Growth inhibition and the regulation of cyclic AMP by the triphenylethylene anti-estrogen tamoxifen in the quail oviduct.
The aim of the present study was to investigate the regulation of cAMP by tamoxifen in quail oviduct. A single injection of tamoxifen to immature female quails induced a transient activation of adenylate cyclase. Enzyme activity began to increase 3 h after the injection, peaked at 6 h and then dropped to control level at 12 h. The same time-response curves were observed following the injection of estradiol benzoate or estradiol benzoate + tamoxifen. Moreover, adenylcyclase exhibited the same sensitivity to exogenous activators (guanylylimidodiphosphate and forskolin) in the different treated groups. Phosphodiesterase activity was left unchanged during the prereplicative period and cAMP concentration was significantly increased at 6 h (+ 44.3%). Then, cAMP concentration continued to increase (+ 73.8% at 24 h) while cAMP phosphodiesterase and adenylcyclase activities remained at control levels. Injected concurrently with estradiol benzoate, tamoxifen completely inhibited the growth promoting effect of estradiol. Tamoxifen also inhibited the activation of adenylcyclase and cAMP phosphodiesterase induced by the hormone alone during the proliferative phase of the tissue. Moreover, the combined treatment led to a sustained elevation of cAMP in the oviduct, whereas estradiol benzoate alone decreased the level of cAMP. These results and those of our previous studies showing a significant correlation between the growth inhibitory potency of triphenylethylene derivatives in vivo and their efficiency to inhibit calmodulin-dependent cAMP phosphodiesterase in vitro, strongly suggest that the differential regulation of cAMP levels by estradiol and tamoxifen is essential for the growth promoting or growth inhibiting activities of these molecules.
Fanidi
A
A
INSERM U 205, Laboratoire de Physiologie-Pharmacodynamie, Villeurbanne, France.
Pageaux
J F
JF
Courion
C
C
Fayard
J M
JM
Laugier
C
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003370:Coturnix; D000242:Cyclic AMP / Q000378:metabolism*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004338:Drug Combinations; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D010057:Oviducts / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D013629:Tamoxifen / Q000494:pharmacology*
D004338:Drug Combinations; D013629:Tamoxifen; D004958:Estradiol; C010452:estradiol-17 beta-benzoate; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D000262:Adenylyl Cyclases