Abstract
Retinaldehyde (RAL), a key intermediate in retinoid metabolism, acts as a retinoic acid (RA) precursor, but is also reduced to retinol (ROH), which can subsequently be esterified to retinyl esters, the storage form of vitamin A. Limited information is available on the metabolism of geometric isomers of RAL as well as on the transplacental distribution of their metabolites, including RA isomers. Such information would be very helpful for the assessment of the teratogenic potency of RAL isomers, as teratogenesis represents a major side effect of retinoid use in pharmacotherapy. In the present study we examined concentrations of retinoids in plasma, maternal tissues, and embryos of pregnant rats 2 h after a single oral dose (100 mg/kg body weight) of all-trans-, 13-cis-, or 9-cis-RAL on gestational day 13. The main findings of this study were the very similar patterns of retinoid metabolites (consisting of retinoids with mainly the all-trans-configuration) after administration of all-trans- and 13-cis-RAL, and the high concentrations of 9-cis-RA, 9,13-dicis-RA, and 9-cis-retinoyl-β-d-glucuronide after dosing with 9-cis-RAL. In addition, all-trans-RA as a RAL metabolite reached the embryos to a much greater extent than any of its cis-isomers. The results are discussed in view of in vitro data on enzymes involved in the biotransformation of RAL isomers.
Footnotes
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Send reprint requests to: Jörn Oliver Sass, Universitätsklinik für Kinder- und Jugendheilkunde, Stoffwechsellabor, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail:Joern-Oliver.Sass{at}uibk.ac.at
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Experimental work was performed at the Institut für Klinische Pharmakologie und Toxikologie, Fachbereich Humanmedizin, Freie Universität Berlin, D-14195 Berlin, Germany. Financial support was granted by the Deutsche Forschungsgemeinschaft (Sfb 174, C6) and by the European Community, BIOTECH program.
- Abbreviations used are::
- RAL
- retinaldehyde
- RA
- retinoic acid
- RAG
- retinoyl-β-d-glucuronide
- RAR
- retinoic acid receptor
- GD
- gestational day
- HPLC
- high-performance liquid chromatography
- E/M ratio
- ratio of embryo versus maternal plasma concentrations
- ROH
- retinol
- Received August 31, 1998.
- Accepted November 16, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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