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Embryotoxic Doses of Vitamin A to Rabbits Result in Low Plasma but High Embryonic Concentrations of All-trans-Retinoic Acid: Risk of Vitamin A Exposure in Humans^1,2,3,

Georg Tzimas⁴, Michael D. Collins^*, Heinrich Bürgin, Hans Hummler and Heinz Nau

Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, D-14195 Berlin, Germany ^* Department of Environmental Health Sciences, School of Public Health, University of California-Los Angeles, Los Angeles, CA 90024-1772 F. Hoffmann-La Roche, CH-4070 Basel, Switzerland

Retinoid pharmacokinetics were examined in plasma, placenta and embryos of gestational d 12 rabbits following application of an embryotoxic dosing regimen (10 mg retinyl palmitate/kg body wt per day from gestational d 7 to 12). Vehicle-treated or untreated rabbits served as controls. Physiological concentrations of all-trans-retinoic acid (all-trans-RA) and 13-cis-RA in rabbit plasma (5–8.33 nmol/L) were very close to the endogenous levels in human plasma. In addition, we identified endogenous all-trans-RA, 3,4-didehydroretinol and 3,4-didehydroretinoic acid in rabbit embryo. Following the last retinyl palmitate administration, apparent steady-state concentrations of all retinoids were reached in the examined compartments of rabbits. The major polar retinoid in plasma was 9,13-di-cis-RA, but its embryonic concentrations were only about 6% of those in plasma. In the embryo, retinol and its esters were found at high concentrations; lower amounts of all-trans-4-oxo-RA and the newly identified 14-hydroxy-4,14-retro-retinol could also be measured. Embryonic concentrations of all-trans-RA were about 100% higher than endogenous levels. The overall exposure of the embryo to this retinoid was, however, substantial. Embryonic area under the concentration time curve values strongly suggest that the embryotoxicity of the applied dosing regimen is mainly due to the action of all-trans-RA. A very remarkable finding of this study is the marginal increase of plasma concentrations of all-trans-RA over their endogenous levels, which is comparable to the human situation after vitamin A intake. This analogy indicates that high vitamin A intake may be associated with a higher risk for teratogenic effects in humans even in the absence of high elevation of plasma all-trans-RA levels.

KEY WORDS: • embryotoxicity • rabbits • retinoic acid • retinol • vitamin A

¹ Part of this work was presented at the Retinoid Conference 1995, October 8–11, Sophia Antipolis, France [Tzimas, G., Collins, M.D., Bürgin, H., Hummler, H. & Nau, H. New aspects of vitamin A metabolism: identification of 9,13-di-cis-retinoic acid as a major plasma metabolite of retinol in rabbits and physiological occurrence of 3,4-didehydroretinoids in rabbit embryo (abs. 56)].

² Supported by the Deutsche Forschungsgemeinschaft (Sfb 174, C6), and the European Commission (BIOTECH-program BIO2-CT93-0471). Georg Tzimas was in part supported by the Deutscher Akademischer Austauschdienst.

³ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

⁴ To whom correspondence and reprint requests should be addressed: Institute für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Garystr. 5, D-14195 Berlin, Germany.

Manuscript received 6 February 1996. Revision accepted 15 May 1996.

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