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Kinetic deuterium isotope effects in cytochrome P450 oxidation reactions
Author(s) -
Guengerich F. Peter
Publication year - 2013
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.3031
Subject(s) - chemistry , kinetic isotope effect , deuterium , cytochrome p450 , limiting , drug metabolism , computational chemistry , stereochemistry , enzyme , organic chemistry , nuclear physics , mechanical engineering , engineering , physics
Cytochrome P450 (P450) enzymes account for ~75% of the metabolism of drugs. Most of the reactions catalyzed by P450s are mixed‐function oxidations, and a C–H bond is (usually) broken. The rate‐limiting nature of this step can be analyzed using the kinetic isotope effect (KIE) approach. The most relevant type of KIE is one termed intermolecular non‐competitive, indicative of rate‐limiting C–H bond breaking. A plot of KIE versus k cat for several P450s showed a correlation coefficient ( r 2 ) of 0.62. Deuterium substitution has been considered as a potential means of slowing drug metabolism or redirecting sites of metabolism in some cases, and several general points can be made regarding the potential for application of deuterium in drug design/development based on what is known about P450 KIEs. Copyright © 2013 John Wiley & Sons, Ltd.