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Roles of Mitogen-Activated Protein Kinases in the Regulation of CYP Genes

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Cells undergo phenotypic changes after exposure to a wide range of exogenous stimuli that include growth factors, proinflammatory cytokines and environmental chemicals. Such stimuli may arise as components of disease pathogenesis and cellular injury, or as a result of exposure to environmental chemicals and radiation. These stimuli modulate the proliferation and differentiation of cells by altering the regulation of genes that control homeostasis. A generalized response appears to be a decline in the expression and function of many cytochrome P450 (CYP) genes in liver and other tissues. Thus, individuals who have been exposed to such exogenous stimuli often exhibit a decreased capacity for drug clearance, which has important consequences for concurrent drug therapy. Several signaling pathways transduce exogenous stimuli within cells, with the mitogen-activated protein kinases (MAPKs) being one of the most important. Evidence is increasing that MAPKs may impair the expression of multiple CYP genes by modulating the activity of transcription factors, including nuclear receptors, the aryl hydrocarbon receptor, and the activator protein-1 complex. MAPKs catalyze the phosphorylation of transcription complexes that incorporate these factors, which modulates their capacity to transactivate target genes, including CYPs. An understanding of the mechanisms that account for the regulatory impact of MAPKs on the transcriptional factors that regulate CYP genes will provide critical insight into the consequences from exposure to injurious stresses that impact cellular function.

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Keywords: 26S proteasome; Aryl hydrocarbon receptor; CAATT-enhancer binding protein; CYP Genes; CYP gene regulation; Cytochrome P450; Extracellular signal-regulated kinas; Hepatocyte nuclear factor; Interleukin; MAP kinases; Mitogen-Activated Protein Kinases; P450; Roles of Mitogen-Activated Protein Kinases in the Regulation of CYP Genes; Sterol Biotransformation; adrenocorticotropic hormone; androgen; angiotensin-II; basic leucine-zipper transcription factors; cellular stress; chenodeoxycholic; coactivators; corepressors; deoxycholic acids; environmental stimuli; epoxygenase gene; es-tradiol; estrogen; ex-ogenous stimuli; glucocorticoid; hepatic nuclear; hypoxia; lithocholic; mineralocor-ticoid receptors; nuclear receptors; oxysterol substrates; pathological stimuli; phosphorylation; posed to nitrative stress induced by; progestin; proteolysis; transcription factors; ubiquitin-directed; xenobiotics

Document Type: Research Article

Publication date: December 1, 2010

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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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