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Research/Review: Insights into the Mutation-Induced Dysfunction of Arachidonic Acid Metabolism from Modeling of Human CYP2J2

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As a kind of monooxygenase with the function of catalyzing many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids, CYP2J2 is an important member of the cytochrome P450 superfamily. Located at the endoplasmic reticulum, CYP2J2 is responsible for epoxidation of endogenous arachidonic acid in cardiac tissue to produce cis-epoxyeicosatrienoic acids (EETs), which have anti-inflammatory and antifibrinolytic properties, and can protect endothelial cells from ischemic or hypoxic injuries. Some polymorphisms, e.g., CYP2J2 with mutation T143A, R158C, I192N or N404Y, could significantly reduce the metabolism of the arachidonic acid, causing or deteriorating the coronary artery disease. However, so far the detailed mechanism for the mutationinduced dysfunction of arachidonic metabolism is still unknown. To reveal its mechanism, a 3D (three-dimensional) structure for human CYP2J2 was developed, followed by docking the arachidonic acid ligand into the active site of the receptor. It was observed based on the binding mode thus found that Gly486 and Leu378 in the active site of the receptor played a key role in recognizing and positioning the carboxyl group of the ligand via hydrogen bonding interactions, and that any of the aforementioned five mutations might have, either directly or indirectly, impact to their role and hence causing the mutation-induced dysfunction of CYP2J2-mediated arachidonic acid metabolism. It is anticipated that the findings as reported in this review article may stimulate new strategy for finding novel therapeutic approaches to treat coronary artery disease.
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Keywords: Arachidonic acid; coronary heart disease; cytochrome P450 2J2; drug metabolism; molecular modeling; polymorphisms; synthesis of cholesterol

Document Type: Research Article

Publication date: June 1, 2014

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  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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