Molecular organization of the microsomal oxidative system: a new connotation for an old term

Abstract

The central role that cytochromes P450 play in the metabolism of drugs and other xenobiotics makes these enzymes a major subject for studies of drug disposition, adverse drug effects and drug-drug interactions. Despite tremendous success in elucidating structures and mechanisms of cytochrome P450 function, the concept of the drug-metabolizing ensemble as a functionally integrated system remains undeveloped. However, eukaryotic cells typically possess a multitude of different cytochromes P450 that are co-localized in the membrane of endoplasmic reticulum (ER); they interact with each other through the formation of dynamic heteromeric complexes (mixed oligomers). There has been growing appreciation of the importance of developing an approach to study the ensemble of cytochromes P450 as an integral system inspired growing interest of researchers to the principles of molecular organization of the microsomal monooxygenase system. Academician Archakov and his colleagues made important contributions to this field during the initial period of studies. Subsequent exploration of the molecular organization of the microsomal monooxygenase system as an integral multienzyme and multifunctional system have had an essential impact on our understanding of the key factors that determine the changes in human drug metabolism and other cytochrome P450-related functions in development and aging, as well as under the influence of various pathologies and environmental factors.