Binding of [3H]Monohydroxytamoxifen by Immature Rat Tissues in Vivo*

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Abstract
The distribution and tissue binding of a [3H] antiestrogen (monohydroxytamoxifen) have been determined in the immature rat and compared with that observed with [3H] estradiol. [3H]Monohydroxytamoxifen (20 μCi equivalent to 0.093 μg trans isomer) produced a prolonged retention of radioactivity in the uterus, vagina, and liver for up to 48 h. Binding of radioactivity in the spleen, heart, and skeletal muscle was lower than that in the liver, uterus, and vagina, rose to maximal levels at 4 h, and decreased thereafter. In contrast [3H]estradiol (10 μCi equivalent to 0.05 μg) rapidly bound in the uterus and vagina (within 2 h) and rapidly decreased toward values in nontarget tissue (spleen, heart, and skeletal muscle) by 24 h. The levels of radioactivity in the blood after [3H]estradiol and [3H]monohydroxytamoxifen treatment reflected the pattern of radioactivity in the uterus and vagina. Increasing the dose of monohydroxytamoxifen by adding 1 μg cold carrier to 18 μCi[3H]monohydroxytamoxifen/ immature rat essentially did not change the retention of radioactivity in the uterus, vagina, heart, and skeletal muscle for up to 3 days. The binding of [3H]monohydroxytamoxifen in the uterus was inhibited by pretreatment of rats with the antiestrogens trioxifene, tamoxifen, and monohydroxytamoxifen and the estrogens estradiol (in a dose-related manner) and diethylstilbestrol. By comparison, progesterone, 5α-dihydrotestosterone, and cortisol were ineffective. Similarly estradiol, tamoxifen, and monohydroxytamoxifen (but not progesterone, 5α-dihydrotestosterone, and cortisol) inhibited estrogen-specific binding of [3H]estradiol and [3H]monohydroxytamoxifen by uterine cytosols in vitro. When different tissues were compared in vivo, increasing doses of monohydroxytamoxifen (but not estradiol) inhibited [3H]monohydroxytamoxifen binding in the liver. Estradiol and monohydroxytamoxifen both inhibited [3H] monohydroxytamoxifen binding in the uterus in a dose-related manner. Estradiol (10 μg), diethylstilbestrol (100 μg), or monohydroxytamoxifen (10 or 100 μg) reversed the binding of prebound [3H]monohydroxytamoxifen by the uterus or vagina. In general, estrogen pretreatment was less effective at inhibiting the binding of [3H]monohydroxytamoxifen than antiestrogen pretreatment, suggesting either the demonstration of an antiestrogen (estrogen-insensitive)-binding component of tissues or, more likely, major pharmacokinetic differences between estrogens and antiestrogens.