Quarmby V E, Fox-Davies C, Newbold R R, Korach K S
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Biol Reprod. 1988 May;38(4):945-54. doi: 10.1095/biolreprod38.4.945.
Nafoxidine (NAF) acts as an estrogen agonist or antagonist depending on the animal model used. In the CD-1 mouse uterus, a three-day uterine bioassay of NAF produced a bell-shaped dose response curve with a maximal uterine wet weight increase at 200 micrograms/kg; this dose produced only a fractional increase in uterine dry weight. Combination treatment with NAF and estradiol antagonized estradiol stimulation of both wet and dry weight parameters. The time course of uterine wet weight stimulation following a single injection of NAF had an early pattern (0-10 h) similar to that of estradiol. However, at later times after stimulation, the patterns changed dramatically: the low NAF dose (200 micrograms/kg) returned to control levels by 24 h; estradiol and the high dose NAF (1.7 mg/kg) showed sustained stimulation, which peaked at 36 h with NAF compared to 24 h for estradiol. Nuclear estrogen receptor (ER) levels were measured after a single injection of 1.7 mg/kg NAF and showed a bimodal pattern similar to that seen with estradiol, with increases at 1 h and 8 h, although the overall ER levels were elevated above those seen with estradiol. Cytosolic ER levels with NAF decreased by 1 h and remained low up to 48 h. NAF treatment did stimulate uterine DNA and RNA synthesis, with a delayed time course compared to estradiol. DNA synthesis following a single 1.7 mg/kg dose of NAF was 2.5 times higher than that produced by 20 micrograms/kg estradiol. NAF treatment resulted in hypertrophy and hyperplasia in the luminal epithelium but not in the glandular epithelium. Long-term exposure to estradiol for 5 wk resulted in development of uterine cystic glandular hyperplasia and increased secretory activity; long-term exposure to NAF produced a more significant tissue hyperplasia but no secretions. These studies show that NAF stimulates some of the receptor-mediated responses attributed to an estrogen agonist in the mouse uterus; but, when co-administered with estradiol, NAF antagonizes some aspects of estrogen action.
萘福昔定（NAF）根据所使用的动物模型表现为雌激素激动剂或拮抗剂。在CD-1小鼠子宫中，对NAF进行的为期三天的子宫生物测定产生了一条钟形剂量反应曲线，在200微克/千克时子宫湿重增加最大；该剂量仅使子宫干重有微小增加。NAF与雌二醇联合治疗拮抗了雌二醇对湿重和干重参数的刺激作用。单次注射NAF后子宫湿重刺激的时间进程在早期模式（0 - 10小时）与雌二醇相似。然而，在刺激后的后期，模式发生了显著变化：低剂量NAF（200微克/千克）在24小时时恢复到对照水平；雌二醇和高剂量NAF（1.7毫克/千克）显示出持续刺激，NAF在36小时达到峰值，而雌二醇在24小时达到峰值。单次注射1.7毫克/千克NAF后测量核雌激素受体（ER）水平，显示出与雌二醇相似的双峰模式，在1小时和8小时增加，尽管总体ER水平高于雌二醇。NAF处理后胞质ER水平在1小时下降，并在长达48小时内保持较低水平。NAF处理确实刺激了子宫DNA和RNA合成，与雌二醇相比时间进程有所延迟。单次1.7毫克/千克剂量的NAF后的DNA合成比20微克/千克雌二醇产生的DNA合成高2.5倍。NAF处理导致腔上皮肥大和增生，但腺上皮未出现。长期暴露于雌二醇5周导致子宫囊性腺增生和分泌活性增加；长期暴露于NAF产生了更显著的组织增生但无分泌物。这些研究表明，NAF刺激了小鼠子宫中一些归因于雌激素激动剂的受体介导反应；但是，当与雌二醇共同给药时，NAF拮抗了雌激素作用的某些方面。
