TAILIEUCHUNG - Báo cáo khoa học: Kinetic deuterium isotope effects for 7-alkoxycoumarin O-dealkylation reactions catalyzed by human cytochromes P450 and in liver microsomes Rate-limiting C-H bond breaking in cytochrome P450 1A2 substrate oxidation

7-Ethoxy (OEt) coumarin has been used as a model substrate in many cyto-chrome P450 (P450) studies, including the use of kinetic isotope effects to probe facets of P450 kinetics. P450s 1A2 and 2E1 are known to be the major catalysts of 7-OEt coumarinO-deethylation in human liver micro-somes. | ềFEBS Journal Kinetic deuterium isotope effects for 7-alkoxycoumarin O-dealkylation reactions catalyzed by human cytochromes P450 and in liver microsomes Rate-limiting C-H bond breaking in cytochrome P450 1A2 substrate oxidation Keon-Hee Kim1 Emre M. Isin2 Chul-Ho Yun1 Dong-Hyun Kim3 and F. P. Guengerich2 1 Hormone Research Center and Schoolof BiologicalSciences and Technology Chonnam National university Gwangju Korea 2 Department of Biochemistry and Center in Molecular Toxicology Vanderbilt University Schoolof Medicine Nashville TN USA 3 Doping ControlCenter Korean Institute of Science and Technology Seoul Korea Keywords alkoxycoumarins coumarins Cytochrome P450 kinetic isotope effects microsomal reactions Correspondence F. P. Guengerich Department of Biochemistry and Center in Molecular Toxicology Vanderbilt University Schoolof Medicine Nashville TN 37232-0146 USA Fax 615 322 3141 Tel. 615 322 2261 E-mail Note The conventions used for kinetic hydrogen isotope effects are Dk intrinsic kinetic deuterium isotope effect DV Hkcat Dkcat and d V K Hkcat HKm Dkcat DKm 2 3 . Received 20 February 2006 accepted 17 March 2006 doi 7-Ethoxy OEt coumarin has been used as a model substrate in many cytochrome P450 P450 studies including the use of kinetic isotope effects to probe facets of P450 kinetics. P450s 1A2 and 2E1 are known to be the major catalysts of 7-OEt coumarin O-deethylation in human liver microsomes. Human P450 1A2 also catalyzed 3-hydroxylation of 7-methoxy OMe coumarin at appreciable rates but P450 2E1 did not. Intramolecular kinetic isotope effects were used as estimates of the intrinsic kinetic deuterium isotope effects for both 7-OMe and 7-OEt coumarin dealkylation reactions. The apparent intrinsic isotope effect for P450 1A2 for O-demethylation for O-deethylation showed little attenuation in other competitive and noncompetitive experiments. With P450 2E1 the intrinsic isotope effect for

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