Bowman S P, Leake A, Morris I D
J Endocrinol. 1982 Aug;94(2):167-75. doi: 10.1677/joe.0.0940167.
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-hydroxytamoxifen 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.
在切除卵巢的大鼠单次给予他莫昔芬或4-羟基他莫昔芬后长达16天的时间里，对下丘脑、垂体和子宫制备的胞质溶胶和细胞核中的高亲和力雌激素受体进行了测量。他莫昔芬使下丘脑、垂体和子宫中胞质溶胶受体的浓度呈剂量依赖性下降。24小时后观察到最低值；胞质溶胶受体浓度恢复缓慢，对于7.0mg/kg和0.7mg/kg剂量的他莫昔芬，分别在4至8天和2至4天之间才达到预期的对照值。除了0.7mg他莫昔芬/kg组下丘脑的核受体浓度未改变外，核受体的变化与胞质溶胶受体的变化呈负相关。4-羟基他莫昔芬（0.14mg/kg）使垂体和子宫中的胞质溶胶受体减少，并使核雌激素受体增加。到第4天，受体浓度已恢复到预期的对照值。下丘脑的雌激素受体浓度未改变。下丘脑受体系统对他莫昔芬和4-羟基他莫昔芬转运的明显抗性可能是由于血脑屏障，因为他莫昔芬对所有三种组织的胞质溶胶受体的表观亲和力相似（解离常数为4nmol/l）。单次给予7.0mg他莫昔芬/kg后测定的他莫昔芬和4-羟基他莫昔芬的血清浓度在24小时后达到最大值，4天时无法检测到，此时核受体和胞质溶胶受体水平仍有变化。4-羟基他莫昔芬的浓度约为他莫昔芬的三分之一。结果表明，他莫昔芬给药后受体的变化不仅仅与他莫昔芬及其代谢产物的血清浓度有关，并且配体在靶组织内的保留可能是一个重要的决定因素。
