不同急性肝损伤大鼠模型对5种CYP450酶的影响

发布时间：2018-04-12 11:08

本文选题：急性肝损伤模型 + Cocktail法　；参考：《中国药学杂志》2017年12期

【摘要】：目的比较研究不同化学品致急性肝损伤大鼠模型体内CYP450酶活性的变化。方法以正常大鼠作为对照,分别采用四氯化碳(CCl_4)、D-氨基半乳糖(D-Gal N)/脂多糖(LPS)、α-萘异硫氰酸酯(ANIT)复制大鼠急性肝损伤模型,以Cocktail探针法,单剂量尾静脉注射由CYP450 5种同工酶的特异性探针底物非那西丁(CYP1A2)、甲苯磺丁脲(CYP2C9)、奥美拉唑(CYP2C19)、右美沙芬(CYP2D6)和咪达唑仑(CYP3A4)配置的Cocktail探针溶液后,从大鼠眼底静脉丛采集不同时间点的血样,采用UPLC-MS/MS检测5种探针药物的血药浓度,采用PK Solution 2~(TM)对数据进行处理,并计算主要药动学参数。与正常大鼠相比,不同模型大鼠的探针药物药动学行为的改变作为CYP450同工酶代谢活力评估依据。结果与正常大鼠相比:CCl_4模型大鼠的CYP1A2、CYP2C9、CYP2C19、CYP2D6与CYP3A4的活性均受到抑制,其中对CYP3A4的抑制作用比较轻微;D-Gal N/LPS模型大鼠的CYP2C9、CYP2D6与CYP3A4的活性均受到诱导,其中对CYP2D6与CYP3A4的诱导较轻微,CYP2C19的活性被抑制,但对CYP1A2的影响不明显;ANIT模型大鼠的CYP2C9、CYP2C19与CYP3A4的活性被诱导,对CYP3A4的诱导较轻微,CYP1A2的活性被强烈抑制,对CYP2D6作用不明显。结论不同化学品致急性肝损伤模型大鼠体内CYP450酶活性存在非常显著差异。
[Abstract]:Objective to compare the changes of CYP450 enzyme activity in rats with acute liver injury induced by different chemicals.Methods the rat models of acute liver injury were induced by CCL _ (4) D galactosamine (D-Gal) / lipopolysaccharide (LPS), 伪 -naphthaleneisothiocyanate (伪 -naphthalene isothiocyanate) as control, and Cocktail probe method was used.Blood samples were collected from rat fundus venous plexus at different time points. UPLC-MS/MS was used to detect the blood concentration of five probe drugs. The data were processed by competitive Solution 2 and the main pharmacokinetic parameters were calculated.The changes of the pharmacokinetic behavior of probe in different model rats were used as the basis for evaluating the metabolic activity of CYP450 isozymes compared with normal rats.The activities of CYP2C19 and CYP2C19 induced by CYP2D6 and CYP3A4 were inhibited slightly, but the activities of CYP2C19 and CYP3A4 in CYP1A2 model rats were not significantly affected. The activities of CYP2C9, CYP2C19 and CYP3A4 were strongly inhibited in CYP3A4, but the effect on CYP2D6 was not obvious.Conclusion there are significant differences in the activity of CYP450 enzyme in rats with acute liver injury induced by different chemicals.
【作者单位】：上海中医药大学附属曙光医院肝病研究所;上海中医药大学中药研究所中药标准化教育部重点实验室中药新资源与质量标准综合评价国家中医药管理局重点研究室;上海中医药大学附属曙光医院心血管研究所;上海高校中医内科学E-研究院;
【基金】：国家国际科技合作专项资助课题(2014DFA31440) 国家科技重大专项资助课题(2014ZX10005001) 上海市医学领军人才计划项目(LJ10005) 上海中医药事业发展三年行动计划项目资助课题(ZY3-CCCX-2-1003)
【分类号】：R-332;R575

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