体外antiprogestational / antiglucocorticoid活动和黄体酮和假定的代谢产物和合成的糖皮质激素受体结合国开行的衍生品——2914年,国开行- 4124和米非司酮。
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Attardi BJ, Burgenson J, Hild SA,小卷
体外antiprogestational / antiglucocorticoid活动和黄体酮和假定的代谢产物和合成的糖皮质激素受体结合国开行的衍生品——2914年,国开行- 4124和米非司酮。
J类固醇生物化学杂志。2004年3月,88 (3):277 - 88。
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15120421 (在PubMed]
- 文摘
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在决定各种antiprogestins生物资料,重要的是要评估荷尔蒙和antihormonal活动,选择性和效力的近端代谢物。米非司酮的早期代谢特点是快速脱甲基和羟基化。类似的初始代谢途径提出了国开行- 2914(国开行:避孕药开发分支NICHD)和国开行- 4124,和他们的假定的代谢物合成。检查功能活动和效能,在各种细胞化验,和相对约束力的亲和力(rba)孕激素受体(PR)和糖皮质激素受体(GR)的假定的mono -和国开行didemethylated代谢物——2914年,国开行- 4124,米非司酮和国开行的17个阿尔法羟基和芳香环衍生品- 2914和国开行- 4124。绑定亲和力兔子宫monodemethylated代谢物的公关和人力PR-A和PR-B与父母相似的化合物。Monodemethylated米非司酮绑定到兔胸腺与亲和力高于Monodemethylated国开行GR - 2914或国开行- 4124。T47D-CO细胞被用来评估抑制R5020-stimulated内生的碱性磷酸酶活性和transactivation PRE(2)胸腺嘧啶核苷激酶(tk)荧光素酶(LUC)记者在瞬时转染质粒。antiprogestational效力是如下:米非司酮/国开行- 2914 /国开行- 4124 / monodemethylated代谢物(IC(50)大约10 (9)M) >芳香环衍生品(IC(50)大约10 (8)M) > didemethylated / 17阿尔法羟基衍生品(IC(50)大约10 (7)M)。Antiglucocorticoid活动是由抑制dexamethasone-stimulated HepG2细胞转录活动。mono和didemethylated代谢物的国开行4124 - 2914和国开行- antiglucocorticoid活动(IC(50)大约10 (6)M)比monodemethylated米非司酮(IC(50)大约10 (8)M)或其他的测试化合物。 At 10(-6)M in transcription assays, none of these compounds showed progestin agonist activity, whereas mifepristone and its monodemethylated metabolite manifested slight glucocorticoid agonist activity. The reduced antiglucocorticoid activity of monodemethylated CDB-2914 and CDB-4124 was confirmed in vivo by the thymus involution assay in adrenalectomized male rats. The aromatic A-ring derivatives-stimulated transcription of an estrogen-responsive reporter plasmid in MCF-7 and T47D-CO human breast cancer cells but were much less potent than estradiol. Taken together, these data suggest that the proximal metabolites of mifepristone, CDB-2914, and CDB-4124 contribute significantly to the antiprogestational activity of the parent compounds in vivo. Furthermore, the reduced antiglucocorticoid activity of CDB-2914 and CDB-4124 compared to mifepristone in vivo may be due in part to decreased activity of their putative proximal metabolites.