Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4
Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4
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DOI：
10.1124/jpet.102.034728
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发表时间：
2002-08-01
影响因子：
3.5
通讯作者：
Fromm, MF
中科院分区：
文献类型：
--
作者：
Bhardwaj, RK;Glaeser, H;Fromm, MF
膳食成分（如葡萄柚汁中的NaCl）和植物化学物质（如圣约翰草）是改变药物代谢和运输的重要因素，从而导致药物处置的个体差异。大多数药物-食物相互作用是由于p -糖蛋白和/或CYP3A4的诱导或抑制。初步数据表明，胡椒碱是黑胡椒的主要成分，可以抑制啮齿动物体内的药物代谢酶，并增加几种药物的血浆浓度，包括人类体内p -糖蛋白底物（苯托英和利福平）。然而，没有直接的数据表明胡椒碱是否是人p-糖蛋白和/或CYP3A4的抑制剂。因此，我们研究了胡椒碱对p糖蛋白介导的地高辛和环孢素在Caco-2细胞单层中极化转运的影响。此外，通过使用人肝微粒体，我们确定了胡椒碱对cyp3a4介导的维拉帕米代谢物D-617和诺维拉帕米形成的影响。胡椒碱抑制地高辛和环孢素A在Caco-2细胞中的转运，IC50值分别为15.5和74.1 muM。cyp3a4催化的D-617和诺维拉帕米的形成以混合方式被抑制，K-i值分别为36 +/- 8（肝脏1）/49 +/- 6（肝脏2）和44 +/- 10（肝脏1）/77 +/- 10 muM（肝脏2）。总之，我们发现胡椒碱抑制药物转运蛋白p -糖蛋白和主要药物代谢酶CYP3A4。由于这两种蛋白都在肠细胞和肝细胞中表达，并在很大程度上有助于许多药物的首过消除，我们的数据表明，饮食中的胡椒碱可能影响人体p -糖蛋白和CYP3A4底物的血浆浓度，特别是如果这些药物是口服给药的话。
Dietary constituents (e. g., in grapefruit juice; NaCl) and phytochemicals (e. g., St. John's wort) are important agents modifying drug metabolism and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human p-glycoprotein and/ or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we deter-mined the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC50 values of 15.5 and 74.1 muM, respectively. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with K-i values of 36 +/- 8 (liver 1)/49 +/- 6 (liver 2) and 44 +/- 10 (liver 1)/77 +/- 10 muM (liver 2), respectively. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concentrations of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.