参盐酸双苯氟嗪代谢大鼠肝微粒体CYP450酶鉴别.pdfVIP

参与盐酸双苯氟嗪代谢的大鼠肝微粒体CYP450 酶的鉴别 郭炜，王永利 （河北医科大学药学院，石家庄 050017 ） 摘要：目的 研究 SD 大鼠肝微粒体中，参与盐酸双苯氟嗪代谢的CYP450 酶亚型。方 法 运用CYP450 酶选择性抑制剂和重组酶实验探讨参与盐酸双苯氟嗪代谢的CYP450 酶亚 型。结果 抑制剂研究和重组酶实验两种分析方法测定结果均显示，大鼠肝微粒体中， CYP2A1、CYP3A 和CYP2C11 是生成M1 和 M5 的酶亚型；代谢盐酸双苯氟嗪生成M2 的 CYP450 酶按作用大小依次为CYP2A1、CYP3A、CYP2C11、CYP2E1 和CYP1A2 ；转化盐 酸双苯氟嗪生成M4 的酶亚型活性高低依次为CYP2A1 和CYP3A、CYP2E1 和CYP2C11， 重组酶实验结果表明，CYP3A2 显示出比 CYP3A1 更强的活性。结论 CYP3A 和 CYP2A1 均参与了大鼠肝微粒体中4 种代谢物的生成反应。 关键词：盐酸双苯氟嗪；大鼠肝微粒体；CYP450 酶；抑制剂；重组CYP450 酶 Identification of rat liver microsomal CYP450 enzymes involved in the metabolism of Dipfluzine hydrochloride ABSTRACT OBJECTIVE To study the involved in the metabolism of Dipfluzine hydrochloride (Dip) in rat liver microsomes. METHODS The CYP450 isoforms involved in the metabolism of Dip were investigated by the experiments of selective CYP450 inhibitors and recombinant CYP450 enzymes. RESULTS The results from experiments of selective CYP450 inhibitors and recombinant rat CYP450 isoforms both confirmed that in rat liver microsomes, CYP2A1, CYP3A and CYP2C11 contributes to M1 and M5 generation. CYP2A1, CYP3A, CYP2E1, CYP2C11 and CYP1A2 metabolize Dip to M2. CYP2A1, CYP3A, CYP2E1 and CYP2C11 contributed to M4 formation. So, CYP3A and CYP2A1 were the major CYP isoenzymes responsible for catalyzing Dip to four metabolites in rat liver microsomes. And the recombinant rat CYP450 isoforms researches indicated that CYP3A2 exhibited more activity than CYP3A1. CONCLUSION Both CYP3A and CYP2A1 are involved in the four metabolites formation in rat liver microsomes. Keywords: Dipfluzine hydrochloride; Rat liver microsomes; CYP450 enzymes; inhibitor; recombinant CYP450 enzymes 盐酸双苯氟嗪（Dip ）是河北医科大学研发的新型哌嗪类钙通道阻滞剂,