CHANGES IN DRUG METABOLISM BY STEROID TREATMENTS OF FEMALE RATS

Studies in our laboratory showed that hepatic endoplasmic reticulum (ER) drug metabolizing activity was decreased during pregnancy in the rat. This raised the question as to whether or not steroid hormones or derivatives are responsible for the altered drug metabolism during pregnancy. To provide an answer, female rats were treated with 16α-hydroxyprogesterone (16-OHP) and 5β-pregnan-3α-ol-20-one (5-PREG). 16-OHP treatment increased liver microsomal cytochrome P-450 content and aminopyrine-N-demethylase (APDM) activity. Parallel with these enzyme changes, 16-OHP caused increases in liver microsomal total phospholipid (PL) content, and in fatty acids of total PL, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) fractions. Both saturated and unsaturated fatty acids were increased in these fractions, unsaturated fatty acids to a greater extent, resulting in an increased unsaturated:saturated fatty acid ratio. In contrast, 5-PREG treatment reduced hepatic microsomal cytochrome P-450 content and APDM activity, and caused a concurrent decrease in liver microsomal total PL, and in fatty acids of total PL, PC and PE fractions. Both saturated and unsaturated fatty acids were reduced, unsaturated fatty acids to a greater degree, resulting in a lower unsaturated:saturated fatty acid ratio. These data indicated that progesterone metabolites can alter drug metabolizing function of the hepatic ER in female rats and may account for the modified pharmacokinetics of drugs observed during pregnancy. Further, the data suggested that changes in drug metabolism elicited by 16-OHP and 5-PREG may be modulated by intrinsic structural alterations in the lipid moieties of the hepatic ER membranes.