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Unoccluded Retinol Penetrates Human Skin In Vivo More Effectively Than Unoccluded Retinyl Palmitate or Retinoic Acid

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      The formation of all-trans retinoic acid is an oxidative process whereby retinol is converted to retinaldehyde and then to retinoic acid. Because retinol causes qualitative molecular changes similar to those produced by retinoic acid, we compared potency of retinol, retinaldehyde, and retinyl palmitate to retinoic acid and assessed the effects of occlusion. Retinoids were prepared in an experimental vehicle of 95% ethanol:propylene glycol (7:3) with anti-oxidant. Induction of retinoic acid 4-hydroxylase activity was the end point for comparison. Retinoic acid concentrations from 0.001% to 0.05% under occlusion produced a linear dose-response induction of 4-hydroxylase activity. The concentrations of the other retinoids under occlusion required to achieve significant induction of enzyme activity were 0.6% retinyl palmitate, 0.025% retinol, and 0.01% retinaldehyde. The linear dose-response was lost with retinoid concentrations in excess of 0.25% retinol or 0.5% retinaldehyde. Statistical analyses showed no difference in 4-hydroxylase activity between unocciuded and occluded retinol treated sites. By contrast, however, unoccluded sites treated with retinoic acid or retinyl palmitate had less induction of 4-hydroxylase activity than occluded sites. Retinol, retinaldehyde, and retinyl palmitate did not produce erythema but did increase epidermal thickness. Although retinol is a weaker retinoid than retinoic acid, the increased penetration of unoccluded retinol in comparison to unoccluded retinoic acid with this prototypic vehicle confers on retinol a more effective delivery of a retinoidal effect than unocciuded retinoic acid. Retinol at 0.25% may be a useful retinoid for application without occlusion because it does not irritate but does induce cellular and molecular changes similar to those observed with application of 0.025% retinoic acid.

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      References

        • Boehnlein J.
        • Sakr A.
        • Lichtin J.L.
        • Bronaugh R.L.
        Characterization of esterase and alcohol dehydrogenase activity in skin. Metabolism of retinyl palmitate to retinol (vitamin A) during percutaneous absorption.
        Pharm Res. 1994; 11: 1155-1159
        • Boerman M.H.E.M.
        • Napoli J.L.
        Cellular retinol-binding protein-supported retinoic acid synthesis.
        J Biol Chem. 1996; 271: 5610-5616
        • Connor M.J.
        Oxidation of retinol to retinoic acid a requirement for biological activity in mouse epidermis.
        Cancer Res. 1988; 48: 7038-7040
        • Duell E.A.
        • Åstrüm A.
        • Griffiths C.E.M.
        • Chambon P.
        • Voorhees J.J.
        Human skin levels of retinoic acid and cytochrome P-450-derived 4-hydroxyretinoic acid after topical application of retinoic acid in vitro compared to concentrations required to stimulate retinoic acid receptor-mediated transcription in vitro.
        J Clin Invest. 1992; 90: 1269-1274
        • Duell E.-A.
        • Kang S.
        • Voorhees J.J.
        Retinoic acid isomers applied to human skin in vivo each induce a 4-hydroxylase that inactivates only trans retinoic acid.
        J Invest Dermatol. 1996; 106: 316-320
        • Elder J.T.
        • Cromie M.A.
        • Griffiths C.E.M.
        • Chambon P.
        • Voorhees J.J.
        Stimulus-selective induction of CRABP-II mRNA: a marker for retinoic acid action in human skin.
        J Invest Dermatol. 1993; 100: 356-359
        • Fisher G.J.
        • Esmann J.
        • Griffiths C.E.M.
        • Talwar H.S.
        • Duell E.A.
        • Hammerberg C.
        • Elder J.T.
        • Finkel L.J.
        • Karabin G.D.
        • Nickoloff B.J.
        • Cooper K.D.
        • Voorhees J.J.
        Cellular, immunologic and biochemical characterization of topical retinoic acid-treated human skin.
        J Invest Dermatol. 1991; 96: 699-707
        • Kang S.
        • Duell E.A.
        • Fisher G.J.
        • Datta S.C.
        • Wang Z.-Q.
        • Reddy A.P.
        • Tavakkol A.
        • Yi J.Y.
        • Griffiths C.E.M.
        • Elder J.T.
        • Voorhees J.J.
        Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels or irritation.
        J Invest Dermatol. 1995; 105: 549-556
        • Kurlandsky S.B.
        • Duell E.A.
        • Kang S.
        • Voorhees J.J.
        • Fisher G.J.
        Auto-regulation of retinoic acid biosynthesis through regulation of retinol esterification in human keratinocytes.
        J Bio Chem. 1996; 271: 15346-15352
        • Kurlandsky S.B.
        • Xiao J.-H.
        • Duell E.A.
        • Voorhees J.J.
        • Fisher G.J.
        Biological activity of all-tans retinol requires metabolic conversion to all-trans retinoic acid and is mediated through activation of nuclear retinoid receptors in human keratinocytes.
        J Biol Chem. 1994; 269: 32821-32827
        • Lowry O.H.
        • Rosebrough N.J.
        • Farr A.L.
        • Randall R.J.
        Protein measurements with the folin phenol reagent.
        J Biol Chem. 1951; 193: 265-275
        • Napoli J.L.
        • Boerman M.H.E.M.
        • Chai X.
        • Zhai Y.
        • Fiorella P.D.
        Enzymes and binding proteins affecting retinoic acid concentrations.
        J Steroid Biochem Mol Biol. 1995; 53: 497-502
        • Roberts A.B.
        • Nichols M.D.
        • Newton D.L.
        • Sporn M.B.
        In vitro metabolism of retinoic acid in hamster intestine and liver.
        J Biol Chem. 1979; 254: 6296-6302
        • Ross A.C.
        Cellular metabolism and activation of retinoids: roles of cellular retinoid-binding proteins.
        FASEB J. 1993; 7: 317-327
        • Saurat J.H.
        • Didierjean L.
        • Masgrau E.
        • Piletta P.A.
        • Jaconi S.
        • Chatellard-Gruaz D.
        • Gumowski D.
        • Masouyé I.
        • Salomon D.
        • Siegenthaler G.
        Topical retinaldehyde on human skin: biologic effects and tolerance.
        J Invest Dermatol. 1994; 103: 770-774
        • Vanden Bossche H.
        • Willemsens G.
        • Janssen P.A.J.
        Cytochrome P-450-dependent metabolism of retinoic acid in rat skin microsomes: inhibition by ketoconazole.
        Skin Pharmacol. 1988; 1: 176-185