afimoxifene and estradiol-3-benzoate

Previous studies demonstrated that estrogen induces two sequential waves of CA1 pyramidal cell activation, evidenced by induction of c-Fos at 2 and 24 h after a single estrogen treatment. The second wave of activation is paralleled by suppression of immunoreactivity for glutamic acid decarboxylase-65kD (GAD65) in CA1 and decreased synaptic inhibition of CA1 pyramidal cells. Here, we report that pretreatment with either of the selective estrogen receptor (ER) modulators, tamoxifen (T) or CI628, has no effect on the first wave of c-Fos expression at 2 h but completely blocks the second wave of c-Fos and the suppression of GAD65 at 24 h. Interestingly, T, given 4 h after estrogen, failed to block c-Fos expression or suppression of GAD65 at 24 h. Electrophysiological experiments showed that the T metabolite, 4OH-T, or CI628 can inhibit the so-called rapid estrogen effect, to potentiate excitatory postsynaptic currents (EPSCs) in CA1 pyramidal cells. Thus, estrogen seems to act within 4 h via classical ERs and/or a rapid estrogen effect, such as EPSC potentiation, to produce activation/disinhibition of pyramidal cells 24 h later. In contrast, the initial activation of pyramidal cells, at 2 h after estrogen, seems to involve neither classical ERs nor rapid potentiation of EPSCs.

Topics: Animals; Estradiol; Excitatory Postsynaptic Potentials; Female; Glutamate Decarboxylase; Isoenzymes; Kinetics; Nitromifene; Ovariectomy; Proto-Oncogene Proteins c-fos; Pyramidal Cells; Rats; Selective Estrogen Receptor Modulators; Tamoxifen

Tamoxifen, a nonsteroidal antiestrogen, is used widely in the treatment of breast cancer and is undergoing evaluation as a chemopreventive agent. In this study, we investigated several long-term effects of tamoxifen in intact adult female rats following acute treatment at various dosages. The effects of tamoxifen on somatic growth, growth hormone (GH) levels, thyroid hormone levels, and on hepatic cytochrome P450 (P450) expression were compared with those of fulvestrant (ICI 182,780), 17beta-estradiol-3-benzoate, and 4-hydroxytamoxifen under the same experimental conditions. Each compound was injected s.c. for two consecutive days, and rats were killed 37 days after treatment. Tamoxifen decreased body weight and serum triiodothyronine (T3) levels at dosages ranging from 0.5 to 200 mg/kg. Ovary weight, uterus weight, peak plasma GH concentration, and hepatic CYP2A1 content were decreased 37 days after treatment with tamoxifen at a dosage of 20 mg/kg, but expression of other P450 enzymes was not affected. However, tamoxifen and 4-hydroxytamoxifen could not be detected in plasma by high performance liquid chromatography analysis at this time, which suggests that the effects of tamoxifen were mediated indirectly. 4-Hydroxytamoxifen exhibited effects similar to those of tamoxifen, indicating that this metabolite contributes to the in vivo activity of tamoxifen. Estradiol benzoate decreased CYP2A1 and increased CYP3A hepatic levels, but had no effect on serum T3 concentration. In contrast, treatment with ICI 182,780 had little or no effect on the endpoints measured. In summary, 2-day tamoxifen treatment of intact adult female rats resulted in persistent suppression of somatic growth, serum T3 levels, and hepatic CYP2A1 expression.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Body Weight; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Estradiol; Female; Gene Expression Regulation, Enzymologic; Liver; Organ Size; Ovary; Rats; Rats, Long-Evans; Steroid Hydroxylases; Tamoxifen; Testosterone; Thyroxine; Time Factors; Triiodothyronine; Uterus