title: Discovery and characterization of novel, potent, and selective cytochrome P450 2J2 inhibitors.
abstract: Cytochrome P450 (CYP) 2J2 is one of the human CYPs involved in phase I xenobiotics metabolism. It is mainly expressed in extrahepatic tissues, including intestine and cardiovascular systems. The general role of CYP2J2 in drug metabolism is not yet fully understood, and the recent discovery that CYP2J2 can metabolize a wide range of structurally diverse drugs and its primary distribution in the intestine suggest its potentially indispensable role in first-pass intestinal metabolism and involvement in drug-drug interaction. To fully characterize its role in drug metabolism, selective and potent inhibitors of CYP2J2 are necessary tools. In the current study, 69 known drugs were screened for the inhibition of CYP2J2, and we discovered a number of marketed drugs as potent and selective CYP2J2 inhibitors. In particular, telmisartan and flunarizine have CYP2J2 inhibition IC(50) values of 0.42 μM and 0.94 μM, respectively, which are at least 10-fold more selective against all other major metabolizing CYPs; moreover, they are not substrates of CYP2J2 and show no time-dependent inhibition toward this CYP. The results of enzyme kinetics studies, supported by molecular modeling, have also elucidated that telmisartan is a mixed-type inhibitor, and flunarizine competitively inhibits CYP2J2. The K(i) for telmisartan is 0.19 μM, with an α value, an indicator of the type of inhibition mechanism, of 2.80, and flunarizine has a K(i) value of 0.13 μM. These newly discovered CYP2J2 inhibitors can be potentially used as a tool to study CYP2J2 in drug metabolism and interaction in a clinical setting.
authors.affiliation: School of Life Science and Technology, Tongji University, 1239 Si Ping Road, Shanghai 200092, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ren
authors.forename: Juan
authors.initials: J
authors.lastname: Zeng
authors.forename: Ye
authors.initials: Y
authors.lastname: Mei
authors.forename: John Z H
authors.initials: JZ
authors.lastname: Zhang
authors.forename: S Frank
authors.initials: SF
authors.lastname: Yan
authors.forename: Jian
authors.initials: J
authors.lastname: Fei
authors.forename: Li
authors.initials: L
authors.lastname: Chen
mesh_terms: D002851:Chromatography, High Pressure Liquid; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D013379:Substrate Specificity
chemical_list: C000717350:CYP2J2 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2