Suicide inactivation of aromatase in human placenta and uterine leiomyoma by 5 alpha-dihydronorethindrone, a metabolite of norethindrone, and its effect on steroid-producing enzymes.
Norethindrone (NET; 17 alpha-ethynyl-19-nortestosterone), a progestogen component of the contraceptive pill, irreversibly inhibits aromatase activity in human placental microsomes. However, it is known also to be aromatized in vitro and in vivo to produce a biologically very active estrogen called ethynylestradiol (EE2). It is therefore inappropriate to administer a high dose of NET to estrogen-dependent cancer patients for a prolonged time period. In this study, we focused on 5 alpha-dihydronorethindrone (5 alpha-DHNET), a metabolite of NET that is not aromatizable, and the inhibitory effects of 5 alpha-DHNET on human placental and uterine leiomyoma microsomal aromatase and other steroid synthetases. 5 alpha-Dihydronorethindrone showed weak affinity for both estrogen and progestogen receptors. It inhibited significantly human placental aromatase activity in a dose-dependent manner (Ki = 9.0 mumol/l; Kinact = 0.024/min), as well as that of uterine leiomyoma, but did not influence cholesterol side-chain cleavage or 17 alpha-hydroxylase, 21-hydroxylase or 11 beta-hydroxylase activities. These results suggest that 5 alpha-DHNET may be useful as an aromatase inhibitor, whose use in large doses is expected to reduce the size of estrogen-dependent tumors.
Yamamoto
T
T
Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Japan.
Tamura
T
T
Kitawaki
J
J
Osawa
Y
Y
Okada
H
H
D000328:Adult; D000818:Animals; D047072:Aromatase Inhibitors; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D009640:Norethindrone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D010920:Placenta / Q000187:drug effects / Q000201:enzymology*; D011247:Pregnancy; D011817:Rabbits; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D014594:Uterine Neoplasms / Q000201:enzymology*
D047072:Aromatase Inhibitors; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C014485:5 alpha-dihydronorethindrone; D006899:Mixed Function Oxygenases; D009640:Norethindrone