Kinetic deuterium isotope effects in cytochrome P450 oxidation reactions

Cytochrome P450 (P450) enzymes account for similar to 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 (c) 2013 John Wiley & Sons, Ltd.