Wade J, Schlinger B A, Hodges L, Arnold A P
Department of Psychology, University of California, Los Angeles 90024-1563.
Gen Comp Endocrinol. 1994 Apr;94(1):53-61. doi: 10.1006/gcen.1994.1059.
Aromatase and 5 beta-reductase activity are expressed at high levels in the zebra finch brain, especially in the telencephalon. Aromatization of androgens to estrogens is thought to be a critical step in the organization and activation of avian sexual behaviors. In contrast, 5 beta-reductase is thought to be an inactivating enzyme, one that catalyzes the conversion of androgens to biologically inactive metabolites. To address the importance of aromatase activity in this system, it is necessary to find an effective and selective aromatase inhibitor, one that has little or no effect on other androgen-metabolizing enzymes. The potency and specificity of fadrozole hydrochloride as an aromatase inhibitor was tested in zebra finch telencephalon. The compound was tested in vitro in primary dissociated cell cultures made from hatching telencephalon and compared to a commonly used inhibitor, 1,4,6-androstatriene-3,17-dione (ATD). Untreated, these cultures express extremely high levels of aromatase and 5 beta-reductase activity and therefore allow sensitive measurement of the effectiveness of inhibitors. Aromatase activity was also measured in homogenates of adult telencephalon following in vivo fadrozole injection. Finally, aromatase and 5 beta-reductase activity were quantified in zebra finch telencephalon following similar intramuscular injections in 4- to 6-day-old birds. In all three cases, fadrozole was highly effective in reducing aromatase activity. Fadrozole increased 5 beta-reductase activity, presumably due to an increase in available substrate, but had no inhibitory effect on the enzyme. ATD was less effective in inhibiting aromatase, and it also inhibited 5 beta-reductase activity at high concentrations.
芳香化酶和5β-还原酶活性在斑胸草雀大脑中高表达，尤其是在端脑。雄激素向雌激素的芳香化被认为是鸟类性行为组织和激活的关键步骤。相比之下，5β-还原酶被认为是一种失活酶，它催化雄激素转化为生物活性较低的代谢产物。为了阐明芳香化酶活性在该系统中的重要性，有必要找到一种有效且选择性的芳香化酶抑制剂，这种抑制剂对其他雄激素代谢酶几乎没有影响。在斑胸草雀端脑中测试了盐酸法倔唑作为芳香化酶抑制剂的效力和特异性。该化合物在由孵化后的端脑制成的原代解离细胞培养物中进行了体外测试，并与常用抑制剂1,4,6-雄甾三烯-3,17-二酮（ATD）进行了比较。未经处理时，这些培养物表达极高水平的芳香化酶和5β-还原酶活性，因此可以灵敏地测量抑制剂的有效性。在体内注射法倔唑后，还测量了成年端脑匀浆中的芳香化酶活性。最后，在4至6日龄鸟类中进行类似的肌肉注射后，对斑胸草雀端脑中的芳香化酶和5β-还原酶活性进行了定量。在所有三种情况下，法倔唑在降低芳香化酶活性方面都非常有效。法倔唑增加了5β-还原酶活性，可能是由于可用底物增加，但对该酶没有抑制作用。ATD在抑制芳香化酶方面效果较差，并且在高浓度时也抑制5β-还原酶活性。
