Kistler A, Tsuchiya T, Tsuchiya M, Klaus M
Pharmaceutical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Arch Toxicol. 1990;64(8):616-22. doi: 10.1007/BF01974689.
The effect of structural modifications on the arotinoid molecule, a new class of retinoids, on their teratogenicity in mice was studied. Animals were treated on days 8 and 9 of gestation, the most susceptible stages to retinoid-induced malformations in rodents. The teratogenic potency of the 13 arotinoids tested varied over a dose range of more than five orders of magnitude. Next, we tested whether the quantitative differences in the teratogenicity of these arotinoids correlates with their activity in high density (micromass) cultures of rat embryonic limb bud and midbrain cells. There was a good quantitative correlation between the in vivo teratogenicity and the in vitro activity in limb bud cells but no correlation was found in midbrain cells. Thus, the limb bud cell culture system may be useful for a preliminary testing to select non-teratogenic retinoids. For the risk assessment in humans, however, the in vitro results should be verified in animals studies.
研究了结构修饰对新型类视黄醇——芳维甲酸分子的影响及其对小鼠的致畸性。在妊娠第8天和第9天对动物进行处理，这是啮齿动物对类视黄醇诱导畸形最敏感的阶段。所测试的13种芳维甲酸的致畸效力在超过五个数量级的剂量范围内变化。接下来，我们测试了这些芳维甲酸致畸性的定量差异是否与其在大鼠胚胎肢芽和中脑细胞的高密度（微团）培养中的活性相关。体内致畸性与肢芽细胞中的体外活性之间存在良好的定量相关性，但在中脑细胞中未发现相关性。因此，肢芽细胞培养系统可能有助于初步筛选非致畸性类视黄醇。然而，对于人类的风险评估，体外结果应在动物研究中得到验证。
