All-trans-retinoyl-β-glucuronide is a potent teratogen in the mouse because of extensive metabolism to all-trans-retinoic acid

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All-trans-retinoyl-β-D-glucuronide (all-trans-RAG) is a water-soluble derivative of all-trans-retinoic acid (all-trans-RA) and has been characterized as an endogenous metabolite of vitamin A in rat bile and kidney. All-trans-RAG was previously demonstrated to be a major metabolite after application of all-trans-RA in several species (mouse, rat, rabbit, monkey); all-trans-RAG was described in these experiments to exhibit a very low placental transfer to the embryo. Because retinoid-like activity has been found after application of all-trans-RAG in vivo as well as in several in vitro systems, and because of its low placental transfer, this glycoconjugate appeared to be an interesting retinoid with possible therapeutic activity, but reduced teratogenicity. Here we investigated the teratogenic activity of all-trans-RAG in comparison to all-trans-RA in mice, and performed accompanying pharmacokinetic studies. Surprisingly, all-trans-RAG was more teratogenic than equimolar doses of all-trans-RA following subcutaneous application on day 11 of gestation in the mouse (20 μmol/kg body weight). Pharmacokinetic studies revealed that all-trans-RAG was extensively hydrolyzed to all-trans-RA and that the plasma area under the concentration-time curve (AUC) of all-trans-RA following all-trans-RAG application exceeded the plasma AUC value of all-trans-RA following application of all-trans-RA. Extensive hydrolysis of all-trans-RAG was also observed after intravenous application of this glycoconjugate. Transfer of all-trans-RAG to the embryo was low, but transfer was high to maternal organs such as the liver and kidney. These in vivo studies suggest that all-trans-RAG serves as a precursor of all-trans-RA by the intravenous and subcutaneous routes, and application of all-trans-RAG results in high and teratogenic in vivo exposure to all-trans-RA.

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