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Effects of Tamoxifen, Tamoxifen Metabolites, and Nafoxidine on Adenosine 3',5'-Monophosphate Phosphodiesterase: Correlations with Growth Inhibitory Activities but not Estrogen Receptor Affinities^*

INSERM U 205, Laboratoire de Physiologie-Pharmacodynamie France
Laboratoire de Chimie Biologique, INSA 69621 Villeurbanne Cedex France

Address all correspondence and requests for reprints to: Prof. Christian Laugier, Laboratoire de Physiologie-Pharmacodynamie, INSA 406, 20 avenue Albert Einstein, 69621 Villeurbanne Cedex, France.ax This work was supported by INSERM and a grant from La Ligue Nationale Francaise contre le Cancer.

Abstract

Triphenylethylenes [Tamoxifen (TAM), TAM metabolites, and nafoxidine] were found to inhibit Ca²⁺-calmodulin (CaM)-dependent cAMP phosphodiesterase (PDE) activity of the quail oviduct, whereas 17β-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, K_i = 3 µM; metabolite Z, traras-4-hydroxytamoxifen, and TAM K_i = 5 µM; nafoxidine, K_i = 8.5 µM; and metabolite Y and cis-4-hydroxytamoxifen, K_i = 50 µM. 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 Ndesmethyltamoxifen 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.

Received February 13, 1989.

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