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Human in vivo pharmacology of topical retinoids

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Abstract

All-trans retinoic acid is used topically for treating a variety of dermatologic conditions ranging from acne to photoaged skin. Although the clinical effects of retinoic acid treatment are often considerable, relatively little is known about the basic mechanisms underlying such effects. With the development of an in vivo human assay we have investigated the pleiotypic effects of topical retinoids from the histologic to the molecular. Histologically, retinoic acid induces epidermal proliferation and differentiation coupled with dermal fibroblast production of collagen. Immunologic effects include stimulation of the antigen-presenting capacity of Langerhans cells and induction of keratinocyte ICAM-1 expression. At the biochemical level, retinoic acid regulates transglutaminase and tyrosinase activities and activates protein kinase C. Both polar metabolites and stereoisomers of all-trans retinoic acid are also biologically active. Molecular biologic techniques have revealed that elevation of mRNA for cellular retinoic acid binding protein II is a retinoid-related event and that nuclear receptors such as retinoic acid receptors and retinoid X-receptors may transduce the retinoid response.

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References

  1. Kligman AM, Grove GL, Hirose R, Leyden JJ (1986) Topical tretinoin for photoaged skin. J Am Acad Dermatol 15: 836–859

    Google Scholar 

  2. Cordero A (1984) La vitamina A acida en la piel senil. Actua Ter Dermatol 6: 49–54

    Google Scholar 

  3. Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ (1988) Topical tretinoin improves photoaged skin: a double-blind, vehicle-controlled study. JAMA 159: 527–532

    Google Scholar 

  4. Leyden JJ, Grove GL, Grove MJ, Thorne EG, Lufrano L (1989) Treatment of photodamaged facial skin with topical tretinoin. J Am Acad Dermatol 21: 638–644

    Google Scholar 

  5. Lever L, Kumar P, Marks R (1990) Topical retinoic acid for the treatment of solar damage. Br J Dermatol 122: 91–98

    Google Scholar 

  6. Weinstein GD, Nigra TP, Pochi PE et al. (1991) Topical tretinoin for treatment of photodamaged skin: a multicenter study. Arch Dermatol 127: 659–665

    Google Scholar 

  7. Olsen EA, Katz I, Levine N et al. (1992) Tretinoin emollient cream: a new therapy for photodamaged skin. J Am Acad Dermatol 26: 215–224

    Google Scholar 

  8. Bhawan J, Gonzalez-Serva A, Nehal K et al. (1991) Effects of tretinoin on photodamaged skin: a histologic study. Arch Dermatol 127: 666–672

    Google Scholar 

  9. Rafal ES, Griffiths CEM, Ditre CM et al. (1992) Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage. N Engl J Med 326: 368–374

    Google Scholar 

  10. Griffiths CEM, Goldfarb MT, Finkel LJ et al. (1994) Topical tretinoin (retinoic acid) treatment for hyperpigmented lesions associated with photoaging in Chinese and Japanese patients: a vehicle controlled trial. J Am Acad Dermatol 30: 67–84

    Google Scholar 

  11. Bulengo-Ransby SM, Griffiths CEM, Kimbrough-Green CK et al. (1993) Topical retinoic acid for hyperpigmentation caused by inflammation of the skin of blacks. N Engl J Med 328: 1438–1443

    Google Scholar 

  12. Griffiths CEM, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, Voorhees JJ (1993) Topical tretinoin (retinoic acid) improves melasma in a vehicle-controlled clinical trial. Br J Dermatol 129: 415–421

    Google Scholar 

  13. Kimbrough-Green CK, Griffiths CEM, Finkel LJ et al. (1994) Topical tretinoin (retinoic acid) for melasma in black patients. Arch Dermatol 130: 727–733

    Google Scholar 

  14. Sendagorta E, Lesiewicz J, Armstrong RB (1992) Topical isotretinoin for photodamaged skin. J Am Acad Dermatol 27: s15-s18

