Effect of ketoconazole on placental aromatase, 3 beta-hydroxysteroid dehydrogenase-isomerase and 17 beta-hydroxysteroid dehydrogenase.
Ketoconazole, an orally-active, broad spectrum mycotic agent, was shown to inhibit in vitro human placental microsomal aromatase but was without effect on 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activities. The Km of placental aromatase for testosterone was 30 +/- 1.1 nmol/l (mean +/- SEM, n = 6). Inhibition (determined by Lineweaver-Burk plot) was non-competitive with respect to substrate with a Ki value of 3.0 +/- 1.4 mumol/l (mean +/- SEM, n = 6). Ketoconazole was without effect on the 3 beta-HSD-I and 17 beta-HSD activities when using [3H] pregnenolone and [3H] oestradiol, respectively, as substrates. Since ketoconazole is known to inhibit cytochrome P-450-dependent enzyme reactions, the results of the present study support the contention that cytochrome P-450 is involved in the aromatisation process.
D015067:17-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D047072:Aromatase Inhibitors; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D007535:Isomerases / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology*; D008861:Microsomes / Q000201:enzymology; D009097:Multienzyme Complexes / Q000378:metabolism*; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D011284:Pregnenolone / Q000378:metabolism; D011375:Progesterone Reductase / Q000378:metabolism*; D013251:Steroid Isomerases / Q000378:metabolism*
C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D047072:Aromatase Inhibitors; D009097:Multienzyme Complexes; D004958:Estradiol; D011284:Pregnenolone; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; D011375:Progesterone Reductase; C032690:3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+)); D007535:Isomerases; D013251:Steroid Isomerases; D007654:Ketoconazole