Kochhar D M, Jiang H, Penner J D, Beard R L
Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107 USA.
Chem Biol Interact. 1996 Mar 8;100(1):1-12. doi: 10.1016/0009-2797(95)03681-4.
Early events that initiate teratogenesis by Accutane or other retinoids in mammalian embryos remain unknown. It would be helpful for mechanistic considerations to know whether or not retinoids act through retinoid receptor-dependent pathways, and if they do, which of the two families of receptors (retinoic acid receptors - RARalpha, beta, gamma or retinoid X receptors - RXRalpha, beta, gamma) are more likely involved. We previously used an in vitro bioassay to demonstrate that those retinoid analogs with binding affinity and transactivational activity limited only to the RXRs have a low potential as teratogens. Here, we have extended the study to examine teratogenicity, in pregnant mice, of a number of synthetic retinoids with varying degrees of receptor selectivity. The ability of each compound to induce fetal limb and craniofacial defects after a single exposure on day 11 of gestation was assessed and compared to that of all-trans retinoic acid (RA). The highest dose selected was 100 mg/kg maternal body weight since such a regimen of all-trans RA affects virtually every exposed embryo without any indication of maternal toxicity. We found that although all RAR agonists were strong teratogens, their potencies varied over a wide magnitude. The teratogenic potencies and receptor transactivation profiles of RAR agonists were not directly correlated since compounds with similar receptor activities presented major differences in potencies. Three compounds were exclusively RXR agonists, and these were not teratogenic under our experimental conditions. Two additional compounds which turned out to be non-teratogenic were distinguished by the fact that they activated neither RARs nor RXRs. These data indicate that although RAR-dependent mechanisms are likely involved in retinoid-induced teratogenesis, there are additional factors which determine teratogenic potency. The absence of teratogenic response in the case of RXR agonists suggests that risk-benefit analyses of such receptor-selective compounds may be fruitful in further studies.
异维甲酸或其他类维生素A在哺乳动物胚胎中引发致畸作用的早期事件仍然未知。了解类维生素A是否通过类维生素A受体依赖性途径发挥作用，如果是，两个受体家族（视黄酸受体——RARα、β、γ或类维生素X受体——RXRα、β、γ）中哪一个更可能参与其中，这对于机制研究将有所帮助。我们之前使用体外生物测定法证明，那些结合亲和力和反式激活活性仅局限于RXRs的类维生素A类似物作为致畸剂的可能性较低。在此，我们扩展了研究，以检查多种具有不同程度受体选择性的合成类维生素A在怀孕小鼠中的致畸性。评估了每种化合物在妊娠第11天单次暴露后诱导胎儿肢体和颅面缺陷的能力，并与全反式视黄酸（RA）进行比较。选择的最高剂量为100mg/kg母体体重，因为这样的全反式RA方案几乎会影响每一个暴露的胚胎，且没有任何母体毒性的迹象。我们发现，尽管所有RAR激动剂都是强效致畸剂，但其效力在很大范围内有所不同。RAR激动剂的致畸效力和受体反式激活谱并不直接相关，因为具有相似受体活性的化合物在效力上存在重大差异。三种化合物是专门的RXR激动剂，在我们的实验条件下它们不具有致畸性。另外两种被证明无致畸性的化合物的特点是它们既不激活RARs也不激活RXRs。这些数据表明，尽管RAR依赖性机制可能参与类维生素A诱导的致畸作用，但还有其他因素决定致畸效力。RXR激动剂情况下无致畸反应表明，对这类受体选择性化合物进行风险效益分析在进一步研究中可能会有成果。
