Quantitative structure-activity relationships in a series of endogenous and synthetic steroids exhibiting induction of CYP3A activity and hepatomegaly associated with increased DNA synthesis.
The results of a quantitative structure-activity relationship (QSAR) study on a total of 14 steroids exhibiting induction of a CYP3A-associated activity and increase in liver weight/DNA synthesis is reported. It is found that different, but related, structural descriptors correlate with increase in ethylmorphine N-demethylase activity (r=0.92) and with the increase in liver weight (r=0.78) and DNA synthesis (r=0.78). Although there is a strong correlation between increase in liver weight and DNA content (r=0.999), neither of these correlated with ethylmorphine N-demethylase activity. These findings are discussed in the light of CYP3A induction, substrate specificity and inhibition; a proposed model of human CYP3A4 based on sequence homology with CYP102, a bacterial P450 of known crystal structure, demonstrates the possible mode of interaction between substrates and inhibitors within the putative active site.
Lewis
D F
DF
Molecular Toxicology Group, School of Biological Sciences, University of Surrey, Surrey GU2 7XH, Guildford, UK.
Ioannides
C
C
Parke
D V
DV
Schulte-Hermann
R
R
D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis* / Q000187:drug effects; D006529:Hepatomegaly / Q000139:chemically induced; D006801:Humans; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013256:Steroids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating