Willhite C C
Toxicol Appl Pharmacol. 1986 May;83(3):563-75. doi: 10.1016/0041-008x(86)90239-5.
The comparative teratogenic potencies of 7,8-dihydroretinoic acid, 7,8-dehydroretinoic acid, 9,10-dihydroretinoic acid, 9-cis-retinal, hydroxenin, oxenin, the C15 analog of all-trans-retinoic acid, abscissic acid, beta-C14 aldehyde, beta-ionone, and psuedoionone were determined in golden Syrian hamsters and compared with that of all-trans-retinoic acid. A single oral dose of each retinoid on Day 8 of gestation failed to induce signs of retinoid intoxication in the dams and the maternal weight gain was not affected significantly, except after treatment with beta-C14 aldehyde, pseudoionone, and the lowest dose of 9-cis-retinal, where maternal weight was depressed. A significant teratogenic response was observed after intubation of 7,8-dihydroretinoic acid, 7,8-dehydroretinoic acid, or 9-cis-retinal. The highest dose of hydroxenin (equivalent to nearly seven times an equimolar teratogenic dose of all-trans-retinoic acid) showed a limited teratogenic response. None of the remaining retinoids induced terata. The results suggest that the side chain plays an important role in retinoid embryotoxicity and that even minor structural alterations of retinoids at the side chain can abolish teratogenic activity. The present results indicate that a polyene chain of greater than five carbon atoms was necessary for retinoid teratogenic activity and that the presence of the ring, the nine-carbon side chain, and the acidic polar terminus was insufficient to ensure teratogenic activity. Retinoid teratogenicity in hamsters required the hydrophobic ring, a terminal polar group with an acidic pKa, and the hydrophobic, curved plane of the tetraene chain.
在金黄叙利亚仓鼠中测定了7,8-二氢视黄酸、7,8-脱氢视黄酸、9,10-二氢视黄酸、9-顺式视黄醛、羟萘酸、氧萘酸、全反式视黄酸的C15类似物、脱落酸、β-C14醛、β-紫罗兰酮和伪紫罗兰酮的相对致畸效力，并与全反式视黄酸进行了比较。在妊娠第8天对每只类维生素A进行单次口服给药，除了用β-C14醛、伪紫罗兰酮和最低剂量的9-顺式视黄醛处理后母体体重下降外，未在母鼠中诱导出类维生素A中毒迹象，且母体体重增加未受到显著影响。在给7,8-二氢视黄酸、7,8-脱氢视黄酸或9-顺式视黄醛插管后观察到显著的致畸反应。羟萘酸的最高剂量（相当于全反式视黄酸等摩尔致畸剂量的近七倍）显示出有限的致畸反应。其余类维生素A均未诱导出畸形。结果表明，侧链在类维生素A胚胎毒性中起重要作用，类维生素A侧链即使有微小的结构改变也可能消除致畸活性。目前的结果表明，类维生素A致畸活性需要大于五个碳原子的多烯链，且环、九碳侧链和酸性极性末端的存在不足以确保致畸活性。仓鼠中的类维生素A致畸性需要疏水环、具有酸性pKa的末端极性基团以及四烯链的疏水弯曲平面。
