中国中药杂志

2016, v.41(09) 1739-1743

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抗肿瘤化合物E7在不同种属肝微粒体酶中的体外代谢研究
In vitro metabolism of anti-tumor compound E7 in different species of liver microsomes

汤明海;王海蓉;王春艳;叶昊宇;
TANG Ming-hai;WANG Hai-rong;WANG Chun-yan;YE Hao-yu;State Key Laboratory of Biotherapy,West China Hospital,Sichuan University;

摘要(Abstract):

采用商品化的人、Beagle犬、食蟹猴、SD大鼠的肝微粒体酶,考察E7在4个种属肝微粒体中的代谢稳定性,比较代谢的种属差异。采用选择性化学抑制剂,测定不同抑制剂对E7代谢速率的影响,分析预测大鼠肝微粒中参与E7代谢的主要亚酶。实验结果显示E7在人、犬、食蟹猴和大鼠4个种属的肝微粒体中体外代谢半衰期T1/2分别为57.75,69.30,16.90,30.13min;体外固有清除率分别为0.004 8,0.004 0,0.016 4,0.009 2 m L·min(-1)·mg(-1)·mg(-1)。推测E7在人和犬肝微粒体中代谢速率相近,均比较慢;在猴和大鼠肝微粒体中代谢速率相近,均比较快;代谢速率存在明显的种属差异。CYP2E1,CYP2A6,CYP1A2和CYP2D6均可能参与代谢E7,而多态性的CYP3A4对其的代谢贡献较小。
To investigate the metabolic stability of E7 in liver microsomes of human,Beagle dog,Cynomolgus monkey and SD rats,and compare the metabolic differences between different species. Selective chemical inhibitors were used to determine the effects of different inhibitors on E7 metabolic rate,and predict the main enzymes involved in E7 metabolism in rat liver microsomes. The experimental results showed that the in vitro half-lives( T1 /2) of E7 in liver microsomes of human,dog,monkey and rats were 57. 75,69. 30,16. 90,30. 13 min respectively. Their intrinsic clearance rate was 0. 004 8,0. 004 0,0. 016 4 and 0. 009 2 m L · min(-1)。推测E7在人和犬肝微粒体中代谢速率相近,均比较慢;在猴和大鼠肝微粒体中代谢速率相近,均比较快;代谢速率存在明显的种属差异。CYP2E1,CYP2A6,CYP1A2和CYP2D6均可能参与代谢E7,而多态性的CYP3A4对其的代谢贡献较小。
To investigate the metabolic stability of E7 in liver microsomes of human,Beagle dog,Cynomolgus monkey and SD rats,and compare the metabolic differences between different species. Selective chemical inhibitors were used to determine the effects of different inhibitors on E7 metabolic rate,and predict the main enzymes involved in E7 metabolism in rat liver microsomes. The experimental results showed that the in vitro half-lives( T1 /2) of E7 in liver microsomes of human,dog,monkey and rats were 57. 75,69. 30,16. 90,30. 13 min respectively. Their intrinsic clearance rate was 0. 004 8,0. 004 0,0. 016 4 and 0. 009 2 m L · min(-1)·mg(-1)·mg(-1)respectively. Hence,it could be speculated that the metabolic rate of E7 was similarly slow in human and dog liver microsomes;while it was similarly fast in monkey and rat liver microsomes. There was significant difference in metabolic rate of E7 between different species. The results showed that CYP2E1,CYP2A6,CYP1A2 and CYP2D6 might participate in metabolism of E7,while the contribution of polymorphic CYP3A4 was small.

关键词(KeyWords): E7;肝微粒体;代谢稳定性;酶表型
E7;liver microsomes;metabolic stability;metabolic phenotype

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金青年基金项目(81402493)

作者(Authors): 汤明海;王海蓉;王春艳;叶昊宇;
TANG Ming-hai;WANG Hai-rong;WANG Chun-yan;YE Hao-yu;State Key Laboratory of Biotherapy,West China Hospital,Sichuan University;

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