高原低氧对药物代谢酶CYP2C9和2C19活性及蛋白表达的影响  

Effect of high altitude hypoxia on the activity and protein expression of CYP2C9 and CYP2C19

作　　者：李向阳[1] 刘永年[2] 袁明[1] 李永平[1] 杨应忠[3] 朱俊博[1] 

机构地区：[1]青海大学医学院药学系,青海西宁810001 [2]青海大学医学院病理生理教研室,青海西宁810001 [3]青海大学医学院高原医学研究中心,青海西宁810001

出　　处：《药学学报》2012年第2期188-193,共6页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(30960457);教育部新世纪优秀人才支持计划(NCET-10-0917)

摘　　要：探讨高原低氧对药物代谢酶CYP2C9、2C19活性和蛋白表达的影响。平原、中度海拔急性缺氧、中度海拔慢性缺氧、高海拔急性缺氧和高海拔慢性缺氧等5组大鼠分别灌胃给予探针药物苯妥英钠(PHT)和奥美拉唑(OMZ),采用RP-HPLC法分别测定给药后12 h血清中苯妥英钠和代谢产物4'-羟基苯妥英(HPPH)以及3 h血清中奥美拉唑和代谢产物5-羟基奥美拉唑(5-OHOMZ)的血药浓度,以HPPH与PHT的浓度比值评价CYP2C9的活性,以5-OHOMZ与OMZ的浓度比值评价CYP2C19的活性。采用ELISA方法测定CYP2C9和2C19的蛋白表达。与平原对照组大鼠比较,中度海拔急性缺氧组、中度海拔慢性缺氧组、高海拔急性缺氧组和高海拔慢性缺氧组大鼠CYP2C9的活性和蛋白表达均无显著性变化。与平原对照组大鼠比较,中度海拔急性缺氧组、中度海拔慢性缺氧组、高海拔急性缺氧组和高海拔慢性缺氧组大鼠CYP2C19的蛋白表达无显著性变化,但高海拔急性缺氧组大鼠CYP2C19的活性显著升高,其他组无显著性变化。研究结果提示,高原低氧对CYP2C19的活性有一定影响。This study is to investigate the effect of high altitude hypoxia on the activity and protein expression of CYP2C9 and CYP2C19. Rats from plain （P） and rats with acute middle altitude hypoxia （AMH）, chronic middle altitude hypoxia （CMH）, acute high altitude hypoxia （AHH） and chronic high altitude hypoxia （CHH） were administered orally phenytoin sodium （PHT） and omeprazole （OMZ） to evaluate the activity of CYP2C9 and CYP2C19, separately. The serum concentrations of PHT and metabolite 4＇-hydroxyphenytoin （HPPH） at 12 h after treatment and the serum concentrations of OMZ and metabolite 5-hydroxy omeprazole （5-OHOMZ） at 3 h after treatment were determined by RP-HPLC. The activity of CYP2C9 and CYP2C 19 was evaluated by the ratio of HPPH to PHT and the ratio of 5-OHOMZ to OMZ, respectively. The protein expressions of CYP2C9 and CYP2C 19 were determined by ELISA method. The activities of CYP2C9 （HPPH/PHT） in P, AMH, CMH, AHH and CHH were 0.67 ± 0.31, 0.75 ± 0.29, 0.76 ± 0.23, 0.79 ± 0.31 and 0.75 ± 0.18, respectively, and the activities of CYP2C19 （5-OHOMZ/OMZ） in P, AMH, CMH, AHH and CHH were 0.17 ± 0.06, 0.20 ± 0.10, 0.11 ± 0.05, 0.37 ± 0.13 and 0.19 ± 0.05, respectively. The protein expressions of CYP2C9 in P, AMH, CMH, AHH and CHH were 4.20 ± 1.27, 3.95 ± 0.81, 3.93 ± 1.11, 4.32 ± 1.03 and 4.12 ± 0.86 ng·g^-1, respectively, and the protein expressions of CYP2C19 in P, AMH, CMH, AHH and CHH were 3.91 ± 1.82, 3.63 ± 2.07, 2.55 ±0.85, 4.78±2.37 and 3.51 ±1.03 ng.g^-1, respectively. The activities and protein expressions of CYP2C9 in AMH, CMH, AHH and CHH were not significantly different with those of P. The protein expressions of CYP2C19 in AMH, CMH, AHH and CHH were not significantly different with those of P, but the activity of CYP2C19 in AHH was significantly higher than that of P. This study found significant changes in the activity of CYP2C 19 under the special environment of acute high altitude hypoxia.

关 键 词：高原 低氧 CYP2C9 CYP2C19 活性 蛋白表达 

分 类 号：R968[医药卫生—药理学]