Differential response of immature rat uterine tissue to ethinylestradiol and the red wine constituent resveratrol
Differential response of immature rat uterine tissue to ethinylestradiol and the red wine constituent resveratrol
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DOI：
10.1007/s002040000186
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发表时间：
2001-01-01
影响因子：
6.1
通讯作者：
Krötlinger, F
中科院分区：
文献类型：
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作者：
Freyberger, A;Hartmann, E;Krötlinger, F
二苯乙烯衍生物白藜芦醇（resveratrol， RES）是葡萄、花生和其他水果中的植物抗菌素。它在结构上与二苯乙烯雌激素有关，最近在一些体外研究中证实了RES的雌激素潜能。本实验测定了未成熟Wistar大鼠连续3天皮下注射RES（18、58、575 mg/kg）和对照雌激素炔雌醇（EE2; 0.3、1、3、30 mg/kg）对子宫营养的影响。检测子宫重量、组织病理变化、核雌激素受体α (ER α)和孕激素受体（PR）蛋白的免疫组化表达、mRNA水平ER α和PR基因表达及过氧化物酶诱导。EE2剂量依赖性地增加子宫重量，增大子宫腔，诱导上皮细胞、间质细胞和子宫内膜细胞肥大。ER α的表达。ee2处理大鼠上皮、间质和子宫内膜核中PR蛋白含量降低，上皮细胞核中PR蛋白含量降低，而间质和子宫内膜核中PR蛋白含量呈剂量依赖性增加。EE2增加子宫PR信使核糖核酸（mRNA）水平，诱导过氧化物酶活性。相比之下，RES对子宫重量的影响较为轻微，组织学上未发现对照组与RES处理大鼠之间的差异。res处理大鼠上皮细胞、间质细胞和子宫内膜细胞中核ER α蛋白的表达呈剂量依赖性降低，而对照组和res处理大鼠的核PR蛋白含量相似。在给药后，发现ER α和PR mRNA水平有降低的趋势，但没有发生过氧化物酶诱导。单次皮下给药500 mg/kg后45分钟血浆RES水平在1-2 ma范围内。总之，尽管使用了最有效的给药途径和极高的剂量，并且血浆水平在体外有效的范围内，但在这项体内研究中，RES的雌激素潜力无法得到证实。讨论了RES的其他药理特性是否介导了RES处理动物的观察变化。
The stilbene derivative resveratrol (RES) is a phytoalexin of grapes, peanuts and other fruits. It is structurally related to stilbene estrogens and an estrogenic potential of RES has recently been demonstrated in a number of in vitro studies. In this investigation, the uterotrophic responses of immature Wistar rats to subcutaneous administration of RES (18, 58, and 575 mg/kg) and the reference estrogen ethinylestradiol (EE2; 0.3, 1, 3, 30 mug/kg) on three consecutive days were determined. Uterine weight, histopathological changes, immunohistochemical expression of nuclear estrogen receptor-alpha (ER alpha) and progesterone receptor (PR) protein, gene expression of ER alpha and PR at the messenger ribonucleic acid (mRNA) level and peroxidase induction were examined. EE2 dose dependently increased uterine weight, enlarged the uterine lumen and induced hypertrophy of epithelial, stromal and myometrial cells. Expression of ER alpha. protein in epithelial, stromal and myometrial nuclei and of PR protein in epithelial nuclei was reduced in EE2-treated rats, while PR protein in stromal and myometrial nuclei was increased in a dose-dependent manner. EE2 increased messenger ribonucleic acid (mRNA) levels of uterine PR and induced peroxidase activity. In contrast, RES rather mildly decreased uterine weight, while histology did not reveal differences between controls and RES-treated rats. Expression of nuclear ER alpha protein was dose dependently decreased in epithelial, stromal and myometrial cells of RES-treated rats, while nuclear PR protein content was similar in controls and RES-treated rats. Following administration of RES, a trend toward reduced levels of ER alpha and PR mRNA was found, while no peroxidase induction occurred. Plasma levels of RES, 45 min after the administration of a single subcutaneous dose of 500 mg/kg, were in the range 1-2 muM. In summary, an estrogenic potential of RES could not be substantiated in this in vivo study, although the most effective route of administration and extremely high doses were used and plasma levels were in the range reported to be effective in vitro. Whether other pharmacological properties of RES could mediate the observed changes in RES-treated animals is discussed.