Drug control of steroid metabolism by the hepatic endoplasmic reticulum

In this review evidence is provided for the interaction between various drugs and steroid hormones in man and between drugs and progestogens in experimental animals. The mechanism by which these drug interactions occur are of fundamental biochemical and pharmacological interest. The importance of practical clinical considerations of drug-steroid interactions has also been discussed. In particular, considering the present tendency to lower the dose of progestogen and estrogen in most contraceptive preparations, any factor that reduces the bioavailability of the steroid hormones becomes very important. Other drugs and environmental chemicals may interact with these steroids and thereby diminish their efficacy. Clinical studies have reported that the most important interfering drugs are some anticonvulsants and antibiotics, and the antituberculosis compound rifampicin. Anticonvulsants and antituberculotics affect microsomal enzyme induction in the liver or interfere with enzyme systems in the gut wall. The action of antibiotics is connected with the pharmacokinetics of contraceptive steroids by an interaction with their enterohepatic circulation. Some environmental factors such as smoking, alcohol, and other dietary variations, and concurrent hepatic disease may modify the disposition of circulating endogenous steroids and exogenous contraceptive steroids. These effects may alter their response accordingly. In our studies drug treatments of rats reduced serum progesterone level irrespective of whether a potent inducer (phenobarbital, 4-methylcoumarin) or a hepatotoxin (carbon tetrachloride, coumarin, alpha-naphthylisothiocyanate) was administered. These treatments affected hepatic progesterone content. Phenobarbital and carbon tetrachloride reduced serum level, but the hepatic incorporation was enhanced by phenobarbital and reduced by carbon tetrachloride. The opposite actions were selective; phenobarbital raised the oxidative pathway of progesterone metabolism but did not modify the reductive pathway. This drug also enhanced progesterone 16 alpha-, 6 beta-, and 20 alpha-hydroxylase, but did not alter delta 4 - 5 alpha-reductase. In contrast, carbon tetrachloride inhibited hydroxylase and enhanced reductase activities. The effects of these test compounds on progesterone-metabolizing enzymes in isolated microsomes in vitro were similar to the in vivo results. It is concluded that the action of various drugs on serum and liver progesterone levels and metabolism is probably related to changes manifest in the function of the hepatic endoplasmic reticulum.