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 activi ty 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 li ver weight (r = 0.78) and DNA synthesis (r = 0.78). Although there is a str ong correlation between increase in liver weight and DNA content (r = 0.999 ), neither of these correlated with ethylmorphine N-demethylase activity. T hese findings an discussed in the light of CYP3A induction, substrate speci ficity and inhibition; a proposed model of human CYP3A4 based on sequence h omology with CYP102, a bacterial P450 of known crystal structure, demonstra tes the possible mode of interaction between substrates and inhibitors with in the putative active site. (C) 2000 Elsevier Science Ltd. All rights rese rved.