During pregnancy, a significant change has been found in the pattern of liver response to drugs. The activity of drug-metabolizing enzymes was inhibited due to the presence of increased amounts of reduced progesterone metabolites produced by the pregnant animal. Treatment of non-pregnant rats with 5alpha-pregnan-3beta-ol-20-one or 5alpha-pregnan-3beta,20beta-diol also caused a decreased drug hydroxylation. On the other hand, the administration of 16alpha-hydroxyprogesterone resulted in an increased activity. The contrasting effects of the different steroids on the function of the endoplasmic reticulum have shown correlation with changes in microsomal phospholipid synthesis. Reduced progesterone derivatives brought about a decrease, whereas hydroxyprogesterone an enhancement. The opposite actions provided evidence to postulate that during pregnancy the formation of endoplasmic reticulum and associated induction processes of drug metabolism might be regulated by a balance displayed in the production of various progesterone metabolites.