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

The FEBS Journal
Keon-Hee KimF P Guengerich

Abstract

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 (9.4 for O-demethylation, 6.1 for O-deethylation) showed little attenuation in other competitive and noncompetitive experiments. With P450 2E1, the intrinsic isotope effect (9.6 for O-demethylation, 6.1 for O-deethylation) was attenuated in the noncompetitive intermolecular experiments. High noncompetitive intermolecular kinetic isotope effects were seen for 7-OEt coumarin O-deethylation in a baculovirus-based microsomal system and five samples of human liver microsomes (7.3-8.1 for O-deethylation), consistent with the view that P450 1A2 is the most efficient P450 catalyzing this reaction in human liver micro...Continue Reading

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Citations

Jun 18, 2014·Plant Physiology and Biochemistry : PPB·Ga-Young LeeChul-Ho Yun
Mar 8, 2013·Journal of Enzyme Inhibition and Medicinal Chemistry·Jinhe PanKuo-Shyan Lin
Mar 12, 2016·Bioconjugate Chemistry·Sarah ZerniaAnnette G Beck-Sickinger
Jul 31, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·John EksterowiczRobert S Foti
Jan 27, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sun-Ha ParkChul-Ho Yun
Jan 11, 2020·Chembiochem : a European Journal of Chemical Biology·Rosa A LuirinkDaan P Geerke
Oct 24, 2009·ChemMedChem·Patrik RydbergLars Olsen
Feb 3, 2012·Chemistry : a European Journal·Zhi SuMartin Newcomb
Aug 2, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Dong-Hyun KimChul-Ho Yun
Feb 2, 2021·The Journal of Physical Chemistry. B·Anil R Mhashal, Dan Thomas Major
Apr 22, 2010·The Journal of Physical Chemistry. B·Patric SchymanSason Shaik
Mar 27, 2018·Journal of Controlled Release : Official Journal of the Controlled Release Society·Brian R HearnDaniel V Santi

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