    Google Scholar 

  15. Alirezai M, Dupuy P, Amblard P et al. (1994) Clinical evaluation of topical istotretinoin in the treatment of actinic keratoses. J Am Acad Dermatol 30: 447–452

    Google Scholar 

  16. Verschoore M, Langner A, Wolska H, Jablonska S, Czernielewski J, Schaefer H (1991) Efficacy and safety of CD271 alcoholic gels in the topical treatment of acne vulgaris. Br J Dermatol 124: 368–371

    Google Scholar 

  17. Griffiths CEM, Voorhees JJ (1993) Topical retinoic acid for photoaging: clinical response and underlying mechanisms. Skin Pharmacol 6[Suppl 1]: 70–77

    Google Scholar 

  18. Gollnick HPM, Orfanos CE (1991) Theoretical aspects of the use of retinoids as anticancer agents. In: Marks R (ed) Retinoids in cutaneous malignancy, Blackwell Scientific, Oxford, pp 41–45

    Google Scholar 

  19. Marks R, Pearse AD, Hashimoto T, Barton S (1984) Overview of mode of action of retinoids. In: Cunliffe WJ, Miller AJ (eds) Retinoid therapy: a review of clinical and laboratory research. MTP Press, The Netherlands, pp 91–99

    Google Scholar 

  20. Kligman AM (1988) The treatment of photodamaged skin with topical retinoic acid. Persp Plast Surg 2: 63–85

    Google Scholar 

  21. Bell E, Ehrlich HP, Sher S et al. (1981) Development and use of a living skin equivalent. J Plast Reconstr Surg 67: 386–392

    Google Scholar 

  22. Regnier M, Asselineau D, Lenoir MC (1990) Human epidermis reconstructed on dermal substrates in vitro: an alternative to animals in skin pharmacology. Skin Pharmacol 3: 70–85

    Google Scholar 

  23. Ashton RE, Connor MJ, Lowe NJ (1984) Histologic changes in the skin of the rhino mouse (hrh hrh) induced by retinoids. J Invest Dermatol 82: 632–635

    Google Scholar 

  24. Kligman LH, Chen HD, Kligman AM (1984) Topical retinoic acid enhances the repair of ultraviolet damaged connective tissue. Connect Tissue Res 12: 139–150

    Google Scholar 

  25. Bryce GF, Bogdan NJ, Brown CC (1988) Retinoic acids promote the repair of the dermal damage and the effacement of wrinkles in the UVB-irradiated hairless mouse. J Invest Dermatol 91: 175–180

    Google Scholar 

  26. Fisher GJ, Esmann J, Griffiths CEM et al. (1991) Cellular, immunologic and biochemical characterization of topical retinoic acid-treated human skin. J Invest Dermatol 96: 699–707

    Google Scholar 

  27. Griffiths CEM, Finkel LJ, Tranfaglia MG, Hamilton TA, Voorhees JJ (1993) An in vivo experimental model for effects of topical retinoic acid in human skin. Br J Dermatol 129: 389–394

    Google Scholar 

  28. Fisher GJ, Tavakkol A, Griffiths CEM et al. (1992) Differential modulation of transforming growth factor-Β1 expression and mucin deposition by retinoic acid and sodium lauryl sulfate in human skin. J Invest Dermatol 98: 102–108

    Google Scholar 

  29. Rubin Al, Rice RH (1986) Differential regulation by retinoic acid and calcium of transglutaminase in cultured neoplastic and normal keratinocytes. Cancer Res 46: 2356–2361

    Google Scholar 

  30. Thacher SM, Rice RH (1985) Keratinocyte-specific transglutaminase of cultured human epidermal cells: relation of cross-linked envelope formation and terminal differentiation. Cell 40: 685–695

    Google Scholar 

  31. Griffiths CEM, Rosenthal DS, Reddy AP et al. (1992) Short-term retinoic acid treatment increases in vivo, but decreases in vitro, epidermal transglutaminase K enzyme activity and immunoreactivity. J Invest Dermatol 99: 283–288

