Advances in the interpretation and prediction of CYP2E1 metabolism from a biochemical perspective.
BACKGROUND
Cytochrome P450 2E1 (CYP2E1) plays a central role in the metabolism and metabolic activation of a large number of small, mostly xenobiotic compounds. These qualities distinguish CYP2E1 from traditional enzymes and pose significant challenges to understanding the role and consequences of CYP2E1-mediated metabolism.


OBJECTIVE
This review discusses recent advances in kinetic profiling, quantitative structure-activity relationships and structural studies that have furthered the development of tools to interpret and predict CYP2E1 metabolism.


METHODS
Analysis of kinetic profiles by specific mechanisms produces important parameters describing specificity, stoichiometry and metabolism of molecules. Quantitative structure-activity relationships reveal a more specific basis for molecular recognition by CYP2E1. The corresponding protein structures imparting these interactions are the focus of chemical modifications, site-directed mutagenesis and homology modeling studies.


RESULTS
Compilation of kinetic profiling for CYP2E1 substrates established the selectivity for small substrates, whose characteristics could be generalized in parameters for hydrophobicity and steric properties as determined by quantitative structure-activity relationships. The possibility of an effector site for monocyclic compounds added an interesting variable to these modeling efforts. Various structural studies identified important residues contributing to binding and catalysis as well as the volume and location of the active site relative to the heme moiety. Pressure and carbon monoxide-binding experiments also demonstrated the inherent conformational flexibility of CYP2E1 that may contribute to rate-limiting steps during catalytic turnover.


CONCLUSIONS
Although combinations of these approaches have reinforced important observations, more work is needed to verify findings and seek broader impacts for various interpretative and predictive tools.
Miller
Grover P
GP
University of Arkansas for Medical Sciences, Department of Biochemistry and Molecular Biology, 4301 W. Markham Street, Slot 516, Little Rock, AR 72205, USA. millergroverp@uams.edu
D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008954:Models, Biological; D016296:Mutagenesis; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D017385:Sequence Homology
D004364:Pharmaceutical Preparations; D019392:Cytochrome P-450 CYP2E1