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 dis position of exogenous 9-cis-retinoic acid and all-trans-retinoic acid during neurulation in Xenopus embryos. Each isomer elicited malformati ons of the heart, eye, and brain, but similar to 2-fold higher concent rations of all-trans-retinoic acid than 9-cis-retinoic acid were requi red 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 Xe nopus embryos were exposed to all-trans-retinoic acid, elevated levels of 4-oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid, all-tra ns-retinoyl-beta-glucuronide, and 13-cis-retinoic acid were detected i n the embryos, whereas embryonic levels of D-cis-retinoic acid were ac tually 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-re tinoic acid were observed in the embryos, At equivalent concentrations , 4-oxo-13-cis-retinoic acid and 13-cis-retinoic acid elicited fewer s evere multiple malformations than all-trans isomers 9,13-di-cis isomer s, 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-t rans-retinoyl-beta-glucuronide was only marginally teratogenic at the highest concentrations tested.