Conceptual biotransformation of 4-oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid and all-trans-retinoyl-beta-glucuronide in rat whole embryo culture.
In cultured rat conceptuses, intraamniotic microinjections of 2500 ng/mL of 4-oxo-13-cis-retinoic acid, 600 ng/mL 4-oxo-all-trans-retinoic acid or 4000 ng/mL all-trans-retinoyl-beta-glucuronide, produce qualitatively and quantitatively similar patterns of dysmorphogenesis as those reported after the intraamniotic microinjection of 250 ng/mL all-trans-retinoic acid [Lee et al., Teratology 44: 313-323, 1991; Creech Kraft et al., Teratology 45: 259-270, 1992]. In the present study, we utilized HPLC techniques to analyze retinoid levels in cultured rat conceptuses, 1.5 hr after intraamniotic microinjections of 4-oxo-13-cis-retinoic acid (2500 ng/mL), 4-oxo-all-trans-retinoic acid (600 ng/mL) or all-trans-retinoyl-beta-glucuronide (4000 ng/mL). Our findings show that, after the microinjections of 4-oxo-all-trans-retinoic acid or 4-oxo-13-cis-retinoic acid (at these selected concentrations), 4-oxo-all-trans-retinoic acid was predominant in the embryos proper at concentrations of about 200 nM. This was roughly equivalent to the levels of all-trans-retinoic acid assayed after microinjections of all-trans-retinoyl-beta-glucuronide (4000 ng/mL). We conclude from these studies that both 4-oxo-all-trans-retinoic acid and all-trans-retinoic acid behave as ultimate or proximate dysmorphogens.
Creech Kraft
J
J
Department of Pharmacology, School of Medicine, University of Washington, Seattle 98195.
Juchau
M R
MR
D000818:Animals; D001711:Biotransformation; D004622:Embryo, Mammalian / Q000378:metabolism*; D015474:Isotretinoin / Q000378:metabolism; D008845:Microinjections; D008954:Models, Biological; D009024:Morphogenesis / Q000187:drug effects; D009924:Organ Culture Techniques; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013997:Time Factors; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology
C002202:4-oxoretinoic acid; C026787:retinoyl glucuronide; D014212:Tretinoin; D015474:Isotretinoin