Opposite regulation of cAMP concentration in the quail oviduct and the mouse uterus by tamoxifen. Correlation with estrogen-antagonist and estrogen-agonist activity.
The ability of estradiol and tamoxifen to regulate cAMP levels and cAMP phosphodiesterase activities has been determined in the quail oviduct and in the mouse uterus. In the quail, tamoxifen (1 mg/kg daily for 3 days) had no effect on oviducal growth but significantly increased cAMP concentration (+49%). Injected concurrently with estradiol, tamoxifen completely inhibited oviduct growth as well as the increase of cAMP phosphodiesterase activity induced by the hormone alone and increased cAMP concentration (+229% over estradiol treated group). In the mouse, estradiol and tamoxifen displayed uterotrophic activity and increased cAMP phosphodiesterase activity. In both groups, cAMP concentration was greatly reduced (-76% in estradiol treated group; -86% in tamoxifen treated group). The opposite regulation of cAMP levels in the quail oviduct and the mouse uterus by tamoxifen reflected large differences in the contribution of calmodulin-dependent and -independent forms of phosphodiesterase to the hydrolysis of cAMP in the two models and the fact that tamoxifen stimulated the activity of the calmodulin-independent isoenzyme, while it competitively inhibited the activation of the calmodulin-dependent isoenzyme by calmodulin. Several lines of evidence strongly suggest that the regulation of cAMP levels is involved in growth-inhibiting or growth-promoting activity of tamoxifen.
Fanidi
A
A
INSERM U 205, Laboratoire de Physiologie-Pharmacodynamie, Villeurbanne, France.
Ahnadi
C
C
Fayard
J M
JM
Pageaux
J F
JF
Laugier
C
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000375:Aging; D000818:Animals; D003370:Coturnix; D000242:Cyclic AMP / Q000378:metabolism*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D007700:Kinetics; D051379:Mice; D010057:Oviducts / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*
D004965:Estrogen Antagonists; D013629:Tamoxifen; C016601:afimoxifene; D004958:Estradiol; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1