Cytochrome-P-450-Dependent Metabolism of Retinoic Acid in Rat Skin Microsomes: Inhibition by Ketoconazole

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Abstract
Epidermal microsomes, prepared from neonatal Wistar or Sprague-Dawley rats, show low levels of retinoic acid (RA) metabolism. The specific activities (as fmol/min/mg protein) of epidermal microsomes, using [15–14C]-RA as substrate, are 232 (Wistar rats) and 222 (Sprague-Dawley rats). Topical application of RA (1 mg) on 4-day-old rats induces a 3.3-and 3.9-fold increase in epidermis microsomal RA metabolism. A 4.6- to 8.1-fold increase is observed 24 h after topical application of 3-methylcholanthrene (0.5 mg). By contrast, phenobarbital (1 mg topically) has a much smaller inducing effect. So far the chemical structure of the metabolites has not been identified. The Rf values of two major compounds correspond with those of 4-hydroxy- and 4-ketoretinoic acid, formed after incubation of hamster liver microsomes in the presence of [15–14C]-RA. The RA metabolism in rat epidermal micromes shows the typical characteristics of a cytochrome-P-450 (P450)-dependent enzyme system, i.e. a requirement for NADPH and oxygen and inhibition by CO and SKF-525A. Ketoconazole and miconazole, imidazole antifungal agents and inhibitors of some fungal and mammalian P450-dependent enzymes, inhibit in vitro RA metabolism by rat epidermal microsomes. 50% inhibition is achieved at 6.5 × 10-7 and ≧ 10-5 mol/l, respectively. The triazole antifungal agent, itraconazole, has no effect at concentrations up to 10-5 mol/l. Topical treatment of 4-day-old Wistar rats with ketoconazole, at doses of 1, 5 and 10 mg/kg, 1 h before the application of RA (1 mg/rat) results in a dose-dependent inhibition of RA metabolism by epidermal microsomes, prepared 24 h later. Our data show a P450-dependent RA metabolism in rat epidermal microsomes and suggest that ketoconazole may prove to be effective in maintaining biologically active levels of RA in epidermal cells.

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