Competitive interactions between cytochromes P450 2A6 and 2E1 for NADPH-cytochrome P450 oxidoreductase in the microsomal membranes produced by a baculovirus expression system

Archives of Biochemistry and Biophysics
Y TanC S Yang

Abstract

The present study investigated the interactions between cytochrome P450 (P450) enzymes and the NADPH:cytochrome oxidoreductase (OR) in the microsomal membrane. Microsomes containing human cytochrome P450 2A6 (h2A6) coexpressed with human OR (hOR) via a baculovirus expression system displayed coumarin hydroxylase activity with apparent Km and Vmax values of 0.41 microM and 4.05 nmol/min/nmol P450, respectively. Incorporation of purified rat liver cytochrome b5 (b5) into the microsomes increased the Vmax 2.5-fold, but did not affect the Km. The N-nitrosodimethylamine (NDMA) demethylase activity of human cytochrome P450 2E1 (h2E1) coexpressed similarly was characterized previously. Coumarin was shown not to be a substrate nor an inhibitor of h2E1, and NDMA was not a substrate nor an inhibitor of h2A6. In microsomes containing h2A6, h2E1, and hOR (M-h2A6-h2E1-hOR) obtained from a triple expression system, the two P450 enzymes were shown to compete with each other for interaction with hOR. In incubations with M-h2A6-h2E1-hOR, the presence of a h2A6 substrate (coumarin) decreased NDMA demethylase activity by a maximum of 47%, and the presence of a h2E1 substrate (NDMA) decreased coumarin hydroxylase activity by a maximum of 19%. This...Continue Reading

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Citations

Feb 16, 2005·Biochemistry·Rusty W KelleyWayne L Backes
May 19, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Murali SubramanianTimothy S Tracy
Mar 11, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Murali SubramanianTimothy S Tracy
Aug 22, 2001·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·D SchwarzI Roots
Oct 13, 2009·Drug Metabolism Reviews·Yuji IshiiHideyuki Yamada
Mar 15, 2011·Expert Opinion on Drug Metabolism & Toxicology·Dmitri R Davydov
Dec 14, 2011·Pharmacology & Therapeutics·James R Reed, Wayne L Backes
Jun 29, 2012·The Biochemical Journal·James R ReedWayne L Backes
Mar 11, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Chris D BostickPeter M Gannett
Jan 27, 2005·Molecular Genetics and Metabolism·Lina S Correa-Cerro, Forbes D Porter
Oct 29, 2017·The Journal of Biological Chemistry·Aaron G Bart, Emily E Scott
Mar 17, 2005·Drug Metabolism and Pharmacokinetics·Hiroyuki YasuiHiromu Sakurai
Aug 27, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Diane RamsdenTimothy S Tracy
Feb 19, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·P Wiercinska, E J Squires
Oct 16, 2004·Molecular Pharmacology·Jacqueline J FremontChristopher D King
Mar 26, 2015·Nanotechnology·Christopher D BostickDavid Lederman
Jan 25, 2005·The Journal of Biological Chemistry·Chul-Ho YunF Peter Guengerich
Jun 20, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Richard WeaverRob J Riley
May 16, 2015·Biomedit︠s︡inskai︠a︡ khimii︠a︡·D R Davydov
May 3, 2003·Pharmacology & Therapeutics·Wayne L Backes, Rusty W Kelley
Feb 1, 2005·Archives of Biochemistry and Biophysics·Tsutomu ShimadaF Peter Guengerich

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