Astroff B, Safe S
Department of Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station 77843.
Toxicol Appl Pharmacol. 1988 Sep 30;95(3):435-43. doi: 10.1016/0041-008x(88)90361-4.
The ED50s for the dose-response induction of hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the female Sprague-Dawley rat were 3.3 and 2.7 nmol/kg, respectively. In contrast, the corresponding ED50 values for induction by the nontoxic 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) were 524 and 578 mumol/kg for AHH and EROD, respectively, and TCDD was greater than 1.5 X 10(5) more potent than MCDF as an agonist for this response. Cotreatment of the female rats with MCDF (20, 50, or 100 mumol/kg) and TCDD (6.4 nmol/kg) showed that MCDF partially antagonized the induction of AHH and EROD by TCDD and this corresponded with results previously reported in the male rat. Like TCDD, MCDF also caused a dose-response decrease in uterine and hepatic cytosolic and nuclear estrogen (ERc and ERn) and progesterone (PRc and PRn) receptor levels. The relative TCDD/MCDF potencies for the reduction of uterine ERc, ERn, PRc, and PRn levels were 293, 569, 560, and 459, respectively, and comparable potency ratios (693, 409, 405, and 424, respectively) were observed in the liver. Since MCDF was active as an antiestrogen at dose levels which caused only minimal induction of hepatic monooxygenases, it is unlikely that induction of these enzymes and the subsequent increased metabolism of estradiol play a role in the antiestrogenic effects of MCDF (or TCDD). The reasons for the differences in the relative potency of MCDF for the "traditional" Ah receptor-mediated response (i.e., AHH induction) and the modulation of steroid hormone receptor binding levels are unknown. MCDF, a compound which exhibits relatively high TCDD receptor binding activity and low toxicity, represents a new class of nontoxic halogenated aromatic antiestrogens that can be utilized to further probe the mechanism of this response in model systems.
在雌性斯普拉格 - 道利大鼠中，2,3,7,8 - 四氯二苯并 - p - 二恶英（TCDD）诱导肝微粒体芳烃羟化酶（AHH）和乙氧基异吩恶唑酮 - O - 脱乙基酶（EROD）剂量反应的半数有效剂量（ED50）分别为3.3和2.7 nmol/kg。相比之下，无毒的6 - 甲基 - 1,3,8 - 三氯二苯并呋喃（MCDF）诱导AHH和EROD的相应ED50值分别为524和578 μmol/kg，作为该反应的激动剂，TCDD的效力比MCDF大1.5×10⁵倍以上。用MCDF（20、50或100 μmol/kg）和TCDD（6.4 nmol/kg）共同处理雌性大鼠表明，MCDF部分拮抗TCDD对AHH和EROD的诱导作用，这与先前在雄性大鼠中报道的结果一致。与TCDD一样，MCDF也导致子宫和肝脏胞质及核雌激素（ERc和ERn）和孕激素（PRc和PRn）受体水平呈剂量反应性降低。TCDD/MCDF降低子宫ERc、ERn、PRc和PRn水平的相对效力分别为293、569、560和459，在肝脏中观察到了类似的效力比（分别为693、409、405和424）。由于MCDF在仅引起肝脏单加氧酶最小诱导的剂量水平下就具有抗雌激素活性，因此这些酶的诱导以及随后雌二醇代谢增加不太可能在MCDF（或TCDD）的抗雌激素作用中发挥作用。MCDF对“传统”芳烃受体介导的反应（即AHH诱导）和类固醇激素受体结合水平调节的相对效力差异的原因尚不清楚。MCDF是一种具有相对较高TCDD受体结合活性和低毒性的化合物，代表了一类新型的无毒卤代芳烃抗雌激素，可用于在模型系统中进一步探究这种反应的机制。
