Effect of drugs on progesterone metabolism in the female rat.
Various drugs brought about a reduction of serum progesterone level irrespective of whether or not a potent inducer (phenobarbital, 4-methyl-coumarin) or a hepatotoxin (carbon tetrachloride, alpha-naphthylisothiocyanate, coumarin) has been administered. The decrease by hepatotoxins was highly significant during the estrus phase of the cycle. These treatments affected the hepatic level of progesterone and altered the uptake of [4-14C]progesterone in vivo. The serum level of progesterone was significantly decreased by phenobarbital and carbon tetrachloride; however, the incorporation into the liver was enhanced by phenobarbital and reduced by carbon tetrachloride. This opposing hepatic action showed selectivity; phenobarbital increased the oxidative pathway of progesterone metabolism (formation of 6 beta-, 16 alpha-, 20 alpha-hydroxyprogesterone) but the reductive pathway remained unaltered (formation of pregnanediol, pregnanolone). Conversely, carbon tetrachloride diminished oxidation and raised reduction of progesterone. These results have been confirmed by measurements of progesterone metabolism in vitro using isolated microsomes. Phenobarbital brought about an induction of progesterone 16 alpha-, 6 beta- and 20 alpha-hydroxylase, did not affect progesterone delta 4-5 alpha-dehydrogenase, whereas carbon tetrachloride inhibited hydroxylase and raised dehydrogenase activities. The action of these test compounds on serum and liver levels of progesterone and on the variation of progesterone metabolism seemed to be related to changes manifest in the function of the hepatic endoplasmic reticulum. Similar changes might be associated with the development of mild hepatic lesions induced by various steroids.
D015058:1-Naphthylisothiocyanate / Q000494:pharmacology; D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D004971:Estrus / Q000187:drug effects; D005260:Female; D008099:Liver / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011247:Pregnancy; D011374:Progesterone / Q000097:blood / Q000378:metabolism*; D051381:Rats
D003374:Coumarins; D011374:Progesterone; D015058:1-Naphthylisothiocyanate; D002251:Carbon Tetrachloride; D010634:Phenobarbital