Low teratogenicity of 13-cis-retinoic acid (isotretinoin) in the mouse corresponds to low embryo concentrations during organogenesis: comparison to the all-trans isomer.
Low teratogenicity of 13-cis-retinoic acid (isotretinoin) in the mouse corresponds to low embryo concentrations during organogenesis: comparison to the all-trans isomer.
复制标题
小鼠中 13-顺式视黄酸（异维A酸）的低致畸性对应于器官发生过程中的低胚胎浓度：与全反式异构体相比。
DOI：
10.1016/0041-008x(87)90253-5
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发表时间：
1987
影响因子：
3.8
通讯作者：
Nau,H
中科院分区：
文献类型：
--
作者：
Kraft,JC;Kochhar,DM;Scott,WJ;Nau,H
13-顺式维甲酸（异维甲酸）在治疗剂量（0.5-1.5 mg/kg体重）下对人体具有致畸性，但在极高剂量（> 100 mg/kg）下对小鼠仅具有轻微致畸性。另一方面，异构体全反式视黄酸（维甲酸）在剂量水平比13-顺式异构体低10倍时对小鼠具有致畸性。因此，我们研究了这两种化合物在小鼠中的致畸效力是否存在很大差异，这是它们经胎盘动力学差异的结果。单次口服100 mg全反式或13-顺式视黄酸/kg体重后，在器官发生的两个敏感阶段（即，妊娠第9或11天。全反式维甲酸及其4-氧代代谢物转移到胚胎的程度（胚胎/母体血浆浓度比，10.4）比13-顺式维甲酸及其4-氧代代谢物（胚胎/母体血浆浓度比，10.02）大得多。妊娠第9天的全反式维甲酸胚胎浓度超过了第11天，而13-顺式维甲酸的胚胎水平在两个妊娠阶段都很低。全反式维甲酸的4-氧代代谢产物的浓度通常低于母体药物，而13-顺式维甲酸的4-氧代代谢产物的水平与母体化合物相当，甚至高于母体化合物。母体血浆中C-13异构化产物的浓度低于相应母体药物水平的20%。然而，由于两种异构体的转移程度不同，即使在给予13-顺式-维甲酸后，胚胎中全反式-维甲酸的浓度也超过顺式异构体。我们的研究结果表明，低致畸性的13-顺式-维甲酸在小鼠中的结果是最小的胎盘转移的这种化合物和它的4-氧代代谢产物，这与广泛的胎盘转移和高致畸性的相应的异构体与全反式构型形成鲜明对比。
13-cis-Retinoic acid (isotretinoin) is teratogenic in man at therapeutic doses (0.5–1.5 mg/kg body wt), but only marginally teratogenic in the mouse at exceedingly high doses (> 100 mg/kg). On the other hand, the isomer all-trans-retinoic acid (tretinoin) is teratogenic in the mouse at dose levels which are 10 times lower than those for the 13-cis isomer. We have therefore studied whether the greatly different teratogenic potencies of these two compounds in the mouse are the result of differences in their transplacental kinetics. Following a single oral dose of 100 mg all-trans- or 13-cis-retinoic acid per kg body wt, concentrations of the parent drugs, of the C-13 isomerization products, as well as of their 4-oxo metabolites were determined in maternal plasma and embryo at two sensitive stages of organogenesis, i.e., Days 9 or 11 of gestation. All-trans-retinoic acid and its 4-oxo metabolite were transferred to the embryo to a much greater extent (embryo/maternal plasma concentration ratios, ∼0.4) than the 13-cis-retinoic acid and its 4-oxo metabolite (embryo/maternal plasma concentration ratios, ∼0.02). Embryo concentrations of all-trans-retinoic acid on Day 9 of gestation exceeded those on Day 11, whereas the embryo levels of 13-cis-retinoic acid were minimal at both gestational stages. The concentration of the 4-oxo metabolite of all-trans-retinoic acid was generally lower than that of the parent drug, whereas the level of the 4-oxo metabolite of the 13-cis-retinoic acid was comparable with or even higher than that of the parent compound. Concentrations of the C-13 isomerization products in maternal plasma were less than 20% of corresponding parent drug levels. However, due to the different extent of transfer of the two isomers, the concentration of all-trans-retinoic acid in the embryo exceeded that of the cis isomer even after administration of 13-cis-retinoic acid. Our results indicate that the low teratogenicity of 13-cis-retinoic acid in the mouse is the result of minimal placental transfer of this compound and of its 4-oxo metabolite, which contrast sharply with extensive placental transfer and high teratogenicity of the corresponding isomers with the all-trans configuration.