Antiestrogen Action in Avian Liver: The Interaction of Estrogens and Antiestrogens in the Regulation of Apolipoprotein B Synthesis*

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Abstract
The actions of the short acting antiestrogens, estriol and dimethylstilbestrol, and the triphenylethylene antiestrogens, tamoxifen and CI 628, were studied in rooster liver using basal and estradiol-stimulated apolipoprotein B synthesis as a response. Dose-response studies showed that estriol and dimethylstilbestrol acted as full agonists, eliciting the same maximal apolipoprotein B synthesis as did estradiol, diethylstilbestrol, and estrone. Dimethylstilbestrol showed no antagonism when given with submaximal estradiol doses. Dihydrotestosterone showed neither agonism nor antagonism for apolipoprotein B synthesis, suggesting that androgens are unlikely to participate in apolipoprotein B regulation. Tamoxifen and CI 628 were pure antagonists for estradiol-stimulated apolipoprotein B synthesis. Neither compound altered apolipoprotein B synthesis in control roosters, suggesting little or no agonistic activity for these agents or their metabolites in rooster liver. Tamoxifen administration to estradiol-treated roosters blocked apolipoprotein B synthesis within 1–2 h; thereafter, apolipoprotein B synthesis fell rapidly (within 6 h) to the basal rate. This result was seen whether tamoxifen was given at 2, 3, 8, or 72 h after estradiol, suggesting the absence of stable intermediates in estradiol-stimulated apolipoprotein B synthesis. When tamoxifen-treated roosters were challenged with increasing estradiol doses, tamoxifen inhibition was completely reversed. Neither the lag period nor the maximum slope of the initial response curve for estradiolstimulated apolipoprotein B synthesis was altered by tamoxifen pretreatment. The estradiol dose required to overcome tamoxifen inhibition was much greater than that estimated from experiments in which tamoxifen and estradiol were given simultaneously. This result suggests that pharmacokinetic factors or metabolic conversion of tamoxifen to more potent metabolites may influence attempts to evaluate antiestrogen reversibility. The complete reversibility noted here suggests that tamoxifen inhibition is a passive process in avian liver; that is, occupancy of the estradiol receptor by tamoxifen or its metabolites apparently has little effect on the subsequent activity of the receptor when occupied by estradiol. The complete reversibility by estradiol also indicates that the antiestrogenic actions of tamoxifen are not directly mediated through proteins that bind tamoxifen but not estradiol. (Endocrinology108: 1862, 1981)

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