Elmazar M M, Reichert U, Shroot B, Nau H
Institute of Toxicology and Embryopharmacology, Free University, Berlin, Germany.
Teratology. 1996 Mar;53(3):158-67. doi: 10.1002/(SICI)1096-9926(199603)53:3<158::AID-TERA3>3.0.CO;2-0.
Retinoic acid, an oxidative metabolite of vitamin A, is involved in the control of many biological processes including embryonic development. Excess as well as deficiency of retinoids were found to be teratogenic. The effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors, the RAR's and RXR's, which exhibit a specific temporal and spatial expression during development. The significance of the retinoid receptors was investigated here by studying the teratogenic effects of retinoid ligands with relative selectivity for binding and transactivation of the retinoic acid receptors RAR alpha, RAR beta and RAR gamma. Pregnant NMRI mice were administered 5 or 15 mg/kg of CD 336 (Am 580) (alpha-ligand), CD 2019 (beta-ligand), CD 437 (gamma-ligand) or 37.5 mg/kg all-trans-retinoic acid in 25% Cremophor EL on day 8.25 or day 11 of gestation by gastric intubation. External, visceral and skeletal malformations were observed on day 18 of gestation. The order of teratogenic potency was: alpha-ligand > beta-ligand > gamma-ligand. In addition, these retinoids also produced a different spectrum of defects. The alpha-ligand induced the most varied defects including severe ear, mandible, and limb malformations. The beta-ligand induced defects of the urinary system and liver in greater frequency than expected from its relative potency. The gamma-ligand preferentially induced ossification deficiencies and defects of the sternebrae and vertebral body. Our results show that these three retinoids, which were previously demonstrated to exhibit retinoid-like activities in several systems, exert differing teratogenic activities, in regard to both potency and regioselectivity: we hypothesize that the relative selectivity for binding and transactivation of the three retinoic acid receptors could possibly be related to the differences of teratogenic effects observed in this study. The low potency of the gamma-ligand may lead the way to interesting new retinoids with improved therapeutic ratio.
视黄酸是维生素A的一种氧化代谢产物，参与包括胚胎发育在内的许多生物过程的调控。人们发现，类视黄醇过量和缺乏都会致畸。类视黄醇在正常和异常发育过程中的作用可能由类视黄醇受体家族的两个成员介导，即维甲酸受体（RAR）和维甲酸X受体（RXR），它们在发育过程中表现出特定的时空表达。本文通过研究对维甲酸受体RARα、RARβ和RARγ具有相对选择性结合和反式激活作用的类视黄醇配体的致畸作用，探讨了类视黄醇受体的意义。在妊娠第8.25天或第11天，通过胃管给怀孕的NMRI小鼠灌胃给予5或15mg/kg的CD 336（Am 580）（α配体）、CD 2019（β配体）、CD 437（γ配体）或37.5mg/kg的全反式视黄酸，溶剂为25%的聚氧乙烯蓖麻油（Cremophor EL）。在妊娠第18天观察外部、内脏和骨骼畸形情况。致畸效力顺序为：α配体>β配体>γ配体。此外，这些类视黄醇还产生了不同类型的缺陷。α配体诱导的缺陷最为多样，包括严重的耳部、下颌骨和肢体畸形。β配体诱导泌尿系统和肝脏缺陷的频率高于根据其相对效力预期的频率。γ配体优先诱导骨化缺陷以及胸骨和椎体的缺陷。我们的结果表明，这三种类视黄醇先前已在多个系统中表现出类视黄醇样活性，在效力和区域选择性方面发挥不同的致畸活性：我们推测，对三种维甲酸受体的结合和反式激活的相对选择性可能与本研究中观察到的致畸作用差异有关。γ配体的低效性可能为开发治疗指数更高的新型类视黄醇开辟道路。
