Insights into drug metabolism by cytochromes P450 from modelling studies of CYP2D6‐drug interactions

The cytochromes P450 (CYPs) comprise a vast superfamily of enzymes found in virtually all life forms. In mammals, xenobiotic metabolizing CYPs provide crucial protection from the effects of exposure to a wide variety of chemicals, including environmental toxins and therapeutic drugs. Ideally, the in...

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Bibliographic Details
Published in:British journal of pharmacology 2008-03, Vol.153 (S1), p.S82-S89
Main Authors: Maréchal, J‐D, Kemp, C A, Roberts, G C K, Paine, M J I, Wolf, C R, Sutcliffe, M J
Format: Article
Language:English
Subjects:
Animals
comparative modelling
CYP2D6
Cytochrome P-450 CYP2D6 - chemistry
Cytochrome P-450 CYP2D6 - drug effects
Cytochrome P-450 Enzyme System - chemistry
Cytochrome P-450 Enzyme System - drug effects
Cytochrome P-450 Enzyme System - metabolism
cytochromes P450
docking
Drug Interactions
drug metabolism
homology modelling
Humans
hypothesis‐driven studies
Models, Molecular
Pharmaceutical Preparations - metabolism
Review
Substrate Specificity
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Summary:The cytochromes P450 (CYPs) comprise a vast superfamily of enzymes found in virtually all life forms. In mammals, xenobiotic metabolizing CYPs provide crucial protection from the effects of exposure to a wide variety of chemicals, including environmental toxins and therapeutic drugs. Ideally, the information on the possible metabolism by CYPs required during drug development would be obtained from crystal structures of all the CYPs of interest. For some years only crystal structures of distantly related bacterial CYPs were available and homology modelling techniques were used to bridge the gap and produce structural models of human CYPs, and thereby obtain useful functional information. A significant step forward in the reliability of these models came seven years ago with the first crystal structure of a mammalian CYP, rabbit CYP2C5, followed by the structures of six human enzymes, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6 and CYP3A4, and a second rabbit enzyme, CYP2B4. In this review we describe as a case study the evolution of a CYP2D6 model, leading to the validation of the model as an in silico tool for predicting binding and metabolism. This work has led directly to the successful design of CYP2D6 mutants with novel activity—including creating a testosterone hydroxylase, converting quinidine from inhibitor to substrate, creating a diclofenac hydroxylase and creating a dextromethorphan O‐demethylase. Our modelling‐derived hypothesis‐driven integrated interdisciplinary studies have given key insight into the molecular determinants of CYP2D6 and other important drug metabolizing enzymes. British Journal of Pharmacology (2008) 153, S82–S89; doi:10.1038/sj.bjp.0707570; published online 19 November 2007
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0707570