文章基本信息

标题：Aromatase Inhibition by 4β,5β-Epoxides of 16α-Hydroxyandrostenedione and Its 19-Oxygenated Analogs, Potential Precursors of Estriol Production in the Feto-Placental Unit
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作者：Mitsuteru Numazawa ; Akiko Yoshimura ; Yoko Watari 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2002
卷号：25
期号：12
页码：1566-1569
DOI：10.1248/bpb.25.1566
出版社：The Pharmaceutical Society of Japan
摘要：To gain insight into the nature of the substrate binding site and the catalytic function of aromatase, we studied the inhibition of androstenedione aromatization by 4β,5β-epoxy-16α-hydroxyandrostenedione (4) and its 19-hydroxy and 19-oxo derivatives, 5 and 6, as well as the biochemical aromatization of these steroids in human placental microsomes. The 19-methyl and 19-oxo compounds, 4 and 6, were weak competitive inhibitors of aromatase, with apparent K _i values of 246 μ M and 270 μ M , respectively, whereas the 19-hydroxy compound 5 inhibited aromatase in a non-competitive manner with the K _i of 135 μ M . The 19-methyl compound 4 inactivated aromatase in a time-dependent manner with k _inact of 0.213 min⁻¹ in the presence of NADPH in air, but the other two did not cause it. The conversion of the three epoxides into estrogen, as well as 19-oxygenation of 19-methyl steroid 4 with human placental microsomes in the presence of NADPH in air, were not detected by gas chromatography-mass spectrometry. The present results are consistent with the two binding sites theory in the active site of aromatase.
关键词：aromatase;4β,5β-epoxy-16α-hydroxy steroid;non-competitive inhibition;time-dependent inactivation;gas chromatography-mass spectrometry