The effects of steroidal estrogens in ACI rat mammary carcinogenesis:: 17β-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16α-hydroxyestradiol, and 4-hydroxyestrone
The effects of steroidal estrogens in ACI rat mammary carcinogenesis:: 17β-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16α-hydroxyestradiol, and 4-hydroxyestrone
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DOI：
10.1677/joe.1.05802
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发表时间：
2004-10-01
影响因子：
4
通讯作者：
Mesia-Vela, S
中科院分区：
文献类型：
--
作者：
Turan, VK;Sanchez, RI;Mesia-Vela, S
一些研究者认为，17 β-雌二醇（E-2）的某些羟基化代谢物是在雌激素敏感的啮齿动物模型中诱发乳腺癌的最接近的致癌物。本文报告的研究旨在检查不同水平的E-2的致癌潜力和E-2的遗传毒性代谢产物在对E-2诱导的乳腺癌敏感的体内模型中的作用。在雌性ACI大鼠中皮下植入含有E-2（1、2或3 mg）或2-羟基雌二醇（2-OH E-2）、4-羟基雌二醇（4-OH E-2）、16 α-羟基雌二醇（16 α-OH E-2）或4-羟基雌酮（4-OH E-1）（与2 mg E-2等摩尔）的胆固醇颗粒，确定了乳腺肿瘤的潜在诱导作用。用1、2或3 mg E-2治疗导致在12至17周之间首次出现乳腺肿瘤，并且分别在36、19和18周观察到乳腺肿瘤的50%发生率。用1、2或3 mg E-2处理36周的大鼠的最终累积乳腺肿瘤发生率分别为50%、73%和100%。用含有2-OH E-2、4-OH E-2、16 α-OH E-2或4-OH E-1的颗粒处理大鼠未诱导任何可检测的乳腺肿瘤。用1或3 mg E2颗粒剂处理12周的大鼠血清中的E-2水平比对照值增加2- 6倍（类似于30 pg/ml）。用E2处理大鼠增强了E-2向E-1的肝微粒体代谢，但不影响E-2的2-或4-羟基化。总之，我们观察到连续用E-2处理的雌性ACI大鼠中乳腺肿瘤的剂量依赖性诱导;然而，在这些条件下，2-OH E-2、4-OH E-2、16 α-OH E-2和4-OH E-1在诱导乳腺肿瘤方面无活性。
Several investigators have suggested that certain hydroxylated metabolites of 17beta-estradiol (E-2) are the proximate carcinogens that induce mammary carcinomas in estrogen-sensitive rodent models. The studies reported here were designed to examine the carcinogenic potential of different levels of E-2 and the effects of genotoxic metabolites of E-2 in an in vivo model sensitive to E-2-induced mammary cancer. The potential induction of mammary tumors was determined in female ACI rats subcutaneously implanted with cholesterol pellets containing E-2 (1, 2, or 3 mg), or 2-hydroxyestradiol (2-OH E-2), 4-hydroxyestradiol (4-OH E-2), 16alpha-hydroxyestradiol (16alpha-OH E-2), or 4-hydoxyestrone (4-OH E-1) (equimolar to 2 mg E-2). Treatment with 1, 2, or 3 mg E-2 resulted in the first appearance of a mammary tumor between 12 and 17 weeks, and a 50% incidence of mammary tumors was observed at 36, 19, and 18 weeks respectively. The final cumulative mammary tumor incidence in rats treated with 1, 2, or 3 mg E-2 for 36 weeks was 50%, 73%, and 100% respectively. Treatment of rats with pellets containing 2-OH E-2, 4-OH E-2, 16alpha-OH E-2, or 4-OH E-1 did not induce any detectable mammary tumors. The serum levels of E-2 in rats treated with a 1 or 3 mg E2 pellet for 12 weeks was increased 2- to 6-fold above control values (similar to30 pg/ml). Treatment of rats with E2 enhanced the hepatic rnicrosomal metabolism of E-2 to E-1, but did not influence the 2- or 4-hydroxylation of E-2. In summary, we observed a dose-dependent induction of mammary tumors in female ACI rats treated continuously with E-2; however, under these conditions 2-OH E-2, 4-OH E-2, 16alpha-OH E-2, and 4-OH E-1 were inactive in inducing mammary tumors.