title: Aromatization of androstenedione and 16alpha-hydroxyandrostenedione in human placental microsomes. Kinetic analysis of inhibition by the 19-oxygenated and 3-deoxy analogs.
abstract: Inhibition of aromatase activity in human placental microsomes with androstenedione (AD) (1a) and its 19-oxygenated derivatives 1b and 1c, their 16alpha-hydroxy compounds 2 and 3, and 3-deoxyandrost-4-ene compounds 5 and 6 was studied using [1beta-(3)H]AD as a substrate and compared to that with [1beta-(3)H]16alpha-hydroxyandrostenedione (16-OHAD). AD series of steroids, compounds 1, inhibited competitively [1beta-(3)H]AD aromatization whereas other 16alpha-hydroxy steroids 2, 3, 5, and 6 inhibited AD aromatization in a non-competitive manner. On the other hand, all of 16-OHAD series, compounds 2, blocked the [1beta-(3)H]16-OHAD aromatization in a competitive manner whereas the AD series steroids 1 as well as the 3-deoxy-16alpha-hydroxy-17-one steroids 5 and 3-deoxy-16alpha,17beta-diol steroids 6 inhibited 16-OHAD aromatization non-competitively. 3-carbonyl and 16alpha-hydroxy functions of 16-OHAD play a critical role of selection of the 16-OHAD binding site. The results suggest that the AD derivatives 1 are kinetically aromatized at a different site from the 16-OHAD derivatives 2. Physical and/or chemical environments around the aromatase protein in the microsomal membrane may play a significant role in the expression of the substrate specificity, and the present results do not exclude the idea that the placental microsomes have a single binding site.
authors.affiliation: Tohoku Pharmaceutical University, 4-1 Komatsushima-4-Chome, Sendai 981-8558, Japan. numazawa@tohoku-pharm.ac.jp
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Numazawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Watari
authors.forename: Sachiko
authors.initials: S
authors.lastname: Komatsu
authors.forename: Kouwa
authors.initials: K
authors.lastname: Yamashita
authors.forename: Masao
authors.initials: M
authors.lastname: Nagaoka
mesh_terms: D000735:Androstenedione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000378:metabolism; D003500:Cyclization; D005260:Female; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008861:Microsomes / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D047072:Aromatase Inhibitors; D000735:Androstenedione; C018202:16-hydroxyandrost-4-en-3,17-dione; D010100:Oxygen