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High-affinity oestrogen receptors were measured in the cytosol and nuclei prepared from the hypothalamus, pituitary gland and uterus of the ovariectomized rat up to 16 days after a single dose of tamoxifen or 4-hydroxytamoxifen. Tamoxifen produced a dose-related fall in the concentration of cytosol receptors in the hypothalamus, pituitary gland and uterus. Minimum values were observed after 24 h; cytosol receptor concentrations were restored slowly and only reached expected control values between 4 and 8 days and 2 and 4 days for 7·0 mg/kg and 0·7 mg/kg doses of tamoxifen respectively. The nuclear receptor changes were inversely related to the cytosol receptor changes, except that hypothalamic nuclear receptor concentrations after 0·7 mg tamoxifen/kg were not changed. 4-Hydroxytamoxifen (0·14 mg/kg) depleted cytosol and raised nuclear oestrogen receptors in the pituitary gland and uterus. Receptor concentrations had returned to the expected control values by day 4. Oestrogen receptor concentrations in the hypothalamus were unchanged. The apparent resistance of the receptor system in the hypothalamus to translocation by tamoxifen and 4-hydroxytamoxifen was probably due to the blood–brain barrier since the apparent affinity of tamoxifen for the cytosol receptor was similar for all three tissues (dissociation constant 4 nmol/l).

Serum concentrations of tamoxifen and 4-hydroxytamoxifen measured after a single dose of 7·0 mg tamoxifen/kg were maximal after 24 h and undetectable by 4 days, at which time nuclear and cytosol receptor levels were still changed. Concentrations of 4-hydroxy-tamoxifen were approximately one-third those of tamoxifen. The results suggest that the receptor changes after tamoxifen are not simply related to the serum concentration of tamoxifen and its metabolites and that the retention of ligand within the target tissue may be an important determinant.

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