Abstract
This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drug-metabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH–cytochrome P450 reductase, and cytochrome b5. Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b5 and P450 surfaces, showing that b5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.
Footnotes
- Received August 30, 2013.
- Accepted October 15, 2013.
This work was supported in part by the National Institutes of Health [Grants R01 GM031001, F32 GM103069, R01 GM076343, R01 ES004344, and P42 ES013648] and by Gilead Sciences, Inc.
This report is a summary of a session at Experimental Biology 2013 sponsored by the Drug Metabolism Division of the American Society for Pharmacology and Experimental Therapeutics.
1 For reviews on boosted protease inhibitors see the following reviews and references therein:
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- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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