D-异苯环戊胺对大鼠肝微粒体CYP450酶的抑制和诱导作用

Inhibitory and inductive effects of D-iso-phenylcyclopentylamine on CYP450 in rat liver

目的:本文探讨了D-异苯环戊胺对大鼠肝脏细胞色素P450(Cytochrome P450,CYP450)酶活性的抑制和诱导作用。方法:采用探针底物法,通过考察D-异苯环戊胺在体外温孵体系中对大鼠肝微粒体CYP1A1/2,2C6,2D1/2,2E1和3A1/2的IC50值评价其对各亚型的抑制作用。通过考察大鼠连续灌胃10 d后肝微粒体中CYP1A1/2和CYP3A1/2活性的变化评价其诱导作用。结果:D-异苯环戊胺对大鼠肝微粒体CYP2C6和CYP2D1/2的IC50分别为5.3和2.3μmol·L-1,对分别以睾酮和咪达唑仑为底物时CYP3A1/2的IC50分别为8.3和1.7μmol·L-1。30和100 mg·kg-1剂量D-异苯环戊胺连续灌胃给药10 d后,大鼠肝脏CYP1A1/2和CYP3A1/2酶活性为空白对照组的2倍以上。结论:D-异苯环戊胺对大鼠肝微粒体CYP2C6,CYP2D1/2和CYP3A1/2表现出中等强度的抑制作用,对CYP1A1/2和CYP3A1/2有一定的诱导作用。

Objective：To evaluate the inhibitory and inductive effects of D-iso-phenylcyclopentylamine （D- IPCPA） on main CYP450 isoforms in rat liver. Methods：Probe substrate method was used to evaluate the inhibitory effect of D-IPCPA on CYP1A1/2,2C6,2D1/2,2E1 and 3A1/2 by IC50 values. The inductive effect of D-IPCPA was evaluated by comparing the activities of CYP1A2 and CYP3A1/2 with and without continuous administration of D-IPCPA to rats for 10 d. Results：The IC50 values of D-IPCPA on CYP2C6 and CYP2D1/2 were 5.3 and 2.3 μmol·L^-1, respectively. The IC50 values of D-IPCPA on the testosterone 6β-hydroxylation activity and midazolam 1＇-hydroxylation activity of CYP3A1/2 were 8.3 and 1.7 μmol·L^-1, respectively. After multiple dose administration of D-IPCPA at 30 and 100 mg·kg^-1 , the activities of CYP1A1/2 and CYP3A1/2 were more than 2 times of the blank control group. Conclusion： D-IPCPA had moderate inhibitory effect on rat liver CYP2C6, CYP2D1/2 and CYP3A1/2,and showed inductive effect on CYP1A2 and CYP3A1/2.