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Research Article
A quantitative structure–activity relationship analysis on a series of alkyl benzenes metabolized by human cytochrome P450 2E1
Article first published online: 26 FEB 2003
DOI: 10.1002/jbt.10055
Copyright © 2003 Wiley Periodicals, Inc.
1099-0461/asset/cover.gif?v=1&s=464a877af403ab8bb706d1be0c08d11ee0c6d3f2 "Journal of Biochemical and Molecular Toxicology")
Additional Information
How to Cite
Lewis, D. F. V., Sams, C. and Loizou, G. D. (2003), A quantitative structure–activity relationship analysis on a series of alkyl benzenes metabolized by human cytochrome P450 2E1. Journal of Biochemical and Molecular Toxicology, 17: 47–52. doi: 10.1002/jbt.10055
Publication History
- Issue published online: 26 FEB 2003
- Article first published online: 26 FEB 2003
- Manuscript Accepted: 10 OCT 2002
- Manuscript Revised: 7 OCT 2002
- Manuscript Received: 26 JUL 2002
Funded by
- Health and Safety Executive. Grant Number: R51.211
- Abstract
- References
- Cited By
Keywords:
- Alkyl Benzenes;
- Cytochrome P450 2E1;
- Quantitative Structure–Activity Relationships
Abstract
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