Derivation of retinoic acid and metabolites from a teratogenic dose of retinol (vitamin A) in mice.
Derivation of retinoic acid and metabolites from a teratogenic dose of retinol (vitamin A) in mice.
复制标题
DOI：
10.1016/0041-008x(88)90003-8
复制
发表时间：
1988-12
影响因子：
3.8
通讯作者：
D. Kochhar;J. Penner;M. Satre
中科院分区：
文献类型：
--
作者：
D. Kochhar;J. Penner;M. Satre
在发现两种维生素 A 相关药物 Accutane 和 Tigason 是人类致畸剂后，大剂量维生素 A 补充剂被怀疑对发育中的胚胎有害。视黄酸（全反式 RA）是维生素 A 的天然代谢物，参与维生素 A 的许多已知功能，并且可能是致畸的活性剂。在这项研究中，我们给怀孕小鼠单次高剂量口服视黄醇（维生素 A），以评估其经胎盘药代动力学，并测量其代谢物在胚胎中的形成和分布。据估计，在整个动物致畸过程中，视黄醇的活性比视黄酸低 4 倍，在体外生物测定中，视黄醇的活性比视黄酸低 20 倍。完全致畸剂量（200 mg/kg）产生大量视黄酸，其以与视黄醇相似的动力学转移到胚胎中。在给予视黄醇后的前8小时内，代谢物（包括全反式-RA、13-顺式-RA和4-氧代-RA）几乎占胚胎中发现的所有视黄醇衍生物数量的50%。将代谢物的组合峰值浓度（或其 AUC 值）与单独相关的致畸程度进行比较，提供了足够的证据表明代谢物本身是视黄醇诱导致畸的介质。然而，由于视黄醇和视黄酸在胚胎中的浓度都足以充当致畸剂，因此我们目前不能排除它们独立作用的可能性。需要进一步的实验来确定胚胎中检测到的视黄酸是胚胎自身代谢能力的产物还是从母体循环中转移的。
Megadose supplements of vitamin A are under suspicion as hazards to the developing embryo after the discovery that two vitamin A-related drugs, Accutane and Tigason, are human teratogens. Retinoic acid (all-trans-RA) is a natural metabolite of vitamin A which participates in many of the known functions of vitamin A and may be the active agent in teratogenesis. In this investigation we gave a single, high oral dose of retinol (vitamin A) to pregnant mice to assess its transplacental pharmacokinetics as well as to measure the formation and distribution of its metabolites in the embryo. Retinol was estimated to be 4-fold less active than retinoic acid in the whole animal teratogenesis and 20-fold less active in the in vitro bioassay. A fully teratogenic dose, 200 mg/kg, yielded considerable quantities of retinoic acid which were transferred to the embryo with kinetics similar to that of retinol. During the first 8 hr after administration of retinol, the metabolites (including all-rans-RA, 13-cis-RA, and 4-oxo-RA) constituted almost 50% of the quantity of all retinol derivatives found in the embryo. A comparison of combined peak concentrations of the metabolites (or their AUC values) with the extent of teratogenesis associated with them individually provided sufficient evidence to implicate the metabolites themselves as mediators of retinol-induced teratogenesis. However, since both retinol and retinoic acid were present in sufficient concentrations in the embryo to act as teratogens we cannot at present rule out the possibility that they may act independently. Further experimentation will be necessary to address whether retinoic acid detected in the embryo is the product of the embryo's own metabolic capability or is transferred from the maternal circulation.