TY - JOUR T1 - Piperine is a Mechanism-based inactivator of CYP3A JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.088955 SP - dmd.119.088955 AU - Tiantian Cui AU - Qian Wang AU - Xiaoxiao Tian AU - Kehan Zhang AU - Ying Peng AU - Jiang Zheng Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/11/19/dmd.119.088955.abstract N2 - Piperine (PPR) is the representative alkaloid component of piper species (family: Piperaceae). Our rapid screening study found PPR caused time-dependent inhibition of cytochrome P450s (CYP) 3A and 2D6, and CYP3A was inactivated the most. Further study demonstrated PPR is a time-, concentration-, and NADPH-dependent inhibitor of CYP3A, and significant loss (49.5 &plusmn 3.9%) of CYP3A activity was observed after 20 min incubations with 80 μM PPR at 37 °C. The values of KI and kinact were 30.7 μM and 0.041 min-1, respectively. CYP3A competitive inhibitor ketoconazole showed protective effect against the enzyme inactivation. Superoxide dismutase/catalase and GSH displayed minor protection against the PPR caused enzyme inactivation. Ferricyanide partially reduced the enzyme inhibition by PPR. Additionally, NADPH-dependent formation of reactive metabolites from PPR were found in human liver microsomal incubation mixtures. An ortho-quinone intermediate was trapped by NAC in microsomal incubations with PPR. DM-PPR, demethylene metabolite of PPR, showed weak enzyme inactivation relative to that caused by PPR. It appears that both carbene and ortho-quinone intermediates were involved in the inactivation of CYP3A caused by PPR.SIGNIFICANCE STATEMENT CYP3A subfamily members (mainly CYP3A4 and CYP3A5) play a critical role in drug metabolism. Piperine (PPR), a methylenedioxyphenyl derivative combined with an unsaturated ketone, is the major active ingredient of pepper. PPR revealed time- and concentration-, and NADPH-dependent inhibitory effect on CYP3A. Carbene and quinone metabolites were both involved in the observed CYP3A inactivation by PPR. Apparently, the unsaturated ketone moiety did not participate in the enzyme inactivation. The present study sounds an alert of potential risk for food-drug interactions. ER -