紫杉醇对食蟹猴和人CYP1A2、CYP3A4及CYP2A6酶代谢的影响

目的探讨紫杉醇对食蟹猴和人肝微粒体CYP1A2、CYP2A6和CYP3A4酶活性的影响。方法采用食蟹猴和人肝脏微粒体,分别以非那西汀、睾丸酮和香豆素分别作为CYP1A2、CYP2A6、CYP3A4的底物,建立CYP1A2、CYP2A6和CYP3A4体外代谢体系。采用不同浓度的紫杉醇分别与上述3种底物共同孵育于肝微粒体代谢体系中。用HPLC法分别测定各底物的代谢产物扑热息痛、6β-羟基睾丸酮、7-羟基香豆素的产生量,计算IC50值,以评估紫杉醇对CYP1A2、CYP2A6和CYP3A4代谢的影响。结果紫杉醇对食蟹猴肝微粒体3种酶的IC50值分别为570±5.9μmol/L、140±2.9μmol/L和无影响;紫杉醇对人肝微粒体3种酶的IC50值分别为193±6.6μmol/L、253±3.6μmol/L和24±1.6μmol/L。结论紫杉醇对食蟹猴肝微粒体CYP1A2和CYP3A4活性具有一定的抑制作用,但对CYP2A6酶的活性几乎没有影响。紫杉醇对人肝微粒体CYP1A2和CYP3A4活性的抑制作用较弱,但对CYP2A6酶的活性抑制作用较强,提示临床上紫杉醇与作为上述酶底物的药物联合用药时应慎重,以避免因中西药物相互作用所导致的不良反应发生。

Effect of Paclitaxel on Enzyme Metabolism of CYP1A2,CYP3A4 and CYP2A6 in Cynomolgus Monkey and Human Liver Microsomes

Objective To investigate the effect of paclitaxel on the Cynomolgus monkey and human liver microsomes CYP1A2,CYP2A6 and CYP3A4 enzyme activity.Methods To take Phenacetin,testosterone and coumarin medicine as a tool,we adopted the Cynomolgus monkey and human liver microsomes to establish the metabolic system in vitro.The different concentrations of paclitaxel were incubated with the three kinds of substrate in liver microsomes system respectively.To use HPLC to measure the metabolites output included paracetamol,6β-hydroy testosterone and 7-hydroxycoumarin,the IC50 value was calculated to evaluate the effect of the metabolism of CYP1A2,CYP2A6 and CYP3A4.Results The IC50 values about Cynomolgus monkey liver microsomes were 570 ± 5.9 μmol/L,140 ± 2.9 μmol/L and no effect.The IC50 values about human liver microsomes were 193 ± 6.6 μmol /L,253 ± 3.6 μmol /L and 24 ± 1.6 μmol /L.Conclusions Paclitaxel inhibits the activity of CYP1A2 and CYP3A4 liver microsomes,it has little impact on theCYP2A6 enzyme.Paclitaxel has weak inhibitory on human liver CYP1A2 and CYP3A4 enzyme activity,but it has strong inhibition on the CYP2A6 enzyme activity,the results give some mirror to the safety of clinical medication.