丹参酮Ⅱ_A磺酸钠联合思美泰对同种异体1/2原位肝脏移植大鼠P450及肝功能的影响

目的采用改良双袖套法建立大鼠同种异体1/2原位肝脏移植动物模型,观察术后丹参酮Ⅱ_A磺酸钠对细胞色素P450亚型酶活性及肝功能的影响,探讨药物干预机制,为临床治疗肝移植合理用药提供理论依据。方法选择60只大鼠,随机分为空白对照组、模型组、思美泰组及丹参酮组,思美泰组经尾静脉注射思美泰2 mg/(kg·d),丹参酮组在此基础上经尾静脉注射丹参酮Ⅱ_A磺酸钠5 mg/(kg·d)治疗14 d,空白对照组及模型组注射等体积生理盐水。采用高效液相色谱仪检测治疗前后肝微粒体细胞色素P450亚型酶(CYP2E1、CYP1A2、CYP3A4、CYP2D6、CYP2C9),生化检测肝功能中胆汁酸(TBA)、总胆红素(STB)、天冬氨酸氨基转移酶(AST)及丙氨酸氨基转移酶(ALT)、谷氨酰转移酶(GGT)水平,并计算肝移植术大鼠存活率,评价丹参酮Ⅱ_A磺酸钠对大鼠同种异体1/2原位肝脏移植的影响。结果经丹参酮Ⅱ_A磺酸钠及思美泰药物干预,丹参酮组CYP2E1、CYP1A2、CYP2C9、CYP3A4酶活性及TBA、GGT、ALT、AST、STB均明显降低,存活率达60%,与模型组及思美泰组比较,差异均有统计学意义(P<0.05)。结论丹参酮Ⅱ_A磺酸钠抑制大鼠肝微粒体细胞色素P450亚型酶活性,减轻过敏反应,提高同种异体1/2原位肝脏移植大鼠存活率,恢复肝功能,与思美泰联用可增强Na+/K+-ATP酶泵功能,同时,活血化淤、增加肝脏组织供氧相关。

Effects of sodium tanshinone A sulfonate combined with Si Mattel on P450 and liver function in 1/2 allogenic orthotopic liver transplantation rats

Objective The modified two-cuff technique was used to establish rat orthotopic liver transplanta-tion 1/2 animal model to observe the effect of sodium tanshinone A sulfonate on the activity of liver function and P450 isoform of cytochrome P450 enzyme after operation and to explore the mechanism of drug intervention,and provide a theoretical basis for clinical rational use of drugs in treatment of liver transplantation. Methods Sixty rats were ran-domly divided into blank control group,model group,Si Mattel group and tanshinone group. Rats in Si Mattel group were injected with 2 mg/( kg·d) Si Mattel by tail vein;on the basis of Si Mattel group,tanshinone group was intrave-nously injected sodium tanshinone A sulfonate 5 mg/( kg·d) for 14 days;blank control group and model group were injected with the same volume of physiological saline. HPLC method was used to detect the liver microsomal cyto-chrome P450 isoforms (CYP2E1,CYP1A2,CYP3A4,CYP2D6,CYP2C9) before and after treatment,biochemistry method was used to detect the level of bile acid biochemical liver function (TBA),total bilirubin (STB),aspartate aminotransferase (AST) and alanine aminotransferase (ALT),gamma glutamyl transferase (GGT),and the survival rate of liver transplantation was calculated,and the effect of sodium tanshinone A sulfonate on rat allograft orthotopic liver transplantation 1/2 was calculated. Results Through the drug intervention of tanshinone A sulfonic acid sodium and Si Mattel,CYP2E1,CYP1A2,CYP2C9 and CYP3A4 enzyme activity and TBA,GGT,ALT,AST and STB of tan-shinone group were decreased and the survival rate increased to 60%;compared with model group and Si Mattel group, the differences were significant (P<0. 05). Conclusion Tanshinone A sulfonic acid sodium can improve the survival rate and restore liver function of 1/2 allograft orthotopic liver transplantation rats;the mechanism maybe related to in-hibiting the activity of rat hepatic microsomal P450 isoform of cytochrome P450 enzymes,reducing the allergic reac-tion,reinforcing Na+ /K+-ATP enzyme pump function through combination with Si Mattel,promoting blood circulation and removing blood stasis,and increasing hepatic tissue oxygen supply.