retinoyl-beta-glucuronide and 4-oxoretinoic-acid

Following a single oral dose of all-trans retinoic acid (RA) (0.167 mmole) in corn oil to 6 healthy human subjects, the mean serum retinol (ROL) level fell by approximately 20% within 1 h and remained depressed for 24 h. After dosing, RA appeared in the blood within 30 min, peaked at 0.3-0.5 mumol/l, and then declined to very low concentrations after 7 h. All-trans retinoyl beta-glucuronide (RAG) appeared simultaneously with RA in the plasma, albeit more sporadically, whereas only traces of 4-oxoretinoic acid (4-oxoRA) were detected. Some possible physiologic consequences of therapeutic uses of all-trans RA are discussed.

Topics: Adult; Female; Humans; Kinetics; Male; Middle Aged; Tretinoin; Vitamin A

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.

Topics: Animals; Biotransformation; Embryo, Mammalian; Isotretinoin; Microinjections; Models, Biological; Morphogenesis; Organ Culture Techniques; Rats; Rats, Inbred Strains; Stereoisomerism; Time Factors; Tretinoin

4-Oxo-all-trans-retinoic acid, 4-oxo-13-cis-retinoic acid and all-trans-retinoyl-beta-glucuronide were intraamniotically microinjected in rat embryos on day 10 of gestation and cultured until day 11.5. A comparison of the concentration-effect relationships showed that the dysmorphogenic effects produced by these metabolites were qualitatively similar to those of parent all-trans-retinoic acid. Compared with all-trans-retinoic acid (300 ng/ml), the dysmorphogenic effects were elicited by a 2-fold higher concentration of 4-oxo-all-trans-retinoic acid, an approximately 10-fold higher concentration of 4-oxo-13-cis-retinoic acid and a 16-fold higher concentration of all-trans-retinoyl-beta-glucuronide. A surplus of uridine 5'-diphospho-glucuronic acid, microinjected together with 300 ng/ml all-trans-retinoic acid, decreased the observed embryo-toxicity of all-trans-retinoic acid, suggesting the possibility of glucuronidation in tissues of the conceptus per se. The results of the study provide further support for the hypothesis that 4-oxo-all-trans-retinoic acid and all-trans-retinoic acid are, in contrast to the corresponding cis-isomers and glucuronides, ultimate dysmorphogenic retinoids.

Topics: Amnion; Animals; Dose-Response Relationship, Drug; Embryo, Mammalian; Microinjections; Organ Culture Techniques; Rats; Rats, Inbred Strains; Teratogens; Tretinoin