Dose-dependent effects of ethinyloestradiol, diethylstilboestrol and oestradiol on the metabolism of 4-androstene-3,17-dione in rat liver microsomes

Abstract

The effects of administration of ethinyloestradiol (EtE2), 0.1, 0.5 or 1 mu g per day, diethylstilboestrol, 5, 100 or 500 mu g per day, and oestradiol, 1 or 100 mu g per day for 12 days on the hepatic microsomal metabolism of 4-(4-14C)androstene-3,17-dione were studied in castrated male and female rats. When rats were given EtE2 in daily doses of 0.1 and 0.5 mu g, the activities of the 3 alpha- and 17 beta-hydroxysteroid oxidoreducatses increased in both male and female rats. A similar tendency was noted for the 5 alpha-reductase in female rats. On the other hand, the activities of the 3 beta-hydroxysteroid oxidoreductase and 7 alpha-hydroxylase enzyme systems were suppressed in both male and female rats already after administration of 0.1 mu g of EtE2. Diethylstilboestrol, administered in doses of 100 and 500 mu g, and oestradiol, given in a dose of 100 mu g, suppressed the microsomal enzyme activities whereas the lower doses of 5 mu g of diethylstilboestrol and 1 mu g of oestradiol were without effects. The results indicate that oestrogenic compounds given in doses higher than the physiological one have a suppressing effect on microsomal steroid metabolizing enzyme activities. Ethinyloestradiol has a stimulating effect on certain microsomal enzyme activities and an inhibiting effect on others when administered in an amount of 0.5 mu g-kg-1 per day. The findings are discussed in relation to recent reports on impaired drug metabolism in women taking contraceptives.

PIP: The effects of .1, .5, or 1 mcg/day of ethinyl estradiol (EE), 5, 100, or 500 mcg/day diethylstilbestrol (DES), and 1 or 100 mcg/day estradiol (E) for 12 days on the hepatic microsomal metabolism of 4-(4-carbon-14) androstene-3, 17-dione were studied in castrated rats of both sexes. .1 and .5 mcg EE increased the activities of 3alpha- and 17beta-hydroxysteroid oxidoreductases in both female and male animals. However, 1 mcg EE suppressed the activities of 3beta-hydroxysteroid and 7alpha-hydroxylase enzyme systems. Microsomal enzyme activities were suppressed by 100 and 500 mcg DES and 100 mcg E, while the lower doses of DES and E had no effect. The results show that higher than physiologic doses of estrogenic compounds can impair microsomal steroid metabolizing enzyme activities.