Modeling the cytochrome P450-mediated metabolism of chlorinated volatile organic compounds.
Comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) paradigm, has been used to analyze the metabolic rates, as intrinsic clearance, of a series of chlorinated volatile organic compounds (VOCs). A comparison between 3D-QSAR and conventional Hansch-type QSAR is provided. To develop predictive 3D-QSARs for metabolism, the standard CoMFA model based on steric and electrostatic potential fields must be supplemented with hydropathic and molecular orbital information also in the form of three-dimensional fields. A mechanistic interpretation of chlorinated VOC metabolism by cytochrome P450 isozymes is provided as a rationalization for the inclusion of multiple fields in the CoMFA 3D-QSAR model. Models of this type have practical utility in the development of generalized physiologically-based pharmacokinetic models, as well as the rational, structure-based, design and/or selection of compounds for use in the in vivo and in vitro metabolic studies.
Waller
C L
CL
Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Evans
M V
MV
McKinney
J D
JD
D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004563:Electrochemistry; D006843:Hydrocarbons, Chlorinated / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014835:Volatilization
D006843:Hydrocarbons, Chlorinated; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System