Quantitative structure--activity relationships for inducers of cytochromes P450 and nuclear receptor ligands involved in P450 regulation within the CYP1, CYP2, CYP3 and CYP4 families.
The results of quantitative structure-activity relationships (QSARs) are reported for several series of cytochrome P450 inducers, including those which also act as ligands for the various nuclear receptors involved in regulation of the relevant P450 genes, namely, CYP1, CYP2, CYP3 and CYP4. In several examples presented, the QSARs are consistent with homology modelling studies of the nuclear receptor ligand-binding domains (LBDs) based on available crystal structures of the oestrogen and peroxisome proliferator-activated receptors' LBDs. Good correlations (R=0.91-0.99) are found between various structural parameters and biological activity (either in the form of P450 induction or ligand-binding affinity) for the Ah receptor (AhR), human estrogen receptor alpha (hER alpha), human glucocorticoid receptor (hGR) and the rat peroxisome proliferator-activated receptor alpha (rPPAR alpha).
Lewis
D F V
DF
School of Biomedical and Life Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. d.lewis@surrey.ac.uk
Jacobs
M N
MN
Dickins
M
M
Lake
B G
BG
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D003577:Cytochrome P-450 Enzyme System