Understanding cooperativity in human p450 mediated drug-drug interactions.
Multiple drugs can interact, often leading to adverse side effects. One well documented site for these interactions includes the group of cytochrome P450 monoxygenases. Several human hepatic systems are known to bind more than a single substrate molecule which can give rise to the terms "homotropic and heterotopic cooperativity" to define the resultant thermodynamic and kinetic properties observed in drug metabolism investigations. We provide a means for understanding and quantitating these drug-drug interactions by documenting the functional properties of the various states of the enzyme and show that, even in the absence of true binding cooperativity, significant non-Michaelis metabolic profiles are possible.
Sligar
Stephen G
SG
Department of Biochemistry, College of Medicine and the Center for Biophysics and Computational Biology, University of Illinois, Urbana, Illinois 61801, USA. s-sligar@uiuc.edu
Denisov
Ilia G
IG
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*