METABOLISM OF 13-CIS-RETINOIC ACID BY A RAT-LIVER 9000G SUPERNATANT PREPARATION

Abstract

[13-cis-Retinoic acid (13-cis-RA) is clinically effective in treating cystic acne and certain disorders of keratinization.] The in vitro metabolites formed on incubation of 13-cis-RA (isotretinoin) with a 9000 g rat liver supernatant system were isolated by HPLC (high pressure liquid chromatography) and identified by their mass and NMR spectra. The major metabolic pathway was hydroxylation at C4 to give 4-hydroxy-13-cis-RA, which was rapidly oxidized to 4-oxo-13-cis-RA, the major isolated metabolite. Further metabolism of this 4-oxo metabolite led to 2 novel compounds, 2-hydroxy-4-oxo-13-cis-RA and 3-hydroxy-4-oxo-13-cis-RA. Small amounts of 13-cis-RA and 4-oxo-13-cis-RA were enzymatically converted to their all-trans isomers. Support for these pathways was obtained by the metabolism of reference samples of 4-hydroxy-13-cis-RA, 4-oxo-13-cis-RA, all-trans-RA and 4-oxo-all-trans-RA. Oxidation at C4 is evidently a major metabolic pathway of 13-cis-RA in both rats and humans.