A quantitative structure-activity relationship analysis on a series of alkyl benzenes metabolized by human cytochrome P450 2E1

The results of quantitative structure–activity relationships for eight alkyl benzenes undergoing oxidative metabolism via human CYP2E1 are reported. Molecular orbital calculations via the AM1 method were employed for the generation of electronic structural descriptors against experimentally generate...

Full description

Saved in:
Bibliographic Details
Published in:Journal of biochemical and molecular toxicology 2003, Vol.17 (1), p.47-52
Main Authors: Lewis, David F. V., Sams, Craig, Loizou, George D.
Format: Article
Language:English
Subjects:
Aged
Alkyl Benzenes
Benzene Derivatives - chemistry
Benzene Derivatives - metabolism
Binding Sites
Cytochrome P-450 CYP2E1 - metabolism
Cytochrome P450 2E1
Female
Humans
Hydrophobic and Hydrophilic Interactions
Kinetics
Male
Microsomes, Liver - enzymology
Middle Aged
Models, Chemical
Protein Binding
Quantitative Structure-Activity Relationship
Quantitative Structure-Activity Relationships
Substrate Specificity
Thermodynamics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The results of quantitative structure–activity relationships for eight alkyl benzenes undergoing oxidative metabolism via human CYP2E1 are reported. Molecular orbital calculations via the AM1 method were employed for the generation of electronic structural descriptors against experimentally generated kinetic data for CYP2E1‐mediated metabolism. The findings point to the importance of electronic structural properties of the molecules themselves, particularly the role of frontier orbitals, in determining rates of metabolism. Other factors appear to be responsible for the affinity of these substrates for the CYP2E1 enzyme however, such as its lipophilic character. The results are consistent with the interactive molecular modeling of these compounds within the putative active site of human CYP2E1 constructed from the CYP2C5 template, where it was found that π–π stacking interactions between aromatic rings are important for the binding of substrates to the CYP2E1 active site, together with contributions from desolvation entropy changes accompanying substrate binding. © 2003 Wiley Periodicals, Inc. J Biochem Mol Toxicol 17:47–52, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10055
ISSN:1095-6670
1099-0461
DOI:10.1002/jbt.10055