    Google Scholar 

  32. Rosenthal DS, Griffiths CEM, Yuspa SH, Roop DR, Voorhees JJ (1992) Acute or chronic topical retinoic acid treatment of human skin in vivo alters and expression of epidermal transglutaminase, loricrin, involucrin, filaggrin and keratins 6 and 13 but not keratins 1, 10 and 14. J Invest Dermatol 98: 343–350

    Google Scholar 

  33. Bernard BA, Reano A, Darmon YM, Thivolet J (1986) Precocious appearance of involucrin and epidermal transglutaminase during differentiation of psoriatic skin. Br J Dermatol 114: 279–283

    Google Scholar 

  34. Griffiths CEM, Finkel LJ, Ortiz-Ferrer L et al. (1994) Retinoic acid induced irritation and efficacy are separable, suggesting mechanisms other than irritation as dey determinants of retinoic acid induced improvement of photodamage. J Invest Dermatol 102: 555A

    Google Scholar 

  35. Griffiths CEM, Russman AN, Majmudar G, Singer RS, Hamilton TA, Voorhees JJ (1993) Restoration of collagen formation in photodamaged skin by tretinoin (retinoic adic). N Engl J Med 329: 530–535

    Google Scholar 

  36. Talwar HS, Griffiths CEM, Hamilton TA, Voorhees JJ, Fisher GJ (1994) Type I and III collagen precursors are reduced in severe chronically photodamaged human skin. J Invest Dermatol 102: 622A

    Google Scholar 

  37. Schwartz E, Cruikshank FA, Mezick JA, Kligman LH (1991) Topical all-trans retinoic acid stimulates collagen synthesis in vivo. J Invest Dermatol 96: 975–978

    Google Scholar 

  38. Woodley DT, Zelickson AS, Briggaman et al. (1990) Treatment of photoaged skin with topical tretinoin increases epidermal-dermal anchoring fibrils: a preliminary report. JAMA 163: 3057–3059

    Google Scholar 

  39. Grove GL, Grove MJ, Zerwick CR, Leyden JJ (1988) Determination of topical tretinoin effects on cutaneous microcirculation in photoaged skin by laser Doppler velocimetry. J Cutan Aging Cosmet Dermatol 1: 27–33

    Google Scholar 

  40. Meunier L, Bohjanen K, Voorhees JJ, Cooper KD (1993) In vivo retinoid upregulation of human epidermal Langerhans cell-antigen presenting activity in association with upregulation of class II MHC CD1c and CD11c. J Invest Dermatol 100: 562A

    Google Scholar 

  41. Glick AB, Flanders KC, Danielpour D, Yuspa SH, Sporn MB (1989) Retinoic acid induces transforming growth factor-Β2 in cultured keratinocytes and mouse epidermis. Cell Regul 1: 87–97

    Google Scholar 

  42. Sporn MB, Roberts AB, Wakefield LM, Crombrugghe B de (1987) Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol 105: 1039–1045

    Google Scholar 

  43. Orlow SJ, Chakraborty AK, Pawelek JM (1990) Retinoic acid is a potent inhibitor of inducible pigmentation in murine and hamster melanoma cell lines. J Invest Dermatol 95: 462–464

    Google Scholar 

  44. Talwar HS, Griffiths CEM, Fisher GJ, Russman AN, Drach K, Benrazavi S, Voorhees JJ (1993) Differential regulation of tyrosinase activity in skin of white and black individuals in vivo by topical retinoic acid. J Invest Dermatol 100: 800–805

    Google Scholar 

  45. Ho KL, Halliday GM, Barnetson R St.C (1992) Topical retinoic acid augments ultraviolet light-induced melanogenesis. Melanoma Res 2: 41–45

    Google Scholar 

  46. Duell EA, Astrom A, Kang S, Griffiths CEM, Voorhees J (1994) All-trans, 9-cis and 13-cis retinoic acid each induce a cytochrome P450 4-retinoic acid hydoxylase which causes all-trans but not 9-cis retinoic acid to self metabolize. J Invest Dermatol 102: 641A

