Induction of RAR-beta 2 gene expression in embryos and RAR-beta 2 transactivation by the synthetic retinoid Ro 13-6307 correlates with its high teratogenic potency.
Induction of RAR-beta 2 gene expression in embryos and RAR-beta 2 transactivation by the synthetic retinoid Ro 13-6307 correlates with its high teratogenic potency.
复制标题
合成类维生素A Ro 13-6307 诱导胚胎中 RAR-β 2 基因表达和 RAR-β 2 反式激活与其高致畸效力相关。
DOI：
10.1006/taap.1993.1183
复制
发表时间：
1993
影响因子：
3.8
通讯作者：
Kochhar,DM
中科院分区：
文献类型：
--
作者：
Soprano,DR;Tairis,N;Gyda3rd,M;Harnish,DC;Jiang,H;Soprano,KJ;Kochhar,DM
维生素A（视黄醇），其代谢产物全反式视黄酸（RA），和许多合成类似物（类维生素A）表达可变效力作为致畸剂。虽然类维生素A的生物活性由核RA受体（RAR）和类维生素A X受体（RXR）介导，但尚不清楚这些受体中是否有任何一种介导致畸性，以及效力是否也取决于配体-受体相互作用的性质。先前的证据表明，一种特异性亚型RAR-β2在介导类维生素A致畸性中发挥作用。在这里，我们使用了一种具有三烯侧链的芳香族维甲酸Ro 13-6307来研究其与RAR-β2的相互作用，因为其致畸性要高得多，并且其对胚胎的可及性比RA低得多。给予妊娠小鼠完全致畸剂量的Ro 13-6307（10 mg−kg）优先升高易感胚胎区域的RAR-β2 mRNA水平（最大诱导，肢芽中为对照组的10- 12倍），其方式与完全致畸剂量的全反式RA（100 mg−kg）相当。在共转染实验中，使用连接到报告基因的RAR-β2启动子，发现Ro 13-6307和RAR-β2在转录反式激活中的功效比全反式RA高30-40倍。由于从先前的研究中估计Ro 13-6307的致畸效力是全反式RA的44倍，因此我们认为这种合成类维生素A的致畸性通常与其增强受体功能的能力成比例。
Vitamin A (retinol), its metabolite all-trans retinoic acid (RA), and many synthetic analogs (retinoids) express variable potencies as teratogens. Although biological activities of retinoids are mediated by nuclear RA receptors (RARs) and retinoid X receptors (RXRs), it is not known if any of these receptors mediate teratogenicity, and if the potency also depends on the nature of the ligand-receptor interactions. Previous evidence has implicated that one specific isoform, RAR-β2, does play a role in mediating retinoid teratogenicity. Here, we employed an aromatic retinoid with a triene side chain, Ro 13-6307, to study its interactions with RAR-β2 since its teratogenicity is much higher and its accessibility to the embryo is much lower than RA. A fully teratogenic dose of Ro 13-6307 (10 mg−kg) given to pregnant mice preferentially elevated the level of RAR-β2 mRNA in susceptible embryonic regions (maximal induction, 10- to 12-fold above control in limb buds) in a manner comparable to a fully teratogenic dose of all-trans RA (100 mg−kg). Using the RAR-β2 promoter linked to a reporter gene in cotransfection experiments, the efficacy of Ro 13-6307 and RAR-β2 in transcription transactivation was found to be 30-40 times greater than all-trans RA. Since the teratogenic potency of Ro 13-6307 is estimated from a previous study to be 44-fold greater than all-trans RA, we suggest that the teratogenicity of this synthetic retinoid is generally proportional to its ability to enhance receptor function.