Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5843997 | Pharmacology & Therapeutics | 2014 | 28 Pages |
Abstract
Beyond their contribution to the metabolism of xenobiotics, cytochrome P450 (CYP) epoxygenases are actively involved in the metabolism of endogenous substances, like arachidonic acid (AA). The main human CYP epoxygenases, i.e. CYP2C8, CYP2C9, CYP2C19 and CYP2J2, convert AA to four regioisomer epoxyeicosatrienoic acids (EETs). EETs possess a wide range of established protective effects on the human cardiovascular system of which anti-inflammatory actions have gained great recent interest. The expression of CYP epoxygenases is regulated through an extremely complex network of nuclear receptors, microRNAs and genetic/epigenetic factors. Accordingly, a large number of biological variables as well as xenobiotics and environmental factors can influence the expression of CYP epoxygenases, resulting in a significant intra- and inter-individual variability in the expression and activity of these enzymes and subsequently in EET biosynthesis. Moreover, human CYP epoxygenases are mainly expressed in the liver; however, these enzymes are also expressed, at various extents, in most extrahepatic tissues, resulting in a marked inter-tissue variability in the expression of CYP epoxygenases. The inter-tissue, inter- and intra-individual variability in the expression of epoxygenases may lead to differences in the relative abundance of EETs among tissues, among individuals of a population and/or different ethnicities and in a given individual under various conditions. The variation in the abundance of EETs may explain, at least in part, the inter-tissue and inter-individual differences observed in the prevalence of inflammation-related disorders including cardiovascular disease, and why in a given individual, various conditions can contribute to the development of diseases with an important inflammatory component.
Keywords
TGFNADPHHSP90HDACbZIPPORSRC-1PP-2AEEQAP-1SHPEDPGTFEDHFFXRVDREicosapentaenoicLXRHNF4αPXRLPSEPANF-κBCCRPLETFAHRmRNARORCNVfarnesoid X receptormessenger RNAsEHArachidonic acidepoxyeicosatrienoic acidsepoxyeicosatrienoic acidepoxydocosapentaenoic acidepoxyeicosatetraenoic acidhydroxyeicosatetraenoic acidPolyunsaturated fatty acidsPUFADocosahexaenoic acidsinflammationEpoxygenasetransforming growth factorVariabilitycopy number variationEETDHAbasic leucine zipperEndothelial cellCytochrome P450small heterodimer partnertranscriptional intermediary factor 2general transcription factorLiver-enriched transcription factorhepatocyte nuclear factor 4αendothelium-derived hyperpolarizing factorsnuclear transcription factor kappa Bchicken ovalbumin upstream promoter transcription factorPhosphatase 2AlipopolysaccharideCARDNA methylationMicroRNAMiRNAnicotinamide adenine dinucleotide phosphateHETEhistone deacetylasesHeat shock protein 90activator protein-1liver X receptoraryl hydrocarbon receptorconstitutive androstane receptorVitamin D receptorPregnane X receptorglucocorticoid receptorNuclear receptor
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Authors
Payman Shahabi, Gérard Siest, Urs A. Meyer, Sophie Visvikis-Siest,