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1 - 3 of 3 for ""Cytochrome p450""
The Roles of Cytochrome P450 in Ischemic Heart Disease
Cytochrome P450 (CYP) represents a large family of enzymes that catalyze the oxidation of endogenous and exogenous compounds. The functions of CYP enzymes in the metabolism of xenobiotics have well been established in the liver. However some CYP enzymes are highly expressed in the heart and catalyze arachidonic acid oxidation to a variety of eicosanoids which attenuates ischemiareperfusion injury of the heart. CYP-mediated cardioprotection is associated with activation of multiple pathways such as sarcolemmal and mitochondrial potassium channels p42/p44 MAPK and PI3K-AKT signaling in cells. CYP enzymes also represent a significant source of reactive oxygen species (ROS) that may target cellular homeostatic mechanisms and mitochondria. CYP isoforms expressed in the heart are critical for generation of epoxyeicosatrienoic acids (EETs) and ROS. It has been demonstrated that CYP2J2 generates cardioprotective EETs whereas another isozyme in the heart CYP2C generates EETs as well as detrimental ROS. Genetic polymorphisms of CYP2C or CYP2J2 have a pathologic impact on coronary artery diseases. Cardiac CYP enzymes can be involved in drug metabolism within the heart and influence pharmacologic efficacy. Metabolism mediated by CYP enzymes influences the survival of cardiomyocytes during ischemia which is critical for treatment of human ischemic heart disease. In this review we summarize current knowledge of this enzyme family and discuss the roles of CYP in ischemia-reperfusion injury of the heart.
PET Imaging of Multidrug Resistance in Tumors Using 18F-Fluoropaclitaxel
The failure of solid tumors to respond to chemotherapy is a complicated and clinically frustrating issue. The ability to predict which tumors will respond to treatment could reduce the human and monetary costs of cancer therapy by allowing pro-active selection of a chemotherapeutic to which the tumor does not express resistance. PET/CT imaging with a radiolabeled form of paclitaxel F-18 fluoropaclitaxel (FPAC) may be able to predict the uptake of paclitaxel in solid tumors and as a substrate of P-glycoprotein it may also predict which tumors exhibit multidrug resistance (MDR) a phenotype in which tumors fail to respond to a wide variety of chemically unrelated chemotherapeutic agents. This article reviews the synthetic preclinical and early human data obtained during the development phase of this promising new radiopharmaceutical.
Drug Metabolite Generation Using a Laboratory Evolved NADPH Independent Cytochrome P450: Application of in vitro and in silico Approaches
Twelve disparate drugs were subjected to metabolite generation by a laboratory evolved bacterial cytochrome P450 to investigate feasibility of the bacterial CYP to generate drug metabolites. Seven drugs were metabolised by the bacterial cytochromes to give diverse metabolites which were compared to human metabolites reported in literature. Several non human metabolites were also generated by the bacterial CYP in addition to the known human metabolites. From docking studies and in silico sites of metabolism results it was shown that the binding mode of the drug molecule and its distance from the active site in the binding pocket of the CYP was important for metabolism. This contribution reports for the first time previously uncharacterised metabolites of this bacterial cytochrome and demonstrates the potential usefulness of human CYP-based prediction software when used in combination with bacterial CYPs for metabolite generation.