Pre- and post-translational regulation of aromatase by steroidal and non-steroidal aromatase inhibitors.
Treatment of castrated quail with testosterone (T) reliably activates male copulatory behavior and, at the same time, increases the aromatase activity (AA), the number of aromatase-immunoreactive (ARO-ir) cells and the concentration of aromatase mRNA as measured by RT-PCR in the brain. All these effects can be mimicked by estrogens. The behavioral effects of T can be blocked by a variety of aromatase inhibitors and, in parallel, the AA is strongly inhibited in the preoptic area (POA). We showed recently that the steroidal inhibitor, 4-OH-androstenedione (OHA) markedly decreases the immunostaining density of brain ARO-ir cells while the non-steroidal inhibitor, R76713 (racemic Vorozole; VOR) unexpectedly increased the density of this staining, despite the fact that the enzyme activity was completely inhibited. To generalize these findings and try to identify the underlying mechanism, we compared here the effects of two steroidal (OHA and androstatrienedione [ATD]) and two non-steroidal (VOR and Fadrozole [FAD]) aromatase inhibitors on the aromatase immunostaining and aromatase mRNA concentration in the brain of castrated quail concurrently treated with T. The 4 inhibitors significantly blocked the activation by T of male copulation. The two steroidal inhibitors decreased the immunostaining of brain ARO-ir cells but both VOR and FAD markedly enhanced the density of this staining. In parallel, OHA and ATD completely blocked the T-induced increase in aromatase mRNA concentration, while VOR and FAD had no effect on these RNA concentrations in the POA-anterior hypothalamus and they decreased them only slightly in the posterior hypothalamus. Taken together these results suggest that the inhibition of AA by ATD or OHA and the subsequent removal of locally produced estrogens blocks the synthesis of aromatase presumably at the transcriptional level. By contrast, the two non-steroidal inhibitors tested here block AA but in parallel increase the aromatase immunostaining. This effect does not result from an enhanced transcription and it is therefore speculated that these compounds increase either the translation of the aromatase mRNA or the half-life of the protein itself.
Foidart
A
A
Laboratory of Biochemistry, University of Liège, Belgium.
Tlemçani
O
O
Harada
N
N
Abe-Dohmae
S
S
Balthazart
J
J
D000818:Animals; D001141:Aromatase / Q000096:biosynthesis / Q000378:metabolism*; D047072:Aromatase Inhibitors; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002988:Cloaca / Q000033:anatomy & histology / Q000201:enzymology; D004967:Estrogens / Q000502:physiology; D005260:Female; D006207:Half-Life; D007150:Immunohistochemistry; D008297:Male; D008969:Molecular Sequence Data; D011301:Preoptic Area / Q000187:drug effects / Q000201:enzymology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011784:Quail / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013256:Steroids / Q000494:pharmacology*
D047072:Aromatase Inhibitors; D004967:Estrogens; D012333:RNA, Messenger; D013256:Steroids; D001141:Aromatase