IN-VITRO METABOLISM OF 3 MAJOR ISOMERS OF RETINOIC ACID IN RATS - INTERSEX AND INTERSTRAIN COMPARISON

Cytochrome P450 expression in liver is influenced by several factors, including sex and strain, Whereas little is known about their metaboli c capabilities, Hairless rats are widely used for the studies of topic al agents. We compared Sprague-Dawley and Hairless rat metabolic behav ior to validate the use of Hairless rats in pharmacokinetic and metabo lic studies of topically applied drugs. Liver microsomes of male and f emale rats of both strains were used to investigate the in vitro metab olism of three retinoic acid (RA) isomers: all-trans-RA, 13-cis-RA, an d 9-cis-RA. In all cases, a major isomerization of the tested isomer i n the two others was observed. This process was independent of the pre sence of NADPH, but depended on the presence of microsomal proteins. I n addition, we observed, to a lesser extent, the formation of 4-oxo me tabolites (4-oxo-all-trans-RA, 4-oxo-13-cis-RA, and 4-oxo-9-cis-RA), w ith the rate of formation of each of these compounds varying with the nature of the isomer incubated. The 4-oxo metabolites formed were stat istically greater in male than in female rats in the two strains studi ed, No significant difference in RA biotransformation was observed bet ween Sprague-Dawley and Hairless rats. In addition, no major differenc e was observed between the two strains concerning the expression of th e different cytochrome P450 isoforms studied. In conclusion, phase I m etabolism of RAs characterized by C-4-hydroxytation varied with sex, b ut not within the two strains studied in rats. These results strengthe n the relevance of the use of Hairless rats in pharmacokinetic and met abolic studies of topical agents, including retinoids.