Metabolism and Biological Activities of Topical 4-Oxoretinoids in Mouse Skin Olivier Sorg, Christian Tran, Pierre Carraux, Denise Grand, Christelle Barraclough,

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Metabolism and Biological Activities of Topical 4-Oxoretinoids in Mouse Skin Olivier Sorg, Christian Tran, Pierre Carraux, Denise Grand, Christelle Barraclough, Jean-François Arrighi, Patrick Descombes, Vincent Piguet, Jean-Hilaire Saurat Journal of Investigative Dermatology Volume 128, Issue 4, Pages 999-1008 (April 2008) DOI: 10.1038/sj.jid.5701106 Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Chemistry of 4-oxoretinoids. (a) Structure of 4-oxoretinol and 4-oxoretinal. (b) Analysis of retinoids by HPLC. The figure shows an HPLC chromatogram from an epidermal sample of a mouse tail that was treated with topical oxoROL. Peaks 1, 2, 4, 5, and 6 were obtained by measuring the absorbance at 325nm, whereas peaks 1′, 2′, and 3′ were obtained by measuring the absorbance at 385nm, in order to show a small peak of oxoRAL. Peak identification: 1, 1′: oxoRA; 2, 2′: oxoROL; 3′: oxoRAL; 4: ROL; 5: ROL acetate (internal standard); 6: retinyl esters. Retention time for RA (which is not visible on this chromatogram for oxoROL treatment) is 6.1minutes. It cannot be confused with the peak at 5.5minutes corresponding to BHT (an antioxidant in retinoid creams), which has an absorption maximum at 277nm. Journal of Investigative Dermatology 2008 128, 999-1008DOI: (10.1038/sj.jid.5701106) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Epidermal hyperplasia. (a) Epidermal thickness: C57BL/6 mice (5 per treatment) were treated once daily for 14 days with the mentioned retinoids or vehicle on the tail. Histological slices were stained with hematoxylin and eosin. Bar=50μm. (b) Measure of epidermal thickness (mean of 5 fields±SE); significant differences from vehicle are indicated. (c) Repression of K2E keratin: mRNA transcripts for mK2E keratin were assayed by Northern blots. (d) Densitometric analysis of blots shown in c (mean of pixel values±SE); significant differences from vehicle are indicated. Journal of Investigative Dermatology 2008 128, 999-1008DOI: (10.1038/sj.jid.5701106) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Metaplastic response. (a) Regression of parakeratosis: C57BL/6 mice (5 per treatment) were treated as indicated in Figure 2a legend. Histological slices were stained with hematoxylin and eosin. The stratum granulosum appears as a black superficial layer. Bar=50μm. (b) Length of parakeratosis (distance between two adjacent granular layers in interfollicular epidermis; mean of 5 mice±SE); significant differences from vehicle are indicated. (c) Repression of Hb4 keratin: mRNA transcripts for mHB4 keratin were assayed by Northern blots. (d) Densitometric analysis of blots shown in c (mean of pixel values±SE); significant differences from vehicle are indicated. Journal of Investigative Dermatology 2008 128, 999-1008DOI: (10.1038/sj.jid.5701106) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Irritation. (a) Inflammation: C57BL/6 mice (5 per treatment) were treated once daily for 4 days with the mentioned retinoids or vehicle on the ears, then MPO activity was determined in the skin. Results (mean±SE) are expressed as fold induction, as compared to vehicle-treated ears; significant differences from vehicle are indicated. (b) Lipid peroxidation: hairless mice (5 per treatment) were treated on the back once daily for 3 days with the mentioned retinoids or vehicle followed by topical menadione or its solvent, then epidermal lipid peroxides were assayed 30minutes after the last menadione treatment. Results (mean±SE) are expressed as nmol lipid peroxides/g ww; significant differences from vehicle+solvent are indicated. Abbreviations: Veh, retinoid vehicle; Solv, menadione solvent (ethanol/PEG400/water (3:1:1)); M, menadione 50mM. Journal of Investigative Dermatology 2008 128, 999-1008DOI: (10.1038/sj.jid.5701106) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Genomic analysis of retinoid-like activity. C57BL/6 mice (4 per treatment) were treated as indicated in Figure 2a legend, then total RNA was extracted and complementary DNA was analyzed by qPCR for representative genes of retinoid activity. Results, expressed as means±SE, represent the fold induction compared with vehicle-treated mice; significant differences from vehicle are indicated. Journal of Investigative Dermatology 2008 128, 999-1008DOI: (10.1038/sj.jid.5701106) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Inhibition of DC maturation. The maturation of human DCs was induced by LPS. The degree of maturation was defined as the percentage difference between the number of DCs double-positive for MHC-II and CD83 in retinoid-treated cells, compared with those treated with solvent. The effect of a pretreatment by RA, RAL, or oxoRAL 1μM in 0.1% ethanol was compared with that of 0.1% ethanol. The results are expressed as the means±SE of four separate experiments; significant differences from ethanol+LPS are indicated. Journal of Investigative Dermatology 2008 128, 999-1008DOI: (10.1038/sj.jid.5701106) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 7 Simplified diagram of retinoid metabolism and action. OxoRAL and oxoROL were integrated to the metabolism and action of retinoids. The mechanism of conversion of RAL and ROL into oxoRAL and oxoROL is still unknown. R and X represent ligands for the nuclear receptors RAR and retinoid X receptor, respectively. Abbreviations: BCO, β-carotene 15,15′-monooxygenase; CAR, provitamin A carotenoids; LRAT, lectithin:retinol acyltransferase; RALDH, retinal dehydrogenase; RARE, retinoic acid response element; REH, retinyl ester hydrolase; RoDH, retinol dehydrogenase. Journal of Investigative Dermatology 2008 128, 999-1008DOI: (10.1038/sj.jid.5701106) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions