XENOPUS-LAEVIS - A MODEL SYSTEM FOR THE STUDY OF EMBRYONIC RETINOID METABOLISM .3. ISOMERIZATION AND METABOLISM OF ALL-TRANS-RETINOIC ACID AND 9-CIS-RETINOIC ACID AND THEIR DYSMORPHOGENIC EFFECTS IN EMBRYOS DURING NEURULATION

These investigations provide data pertaining to the metabolism and disposition of exogenous 9-cis-retinoic acid and all-trans-retinoic acid during neurulation in Xenopus embryos. Each isomer elicited malformations of the heart, eye, and brain, but similar to 2-fold higher concentrations of all-trans-retinoic acid than 9-cis-retinoic acid were required to produce qualitatively and quantitatively similar dysmorphogenic effects, The dysmorphogenic effects of all-trans-retinoic acid could not be attributed to the isomerization of all-trans-retinoic acid to 9-cis-retinoic acid, Evidence is provided that all-trans-retinoic acid and 9-cis-retinoic acid are both direct-acting dysmorphogens, After Xenopus embryos were exposed to all-trans-retinoic acid, elevated levels of 4-oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid, all-trans-retinoyl-beta-glucuronide, and 13-cis-retinoic acid were detected in the embryos, whereas embryonic levels of D-cis-retinoic acid were actually slightly lower than endogenous levels during early neurulation. After embryos were exposed to 9-cis-retinoic acid during neurulation, elevated levels of 4-oxo metabolites, glucuronides and 9,13-di-cis-retinoic acid were observed in the embryos, At equivalent concentrations, 4-oxo-13-cis-retinoic acid and 13-cis-retinoic acid elicited fewer severe multiple malformations than all-trans isomers 9,13-di-cis isomers, or 9-cis isomers, The dysmorphogenic effect of 9,13-di-cis-retinoic acid may be caused by ifs isomerization to 9-cis-retinoic acid, All-trans-retinoyl-beta-glucuronide was only marginally teratogenic at the highest concentrations tested.