FADROZOLE - A POTENT AND SPECIFIC INHIBITOR OF AROMATASE IN THE ZEBRAFINCH BRAIN

Aromatase and 5 beta-reductase activity are expressed at high levels i n the zebra finch brain, especially in the telencephalon. Aromatizatio n of androgens to estrogens is thought to be a critical step in the or ganization and activation of avian sexual behaviors. In contrast, 5 be ta-reductase is thought to be an inactivating enzyme, one that catalyz es the conversion of androgens to biologically inactive metabolites. T o address the importance of aromatase activity in this system, it is n ecessary to find an effective and selective aromatase inhibitor, one t hat has little or no effect on other androgen-metabolizing enzymes. Th e potency and specificity of fadrozole hydrochloride as an aromatase i nhibitor was tested in zebra finch telencephalon. The compound was tes ted in vitro in primary dissociated cell cultures made from hatchling telencephalon and compared to a commonly used inhibitor, 1,4,6-androst atriene-3,17-dione (ATD). Untreated, these cultures express extremely high levels of aromatase and 5 beta-reductase activity and therefore a llow sensitive measurement of the effectiveness of inhibitors. Aromata se activity was also measured in homogenates of adult telencephalon fo llowing in vivo fadrozole injection. Finally, aromatase and 5 beta-red uctase activity were quantified in zebra finch telencephalon following similar intramuscular injections in 4- to 6-day-old birds. In all thr ee cases, fadrozole was highly effective in reducing aromatase activit y. 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 in hibited SP-reductase activity at high concentrations. (C) 1994 Academi c Press, Inc.