Romkes M, Safe S
Department of Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station 77843.
Toxicol Appl Pharmacol. 1988 Mar 15;92(3):368-80. doi: 10.1016/0041-008x(88)90177-9.
The comparative antiestrogenic effects of progesterone and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cytosolic and nuclear estrogen (ERc and ERn, respectively) and progesterone (PRc and PRn, respectively) receptor levels were determined in female Long Evans rats. Estradiol treatment typically increases ER and PR levels in target cells or tissues and these proteins have been proposed as markers of estrogen action. 2,3,7,8-TCDD causes a dose-dependent decrease in uterine ERc, ERn, PRc, and PRn levels which persist up to 7 days. Progesterone treatment caused significant decreases in uterine ERc, ERn, and PRn levels; however, after 7 days, the effects of the hormone on receptor levels were diminished. The effects of 2,3,7,8-TCDD and progesterone on hepatic ER and PR levels were comparable to those observed in the uterus. Treatment of the rats with estradiol (5 micrograms/kg), estradiol (5 micrograms/kg) plus progesterone (1 mg/animal), or 2,3,7,8-TCDD (80 micrograms/kg) showed that both progesterone and 2,3,7,8-TCDD significantly antagonized the estradiol-mediated increases in uterine (and hepatic) ERc, ERn, PRc, and PRn levels and for 2,3,7,8-TCDD the decreased receptor levels persisted for up to 7 days. In vitro studies with freshly isolated uterine strips demonstrated that both 2,3,7,8-TCDD and progesterone antagonized the estradiol-mediated increases in ER and PR levels. Previous studies suggest that the antiestrogenic activity of progesterone is due, in part, to the induction of proteins which are involved in decreasing ERn levels in target cells. Moreover in the uterine strip assay procedure, it was previously shown and reproduced in this study that the decrease in uterine ERn by progesterone was inhibited by both protein and RNA synthesis inhibitors over a 4-hr incubation period. In contrast, the 2,3,7,8-TCDD-mediated decrease in uterine ERn was inhibited only by actinomycin D and not by cycloheximide or puromycin. These in vitro studies thus confirm that both progesterone and 2,3,7,8-TCDD exhibit comparable antiestrogenic effects in vivo and in vitro; however, the results suggest that these effects are expressed through different mechanisms.
在雌性长 Evans 大鼠中测定了孕酮和 2,3,7,8-四氯二苯并 -p-二噁英（TCDD）对胞质雌激素受体（ERc）和核雌激素受体（ERn）以及孕酮受体（PRc 和 PRn）水平的比较抗雌激素作用。雌二醇处理通常会增加靶细胞或组织中的 ER 和 PR 水平，并且这些蛋白质已被提议作为雌激素作用的标志物。2,3,7,8-TCDD 会导致子宫 ERc、ERn、PRc 和 PRn 水平呈剂量依赖性下降，这种下降可持续长达 7 天。孕酮处理导致子宫 ERc、ERn 和 PRn 水平显著下降；然而，7 天后，该激素对受体水平的影响减弱。2,3,7,8-TCDD 和孕酮对肝脏 ER 和 PR 水平的影响与在子宫中观察到的相似。用雌二醇（5 微克/千克）、雌二醇（5 微克/千克）加孕酮（1 毫克/只动物）或 2,3,7,8-TCDD（80 微克/千克）处理大鼠表明，孕酮和 2,3,7,8-TCDD 均显著拮抗雌二醇介导的子宫（和肝脏）ERc、ERn、PRc 和 PRn 水平的升高，并且对于 2,3,7,8-TCDD，受体水平的降低可持续长达 7 天。对新鲜分离的子宫条进行的体外研究表明，2,3,7,8-TCDD 和孕酮均拮抗雌二醇介导的 ER 和 PR 水平的升高。先前的研究表明，孕酮的抗雌激素活性部分归因于诱导参与降低靶细胞中 ERn 水平的蛋白质。此外，在子宫条测定程序中，先前已证明并在本研究中重现，在 4 小时的孵育期内，蛋白质和 RNA 合成抑制剂均抑制了孕酮引起的子宫 ERn 降低。相比之下，2,3,7,8-TCDD 介导的子宫 ERn 降低仅被放线菌素 D 抑制，而不被环己酰亚胺或嘌呤霉素抑制。因此，这些体外研究证实，孕酮和 2,3,7,8-TCDD 在体内和体外均表现出相似的抗雌激素作用；然而，结果表明这些作用是通过不同机制表达的。
