Inhibition of rat ovarian 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17 alpha-hydroxylase and 17,20 lyase by progestins and danazol.
The site of action of synthetic progestins or danazol in the treatment of endometriosis is considered to be mainly the hypothalamo-pituitary level, but the direct action to the uterine endometrium and the ovary is also suggested. We investigated the effect of these synthetic steroids to rat ovarian steroidogenic enzymes. The effect of norethisterone, levonorgestrel, danazol, gestrinone, desogestrel and 3-keto-desogestrel was studied in vitro. The sources of the enzymes were prepared from ovaries of immature rats treated either with pregnant mare serum gonadotropin (PMS) and human chorionic gonadotropin (hCG) for 3 beta-hydroxy steroid dehydrogenase (3 beta-HSD), or with PMS for 17 alpha-hydroxylase and 17,20 lyase. The substrates used were pregnenolone (P5) for 3 beta-HSD, progesterone (P4) for 17 alpha-hydroxylase, and 17 alpha-hydroxy-progesterone (17 alpha-OH-P4) for 17,20 lyase. The substrates were incubated with the enzyme sources and coenzymes, and the products formed were measured. All the steroids inhibited 3 beta-HSD, and the inhibition by gestrinone (Ki = 3.0 microM) and 3-keto-desogestrel (17.5 microM) was particularly marked. Only desogestrel (Ki = 30.3 microM) and danazol (168 microM) inhibited 17 alpha-hydroxylase. All the steroids inhibited 17,20 lyase, and the inhibition by desogestrel (Ki = 0.70 microM), danazol (0.80 microM), and gestrinone (30 microM) was particularly marked.
Arakawa
S
S
Department of Obstetrics and Gynecology, Teikyo University School of Medicine, Tokyo, Japan.
Mitsuma
M
M
Iyo
M
M
Ohkawa
R
R
Kambegawa
A
A
Okinaga
S
S
Arai
K
K
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003613:Danazol / Q000494:pharmacology*; D005260:Female; D007700:Kinetics; D010053:Ovary / Q000201:enzymology*; D011245:Pregnadienes / Q000494:pharmacology*; D045167:Progesterone Congeners / Q000494:pharmacology*; D051381:Rats; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*; D013997:Time Factors
D065607:Cytochrome P-450 Enzyme Inhibitors; D011245:Pregnadienes; D045167:Progesterone Congeners; D003577:Cytochrome P-450 Enzyme System; D015096:3-Hydroxysteroid Dehydrogenases; D013250:Steroid Hydroxylases; D013254:Steroid 17-alpha-Hydroxylase; D000446:Aldehyde-Lyases; D003613:Danazol