Stimulatory and inhibitory effects of estrogen on uterine DNA synthesis.
Stimulatory and inhibitory effects of estrogen on uterine DNA synthesis.
复制标题
雌激素对子宫 DNA 合成的刺激和抑制作用。
作者：
F. Stormshak;R. Leake;N. Wertz;Jack Gorsk
雌激素治疗后在子宫的长期反应的诱导进行了讨论，特别提到DNA合成。未成熟雌性大鼠每天注射雌二醇-17 β或雌三醇（0.01 - 1 μ g）或两种类固醇的组合，连续1天、2天或3天，在最后一次注射溶媒或类固醇后12 - 24 h处死。测定了[~ 3 H]胸苷掺入DNA、[~（14）C]亮氨酸掺入蛋白质和[~（14）C]葡萄糖氧化成~（14）CO_2的体外掺入。用交换试验或用1 × 10（-8）M [3 H]雌二醇在37 ℃孵育完整子宫1小时后测定核结合雌二醇。注射雌三醇仅部分刺激DNA合成的18至24小时后治疗。然而，注射雌三醇，然后注射雌二醇6小时后导致DNA合成增加，这表明雌激素必须存在长达6小时，以诱导随后的DNA合成。最大的DNA和蛋白质的合成和葡萄糖的氧化发生在注射雌二醇（0.1或1杯）后24小时，但被抑制到控制水平后24小时，最后一次三天注射。每天注射0.01 μ g雌二醇导致类似的DNA合成模式，尽管比注射0.1或1 μ g雌二醇后观察到的幅度小。然而，如果每天注射0.01 μ g雌二醇的大鼠用更高剂量的雌二醇（1 μ g）激发，子宫DNA合成显著增加。这些数据表明，长期暴露于雌激素导致子宫细胞成为代谢“难治性”进一步雌激素刺激。连续注射雌三醇（1杯）或间歇注射雌二醇（1杯）对引起子宫“不应性”无效。雌激素受体结合，易位到细胞核，并保留在细胞核中的受体不受序贯雌激素治疗。抑制性产物的积累被认为是这种现象的可能解释。
The induction of long-term responses in the uterus following estrogen treatment is discussed, with special reference to DNA synthesis. Immature female rats injected daily with estradiol-17beta or estriol (0.01 to 1 mug) or a combination of the two steroids for one, two or three consecutive days were sacrificed at intervals from 12 to 24 h after the last injection of vehicle or steroid. In vitro incorporation of [3H]thymidine into DNA [14C]leucine into protein, and oxidation of [14C)glucose to 14CO2 were determined. Nuclear-bound estradiol was determined by use of exchange assay or following incubation of intact uteri with 1 X 10(-8)M ([3H]estradiol for 1 h at 37 C. Injection of estriol only partially stimulated DNA synthesis by 18 to 24 h post-treatment. However, injection of estriol followed by injection of estradiol 6 h later resulted in increased DNA synthesis, suggesting that estrogen must be present for up to 6 h to induce subsequent DNA synthesis. Maximal DNA and protein synthesis and oxidation of glucose occurred at 24 h after injection of estradiol (0.1 or 1 mug) but was depressed to control levels by 24 h after the last of three daily injections. Daily injections of 0.01 mug of estradiol resulted in a similar pattern of DNA synthesis, although of lesser magnitude than that observed after injection of 0.1 or 1 mug of estradiol. However, if rats receiving daily injections of 0.01 mug estradiol were challenged with a higher dose of estradiol (1 mug), uterine DNA synthesis was markedly increased. The data suggest that prolonged exposure to estrogen causes uterine cells to become metabolically "refractory" to further estrogen stimulation. Sequential injections of estriol (1 mug) or intermittent injections of estradiol (1 mug) were ineffective in causing this uterine "refractoriness". Receptor binding of estrogen, translocation to the nucleus, and retention of receptor in the nucleus were not affected by sequential estrogen treatment. The accumulation of an inhibitory product is suggested as a possible explanation for this phenomenon.