title: In vitro inhibitory effect of piperlonguminine isolated from Piper longum on human cytochrome P450 1A2.
abstract: Piperlonguminine (PL), a major alkaloid isolated from Piper longum fruits, shows several biological activities including anti-tumor, anti-hyperlipidemic and anti-inflammatory effects. Although there have been studies of the biological effects of PL, the potential drug-interaction effect of PL following evaluation of inhibitory effects of cytochrome P450 (CYP) activities was not investigated. Here, to investigate the inhibitory effects of PL on the activities of CYP isoforms, CYP inhibition assays were conducted using a cocktail of probe substrates in pooled human liver microsome (HLMs) and human recombinant cDNA-expressed CYP. PL strongly inhibited CYP1A2-mediated phenacetin O-deethylation with an IC50 value of 8.8 μM, as NADPH-independent inhibition, while other CYPs were not significantly inhibited. A Lineweaver-Burk plot resulted in the inhibition mechanism of PL being divided into two different modes, reversible competitive inhibition in a low concentration range of 0-16 μM with a Ki value of 1.39 μM and uncompetitive inhibitory behavior at a high concentration range of 16-40 μM. In addition, PL only decreased CYP 1A2-catalyzed phenacetin O-deethylase activity with IC50 values of 10.0 μM in human recombinant cDNA-expressed 1A2, not 1A1. Overall, this is the first investigation of potential herb-drug interactions associated with PL conducted by identifying the competitive inhibitory effects of PL on CYP1A2 in HLMs.
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Taegu, 702-701, South Korea.
authors.forename: Min
authors.initials: M
authors.lastname: Song
authors.forename: Jae Yun
authors.initials: JY
authors.lastname: Hwang
authors.forename: Min Young
authors.initials: MY
authors.lastname: Lee
authors.forename: Jun-Goo
authors.initials: JG
authors.lastname: Jee
authors.forename: You Mie
authors.initials: YM
authors.lastname: Lee
authors.forename: Jong-Sup
authors.initials: JS
authors.lastname: Bae
authors.forename: Jeong Ah
authors.initials: JA
authors.lastname: Kim
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Sangkyu
authors.initials: S
authors.lastname: Lee
mesh_terms: D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D004148:Dioxolanes / Q000302:isolation & purification / Q000494:pharmacology*; D005638:Fruit / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D055670:Medicine, Korean Traditional; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D031701:Piper / Q000737:chemistry*; D011994:Recombinant Proteins / Q000235:genetics; D013379:Substrate Specificity; D010881:Piperidones
chemical_list: D019388:Cytochrome P-450 CYP1A2; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004148:Dioxolanes; D011994:Recombinant Proteins; C504573:CYP1A2 protein, human; C498077:piperlongumine; D010881:Piperidones