On the Hormetic Behaviour of Drugs Binding to Different Redox States of Amine Oxidase Enzymes
Deepak Narang, G. Reid McDonald, David J. Smith, Maria Luisa Di Paolo, Dale E. Edmondson and Andrew Holt
DOI : 10.3844/ajptsp.2008.125.136
American Journal of Pharmacology and Toxicology
Volume 3, 2008
Classical monoamine oxidases and copper-containing semicarbazide-sensitive amine oxidases are drug targets for a variety of established and novel pharmaceuticals used to treat conditions such as depression, Parkinsonism and inflammatory disorders. Development of enzyme inhibitors, both historically and currently, assumes an underlying adherence of these enzymes to Michaelis-Menten kinetic principles. In this mini-review, we discuss historical data from several laboratories and novel data from our own laboratories which show clearly that such an assumption is invalid. Rather, these enzymes often display hormetic behaviour towards their substrates, resulting in bell-shaped kinetic plots. We outline possible underlying mechanisms which might account for this behaviour and show how novel reversible hormetic drugs may capitalise on these mechanisms to introduce a new dimension in selectivity. The potential future benefits for therapeutic modulation of amine oxidase activities are discussed.
© 2008 Deepak Narang, G. Reid McDonald, David J. Smith, Maria Luisa Di Paolo, Dale E. Edmondson and Andrew Holt. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.