title: Brief historical overview and recent progress on cytochromes P450: adaptation of aerobic organisms to their chemical environment and new mechanisms of prodrug bioactivation.
abstract: The present brief overview of the history of the development of our knowledge on cytochromes P450 (P450s) illustrates the spectacular progress that have been made on P450 mechanisms and structures especially during these last 20 years. Recently published structures of mammalian P450-substrate complexes have shown the great diversity of size, shape, and binding modes that are offered by the conformationally flexible substrate binding sites of xenobiotic-metabolizing P450s. They have also shown that these binding sites can adapt themselves to the great structural diversity of xenobiotics, to facilitate their oxidation and elimination. Our present detailed knowledge of the mechanisms and chemistry of P450s allows us to understand, at the molecular level, the origin of the various consequences of P450-dependent metabolism of drugs in pharmacology and toxicology. This is here illustrated by recent data on the detailed mechanism of bioactivation of the anti-thrombotic prodrugs ticlopidine, clopidogrel, and prasugrel.
authors.affiliation: Université Paris Descartes, UMR 8601 CNRS, 45, rue des Saints-Pères, 75270 Paris cedex 06, France. daniel.mansuy@parisdescartes.fr
authors.forename: D
authors.initials: D
authors.lastname: Mansuy
mesh_terms: D000222:Adaptation, Physiological; D000332:Aerobiosis / Q000502:physiology*; D000818:Animals; D001711:Biotransformation / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000266:history* / Q000378:metabolism*; D004777:Environment; D005343:Fibrinolytic Agents / Q000378:metabolism; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D011355:Prodrugs / Q000378:metabolism*
chemical_list: D005343:Fibrinolytic Agents; D011355:Prodrugs; D003577:Cytochrome P-450 Enzyme System