阿司匹林丁香酚酯对肝脏主要药物代谢酶活性的影响

Effect of AEE on activities of major drug metabolic enzymes in liver

采用SD大鼠和C57小鼠研究阿司匹林丁香酚酯(AEE)对肝脏主要药物代谢酶活性的影响。首先把研磨的AEE混悬在0.5%羧甲基纤维素钠溶液中,配制成20 g/L的AEE混悬液。将SD大鼠随机分为2组,试验组每日灌喂1次AEE(54 mg/kg),空白对照组每日灌喂1次等量的0.5%羧甲基纤维素钠溶液。连续3周后随机处死一半,取其肝脏,制备肝匀浆液;剩余一半的SD大鼠,停药2周处死,取其肝脏,制备肝匀浆液。采用ELISA考察AEE对肝脏细胞色素P450酶(cytochrome P450,CYP450)的影响。研究AEE对C57小鼠肝脏主要药物代谢酶活性的影响,方法同SD大鼠方法。结果显示,SD大鼠连续灌药3周后,AEE对CYP3A4、CYP2C19、CYP1A2的活性有一定的抑制作用(P<0.05),对CYP2C8的活性有一定的诱导作用(P<0.05);CYP2D6、CYP2C9无显著性差异(P>0.05);停药2周后,发现只有CYP2C19的活性没有恢复,而其余药酶活性都有一定的恢复,与正常组无显著性差异(P>0.05)。C57小鼠连续灌药3周后,AEE对CYP3A4、CYP2C19、CYP1A2、CYP2D6的活性有一定的抑制作用(P<0.05),对CYP2C8的活性有一定的诱导作用(P<0.05),对CYP2C9无显著性差异(P>0.05);停药2周后,发现只有CYP2C19的活性没有恢复,而其余药酶活性都有一定的恢复,与正常组无显著性差异(P>0.05)。结果表明,AEE对SD大鼠的CYP2C8有诱导作用,对CYP3A4、CYP2C19和CYP1A2有抑制作用,而对CYP2C9和CYP2D6无显著性影响(P>0.05);AEE对C57小鼠的CYP2C8有诱导作用,对CYP3A4、CYP2C19、CYP1A2和CYP2D6有抑制作用,而对CYP2C9无显著性影响(P>0.05)。本研究为AEE在动物体内药效及动物用药相互作用研究和临床应用提供了依据。

This research aims to study the effect of aspirin eugenol ester(AEE)on main drug metabolic enzymes in liver,to provide a reference for drug interaction research,and promote rational drug use in the clinic.In this study,the effects of AEE on the activities of major drug-metabolizing enzymes in the liver of two species of experimental rats,namely,the SD rat and the C57 mouse were investigated.Solution of AEE(20 g/L)in 0.5%solution of sodium carboxymethylcellulose was prepared.The SD rats were randomly divided into two groups.Each rat in the experimental group was given AEE(54 mg/kg)once a day,and each rat of the blank control group was given an equal amount of 0.5%sodium carboxymethylcellulose solution once a day.After three consecutive weeks,half of the rats were randomly sacrificed and their livers were taken to prepare liver homogenate.The remaining half of the SD rats were sacrificed two weeks after drug discontinuation,and their livers were taken for preparation of liver homogenate.The effects of AEE on hepatic cytochrome P450enzymes(CYP450)were examined by ELISA.To investigate the effect of AEE on the activities of major drug-metabolic enzymes in the liver of C57mice,the same method as that of SD rats was used.The results showed that after three weeks of continuous treatment,AEE inhibited the activities of CYP3A4,CYP2C19,and CYP1A2(P<0.05),and induced the activity of CYP2C8(P<0.05)in SD rats;CYP2D6and CYP2C9showed no significant difference(P>0.05);only CYP2C19activity did not recover after two weeks of discontinuation;the enzyme activities of other drugs restored to a certain extent,there was no without significant difference from the normal group(P>0.05).After continuous gavage for three weeks in C57mice,AEE inhibited the activities of CYP3A4,CYP2C19,CYP1A2,and CYP2D6(P<0.05),induced the activity of CYP2C8(P<0.05),and there was no significant difference in the activity of CYP2C9(P>0.05);only CYP2C19activity did not recover after 2weeks of discontinuation;the activities of other drug metabolic enzymes restored to a certain extent,without significant difference from the normal group(P>0.05).In conclusion,AEE can induce CYP2C8in SD rats,inhibit CYP3A4,CYP2C19and CYP1A2,but has no significant effect on CYP2C9and CYP2D6(P>0.05);AEE can induce CYP2C8in C57mice and inhibit CYP3A4,CYP2C19,CYP1A2and CYP2D6,but has no significant effect on CYP2C9(P>0.05).The experimental results will provide a reference for the study on the efficacy of AEE in animals and the interaction between animal drugs and their clinical application.