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Laboratoire de Toxicologie et Pharmacie Clinique (M.-N.M., E.S.,
H.S., B.L., A.D.) and
Laboratoire de Pharmacocinétique et
Toxicocinétique (H.B.), Faculté de Pharmacie
Cytochrome P450 expression in liver is influenced by several
factors, including sex and strain. Whereas little is known about their
metabolic capabilities, Hairless rats are widely used for the studies
of topical agents. We compared Sprague-Dawley and Hairless rat
metabolic behavior to validate the use of Hairless rats in
pharmacokinetic and metabolic studies of topically applied drugs. Liver
microsomes of male and female rats of both strains were used to
investigate the in vitro metabolism of three retinoic acid
(RA) isomers: all-trans-RA, 13-cis-RA, and
9-cis-RA. In all cases, a major isomerization of the tested
isomer in the two others was observed. This process was independent of
the presence of NADPH, but depended on the presence of microsomal
proteins. In addition, we observed, to a lesser extent, the formation
of 4-oxo metabolites (4-oxo-all-trans-RA,
4-oxo-13-cis-RA, and 4-oxo-9-cis-RA), with the
rate of formation of each of these compounds varying with the nature of
the isomer incubated. The 4-oxo metabolites formed were statistically
greater in male than in female rats in the two strains studied. No
significant difference in RA biotransformation was observed between
Sprague-Dawley and Hairless rats. In addition, no major difference was
observed between the two strains concerning the expression of the
different cytochrome P450 isoforms studied. In conclusion, phase I
metabolism of RAs characterized by C4-hydroxylation varied
with sex, but not within the two strains studied in rats. These results
strengthen the relevance of the use of Hairless rats in pharmacokinetic
and metabolic studies of topical agents, including retinoids.
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