Effects of ethinyl estradiol and tamoxifen on liver DNA turnover and new synthesis and appearance of gamma glutamyl transpeptidase-positive foci in female rats.
Effects of ethinyl estradiol and tamoxifen on liver DNA turnover and new synthesis and appearance of gamma glutamyl transpeptidase-positive foci in female rats.
复制标题
乙炔雌二醇和他莫昔芬对雌性大鼠肝脏 DNA 周转以及新合成和 γ 谷氨酰转肽酶阳性病灶出现的影响。
作者：
J. Yager;B. Roebuck;Teresa L. Paluszcyk;V. Memoli
我们研究了合成雌激素雌酚（M）和炔雌醇（EE）促进肝癌发生的可能机制。我们的第一个目标是确定慢性EE治疗是否与伴有再生性增生的肝毒性相关。将雌性SD大鼠部分肝切除，并用[3 H]胸苷预标记其肝脏DNA。两周后，大鼠用三种剂量的EE或M（使用皮下植入的定时释放片剂）处理。或在饲料中添加0.05%苯巴比妥（PB）。6周后处死大鼠，测定肝脏DNA中剩余的[3 H]胸苷含量。结果表明，没有一个启动子引起肝毒性，如通过预先标记的DNA的损失所检测到的。EE，而不是M或PB引起了显着的剂量依赖性增大的垂体。进行后续实验以确定肝脏DNA合成对EE、M和PB处理的剂量-时间响应。用这些药物处理雌性SD大鼠，然后在不同时间测定[3 H]-胸苷掺入DNA的情况。结果表明，2.5微克/天的EE和PB（0.05%）导致肝脏DNA合成迅速增加，在24至72小时之间达到峰值，并至少在接下来的7天内保持升高。EE和M给药大鼠的剂量反应实验表明，开始给药后24小时，在低至0.1微克/天的EE剂量下可检测到肝脏DNA合成显著增加; M也显著增加了DNA合成。抗雌激素他莫昔芬（T）不会导致肝脏DNA合成增加。然而，15微克/天的T确实抑制了由EE和2.5微克/天的M引起的DNA合成诱导，但不抑制PB引起的DNA合成诱导（0.05%）。测定T对EE促进γ-谷氨酰转肽酶（GGT）阳性病灶出现的影响。雌性SD大鼠在部分肝切除术后24 h开始单次腹腔注射20 mg/kg二乙基亚硝胺。一周后，大鼠接受EE（5微克/天）、T（15或50微克/天）或EE + T（两种剂量）定时释放片剂治疗。4个月后处死大鼠，测定GGT病灶的发生率、数量和大小。结果显示，正如预期的那样，EE增强了GGT病灶的出现。出乎意料的是，两种剂量的单独T也增强了病灶的外观。（400字处截断摘要）
We investigated possible mechanisms associated with promotion of hepatocarcinogenesis by the synthetic estrogens mestranol (M) and ethinyl estradiol (EE). Our first objective was to determine whether chronic EE treatment was associated with hepatotoxicity accompanied by regenerative hyperplasia. Female Sprague-Dawley (SD) rats were partially hepatectomized and their liver DNA prelabeled with [3H]thymidine. Two weeks later the rats were treated with EE at three doses or M (using timed-release tablets implanted s.c.) or with 0.05% phenobarbital (PB) in the diet. The rats were killed 6 weeks later and the amount of [3H]thymidine remaining in liver DNA determined. The results showed that none of the promoters caused hepatotoxicity as detected by the loss of prelabeled DNA. EE but not M or PB caused a dramatic dose-dependent enlargement of the pituitary. Subsequent experiments were carried out to define the dose-time response of liver DNA synthesis to treatment with EE, M and PB. Female SD rats were treated with these agents and [3H]-thymidine incorporation into DNA was determined at various times thereafter. The results showed that EE at 2.5 micrograms/day and PB (0.05%) caused a rapid increase in liver DNA synthesis which peaked between 24 and 72 h and remained elevated for at least the next 7 days. Dose-response experiments with EE- and M-treated rats demonstrated that 24 h after beginning treatment, significant increases in liver DNA synthesis could be detected at an EE dose as low as 0.1 microgram/day; DNA synthesis was also significantly increased by M. The anti-estrogen tamoxifen (T), did not cause increased liver DNA synthesis. However, T at 15 micrograms/day did inhibit the induction of DNA synthesis caused by EE and M at 2.5 micrograms/day but not by PB (0.05%). The effect of T on promotion by EE of the appearance of gamma glutamyl transpeptidase (GGT)-positive foci was determined. Female SD rats were initiated with a single i.p. dose of diethylnitrosamine at 20 mg/kg given 24 h after partial hepatectomy. One week later the rats were treated with EE (5 micrograms/day), T (15 or 50 micrograms/day) or EE plus T at both doses using timed-release tablets. The rats were killed after 4 months and the incidence, number and size of the GGT foci determined. The results revealed that, as expected, EE enhanced the appearance of GGT foci. Unexpectedly, T alone at both doses also enhanced the appearance of the foci.(ABSTRACT TRUNCATED AT 400 WORDS)