RT Journal Article
SR Electronic
T1 Xenopus laevis: a model system for the study of embryonic retinoid metabolism. III. Isomerization and metabolism of all-trans-retinoic acid and 9-cis-retinoic acid and their dysmorphogenic effects in embryos during neurulation.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1058
OP 1071
VO 23
IS 10
A1 J C Kraft
A1 M R Juchau
YR 1995
UL http://dmd.aspetjournals.org/content/23/10/1058.abstract
AB 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 approximately 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 dymorphogenic 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 9-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 its isomerization to 9-cis-retinoic acid. All-trans retinoyl-beta-glucuronide was only marginally teratogenic at the highest concentrations tested.