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Mechanism-Based Inactivation of Human Cytochromes P450
Dr. Paul F. Hollenberg, Ph.D
Chair, Department of Pharmacology
The University of Michigan Medical School
Ann Arbor, MI
The cytochrome P450s catalyze the metabolic activation of a wide variety of drugs and other xenobiotics to reactive intermediates which can covalently bind to cellular molecules ultimately leading to toxicity by a variety of different mechanisms. These reactive intermediates may also react with moieties in the P450 active sites that catalyze their formation to form covalent adducts that inactivate the P450 without ever leaving the active site, a process referred to as mechanism-based inactivation. The irreversible inactivation of the human P450s by drugs and other xenobiotics has resulted in a number of clinically significant drug-drug interactions and is of considerable importance in drug discovery and development.
A variety of different types of drugs have been shown to undergo metabolic activation by P450s to very tight-binding or highly reactive intermediates that can inactivate the proteins by binding to the heme or to the apoprotein. Mechanism-based inactivators can be used to probe the active sites of P450s in their catalytically functional conformations. The identification of the site of modification, whether it is on the apoprotein or the heme prosthetic group, can provide valuable information regarding the three-dimensional structure of the active site.
Recent advances in trapping procedures for the identification of reactive intermediates have greatly facilitated these types of studies. We have investigated the abilities of a wide variety of compounds to act as mechanism-based inactivators and determined the structural aspects and functional groups of several classes of molecules that lead to mechanism-based inactivation during metabolism by P450s.
This presentation will focus on studies on the mechanism-based inactivation of human P450s, the trapping and identification of the reactive intermediates responsible for inactivation, and the determination of the sites of modification on the protein responsible for the loss of activity.
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|Dr. Jack H. Dean
Dr. Thomas Baillie
| Challenges & Opportunities in Drug Development from a Drug Safety and Metabolism Perspective
|May 19, 2009
|Eric Johnson, Ph.D.
| Characterization of Substrate/Inhibitor Binding to Drug-Metabolizing Cytochrome P450 Monooxygenases using X-ray Crystallography
|September 30, 2008
|Dr. Kenneth E. Thummel, Ph.D.
| Regulation Of Intestinal CYP3A By VDR: Implications And Safety Of Oral Therapeutics
|May 7, 2008
|Dr. Anthony Lu, Ph.D.
| Why Is The Liver Microsomal Cytochrome P450 Such A Versatile And Unique Enzyme?
|September 12, 2007
|Dr. Scott Obach, Ph.D.
| Leveraging ADME Data In Metabolites In Safety Testing (MIST)
|April 18, 2007
|Dr. Sidney Nelson, Ph.D.
| Drug Metabolism and Chemical Structural Alerts
|September 27, 2006
|Richard B. Kim, MD
| Relevance and Utility of Transporters to Drug Discovery and Development
|September 21, 2005
|Dr. Frederick P. Guengerich, Ph.D.
| Human Cytochrome P450 2A6 as a Case History: Flavors, Smoke, Blue Roses, New Drugs & Basics of a P450
|April 27, 2005
|Dr. Leslie Benet, Ph.D.
|Predicting Drug Disposition via Application of BCS: Transport/Absorption/Elimination Interplay and BDDCS
|September 29, 2004
|Dr. Christopher A. Lipinski, Ph.D.
|ADME/Tox: How Low Can You Go And How Do You Recover?
|April 21, 2004
Our October 2009 meeting is generously sponsored by: