Effects of tamoxifen, tamoxifen metabolites, and nafoxidine on adenosine 3',5'-monophosphate phosphodiesterase: correlations with growth inhibitory activities but not estrogen receptor affinities.
Triphenylethylenes [Tamoxifen (TAM), TAM metabolites, and nafoxidine] were found to inhibit Ca2+-calmodulin (CaM)-dependent cAMP phosphodiesterase (PDE) activity of the quail oviduct, whereas 17 beta-estradiol was inactive. The Ca2+-CaM-independent PDE activity was not affected by triphenylethylenes, suggesting that they do not interact directly with the active site of the enzyme. Kinetic analysis indicated that these drugs competitively inhibited the activation of PDE by CaM with the following potencies: N-desmethyltamoxifen, Ki = 3 microM; metabolite Z, trans-4-hydroxytamoxifen, and TAM Ki = 5 microM; nafoxidine, Ki = 8.5 microM; and metabolite Y and cis-4-hydroxytamoxifen, Ki = 50 microM. Injected alone into immature quails, none of these drugs significantly affected oviduct weight. When administrated together with estradiol benzoate, these drugs reduced the trophic effect of estradiol in a dose-dependent relationship, with ID50 values ranging from 0.07 mg/kg for N-desmethyltamoxifen to 2.02 mg/kg for cis-4-hydroxytamoxifen. The order of growth inhibitory potency was not correlated with estrogen receptor affinities, but was the same as that reported for PDE inhibition. This correlation suggests that interaction of antiestrogen with Ca2+-CaM dependent PDE may be one of the mechanisms responsible for the estrogen antagonist activity of these drugs.
Fanidi
A
A
INSERM U 205, Laboratoire de Physiologie-Pharmacodynamie, Villeurbanne, France.
Courion-Guichardaz
C
C
Fayard
J M
JM
Pageaux
J F
JF
Laugier
C
C
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D007700:Kinetics; D009256:Nafoxidine / Q000494:pharmacology*; D010057:Oviducts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology*; D011784:Quail; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*
D011759:Pyrrolidines; D011960:Receptors, Estrogen; D013629:Tamoxifen; D009256:Nafoxidine; D004958:Estradiol; D015105:3',5'-Cyclic-AMP Phosphodiesterases