Kraft J C, Juchau M R
Department of Pharmacology, School of Medicine, University of Washington, Seattle 98195.
Biochem Pharmacol. 1993 Aug 17;46(4):709-16. doi: 10.1016/0006-2952(93)90558-e.
Experiments in vitro with cultured rat conceptuses demonstrated that 9-cis-retinoic acid (9-cis-RA) (300 ng/mL amniotic fluid) produced branchial arch and somite defects similar to those elicited by equal concentrations of all-trans-retinoic acid (all-trans-RA), but with an increase in cephalic defects that included missing optic vesicles. After conceptuses were intraamniotically microinjected with 600 ng 9-cis-RA/mL amniotic fluid on day 10 of gestation, an unusual heart defect was also observed. HPLC analyses indicated that 9-cis-RA readily underwent conversion to the less active metabolite, 13-cis-retinoic acid (13-cis-RA), in cultured conceptuses during the first 4 hr after treatment but only after 6 hr could elevated levels of the potent dysmorphogen all-trans-RA be detected. In separate experiments, conversion of 13-cis-RA or of all-trans-RA to 9-cis-RA could not be detected during a 6-hr embryo culture period. Endogenous levels of 9-cis-RA in whole rat embryos also were below limits of detection but small quantities of this isomer could be detected in neonatal rat eye and human embryonic brain. Our present study strongly suggests that 9-cis-RA is a direct-acting dysmorphogen with probable specific target sites of action.
对培养的大鼠胚胎进行的体外实验表明，9-顺式视黄酸（9-cis-RA）（羊水浓度为300 ng/mL）产生的鳃弓和体节缺陷与相同浓度的全反式视黄酸（all-trans-RA）引发的缺陷相似，但头部缺陷有所增加，包括视泡缺失。在妊娠第10天对胚胎进行羊膜腔内微量注射600 ng 9-cis-RA/mL羊水后，还观察到一种不寻常的心脏缺陷。高效液相色谱分析表明，9-cis-RA在处理后的前4小时内很容易在培养的胚胎中转化为活性较低的代谢物13-顺式视黄酸（13-cis-RA），但仅在6小时后才能检测到强效致畸剂全反式视黄酸水平升高。在单独的实验中，在6小时的胚胎培养期内未检测到13-cis-RA或全反式视黄酸向9-cis-RA的转化。全大鼠胚胎中9-cis-RA的内源性水平也低于检测限，但在新生大鼠眼睛和人类胚胎大脑中可检测到少量这种异构体。我们目前的研究强烈表明，9-cis-RA是一种直接作用的致畸剂，可能具有特定的作用靶点。
