TAILIEUCHUNG - Báo cáo khoa học: Human liver mitochondrial cytochrome P450 2D6 – individual variations and implications in drug metabolism

Constitutively expressed human cytochrome P450 2D6 (CYP2D6; EC ) is responsible for the metabolism of approximately 25% of drugs in common clinical use. It is widely accepted that CYP2D6 is localized in the endoplasmic reticulum of cells; however, we have identified this enzyme in the mitochondria of human liver samples and found that extensive inter-individual variability exists with respect to the level of the mitochondrial enzyme. | Human liver mitochondrial cytochrome P450 2D6 - individual variations and implications in drug metabolism Michelle Cook Sangar1 Hindupur K. Anandatheerthavarada1 Weigang Tang1 Subbuswamy K. Prabu1 Martha V. Martin2 Miroslav Dostalek F. Peter Guengerich2 and Narayan G. Avadhani1 1 Department of AnimalBiology Schoolof Veterinary Medicine University of Pennsylvania Philadelphia PA USA 2 Department of Biochemistry and Center in Molecular Toxicology Vanderbilt University Nashville TN USA Keywords bimodal targeting signal bufuralol 1 -hydroxylase human CYP2D6 liver mitochondrial CYP2D6 content mitochondrial targeting Correspondence N. G. Avadhani University of Pennsylvania Schoolof Veterinary Medicine 3800 Spruce Street Room 189E Philadelphia PA 19104 USA Fax 1 215 573 6651 Tel 1 215 898 8819 E-mail narayan@ Present address Department of ClinicalPharmacology University Hospitaland Faculty of Health Studies Ostrava University Czech Republic Received 27 February 2009 revised 16 April 2009 accepted 20 April 2009 doi Constitutively expressed human cytochrome P450 2D6 CYP2D6 EC is responsible for the metabolism of approximately 25 of drugs in common clinical use. It is widely accepted that CYP2D6 is localized in the endoplasmic reticulum of cells however we have identified this enzyme in the mitochondria of human liver samples and found that extensive interindividual variability exists with respect to the level of the mitochondrial enzyme. Metabolic assays using 7-methoxy-4-aminomethylcoumarin as a substrate show that the human liver mitochondrial enzyme is capable of oxidizing this substrate and that the catalytic activity is supported by mitochondrial electron transfer proteins. In the present study we show that CYP2D6 contains an N-terminal chimeric signal that mediates its bimodal targeting to the endoplasmic reticulum and mitochondria. In vitro mitochondrial import studies using both N-terminal deletions and point .

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