml沙利度胺经肝微粒体孵育后抑制细胞活力的逆转率分别为7．5％～21．9％和19．1％～38．3％，差异有统计学意义（P〈0．05）。结论沙利度胺的体外抗骨髓瘤作用需要人肝脏代谢，细胞色素酶系中的CYP2C19参与了这一过程。Objective To investigate the effect of human liver microsome on antimyeloma activity of thalidomide（TH） in vitro and identify the role of cytochrome CYP2C19 in it. Methods Human multiple myeloma （MM） cell lines U266, NCI-H929, RPMI 8226, LP-1 and CZ-1 were treated with TH or TH pre-incubated with human liver microsome. Cell viability was detected by MTT assay, and cell cycle and apoptosis by flow cytometry （FCM）. Results TH treatment had no direct effect on cell viability at concentrations of 10 μg/ml, 50 μg/ml and 100 μg/ml, the viabilities of the 5 MM cell lines were 96.2% - 103.7% , 96.3% - 103.7% and 97.9% - 106.5% respectively, being no significant difference from that of control （ P 〉 0.05 ）. However, when preincubated with human liver mierosome, TH significantly inhibited the cell viability with a dose-dependent manner. At concentrations of 10 μg/ml, 50 μg/m] and 100 μg/ml, TH pre-ineubated with human liver microsome led to 12.2% - 22.9% , 25.9% - 36.4% and 34.9% - 46.3% decreases of cell vi- ability, respectively （P 〈 0.05 ）. TH at concentration of 100 μg/ml pre-incubated with human liver microsome caused an increase of 18.5% - 32.5% in apoptosis cells. When omeprazole, a specific inhibitor of cytochrome CYP2C19, was added in the incubation system, the inhibition of cell viability by TH was weakened. At concentrations of 5 μmol/L and 10 μmoL/L, omeprazole reversed the cell viability by 7.5% -21.9% and 19.1% - 38.3% , respectively （P 〈 0.05 ）. Conclusion Treatment of TH with human liver microsome is essential for its antimyeloma activity in vitro, and cytochrome CYP2C19 is involved with this metabolism process.

关 键 词：CYP2C19 沙利度胺 多发性骨髓瘤 细胞凋亡 

分 类 号：R686[医药卫生—骨科学]