    Google Scholar 

  47. Duell EA, Astrom A, Griffiths CEM, Chambon P, Voorhees JJ (1992) Human skin levels of retinoic acid and cytochrome P-450-derived 4-hydroxy retinoic acid after topical application of retinoic acid in vivo compared to concentrations required to stimulate retinoic acid receptor-mediated transcription in vitro. J Clin Invest 90: 1269–1274

    Google Scholar 

  48. Astrom A, Pettersson U, Krust A, Chambon P, Voorhees JJ (1990) Retinoic acid and synthetic analogs differentially activate retinoic acid receptor dependent transcription. Biochem Biophys Res Commun 173: 339–345

    Google Scholar 

  49. Reynolds NJ, Fisher GJ, Griffiths CEM et al. (1993) Retinoic acid metabolites exhibit biological activity in human keratinocytes, mouse melanoma cells and hairless mouse skin in vivo. J Pharmacol Exp Ther 226: 1636–1642

    Google Scholar 

  50. Wauwe J van, Ngen G van, Coene M-C et al. (1992) Liarozole, an inhibitor of retinoic acid metabolism, exerts retinoid-mimetic effects in vivo. J Pharmacol Exp Ther 261: 773–779

    Google Scholar 

  51. Petkovich M, Brand NJ, Krust A, Chambon P (1987) A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 330: 444–450

    Google Scholar 

  52. Giguerre V, Yang N, Segui P, Evans R (1988) Identification of a new class of steroid hormone receptors. Nature 331: 91–94

    Google Scholar 

  53. Brand N, Petkovich M, Krust A et al. (1988) Identification of a second human retinoic acid receptor. Nature 332: 850–853

    Google Scholar 

  54. Krust A, Kastner P, Petkovich M, Zelent A, Chambon P (1989) A third human retinoic and receptor, hRAR-gamma. Proc Natl Acad Sci USA 86: 5310–5314

    Google Scholar 

  55. Mangelsdorf DJ, Ong ES, Dyck JA, Evans RM (1990) Nuclear receptor that identifies a novel retinoic acid response pathway. Nature 345: 224–229

    Google Scholar 

  56. Mangelsdorf DJ, Burgmeyer U, Heyman RA et al. (1992) Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev 6: 329–344

    Google Scholar 

  57. Yu VC, Delsert C, Anderson B et al. (1991) RXR-Β, a coregulator that enhances binding of retinoic acid, thyroid hormone and vitamin D receptors to their cognate response elements. Cell 67: 1251–1266

    Google Scholar 

  58. Evans RM (1988) The steroid and thyroid hormone receptor superfamily. Science 140: 889–895

    Google Scholar 

  59. Rees JL, Redfern CPF (1989) Expression of the α and Β retinoic acid receptors in skin. J Invest Dermatol 92: 818–820

    Google Scholar 

  60. Elder JT, Fisher GJ, Zhang Q-Y et al. (1991) Retinoic acid receptor gene expression in human skin. J Invest Dermatol 96: 425–433

    Google Scholar 

  61. Fisher GJ, Talwar HS, Xiao J-H, Datta SC, Reddy AP, Voorhees JJ (1994) Quantitation of endogenous nuclear retinoid receptor proteins in human epidermis in vivo: high levels of retinoic acid receptor gamma and retinoid X receptor alpha that bind to a retinoic acid response element exclusively as heterodimer. J Invest Dermatol 102: 554A

    Google Scholar 

  62. Levin AA, Sturzenbecker LJ, Kazmer S et al. (1992) 9-cis retinoic acid steroisomer binds and activates the nuclear receptor RXR-α. Nature 355: 359–361

    Google Scholar 

  63. Heyman RA, Mangelsdorf DJ, Dyck JA et al. (1992) 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68: 397–406

    Google Scholar 

  64. Lee MS, Kliewer SA, Provencal J, Wright PE, Evans RM (1993) Structure of the retinoid X receptor-DNA binding domain: a helix required for homodimeric DNA binding. Science 260: 1117–1121

    Google Scholar 

  65. Leid M, Kastner P, Lyons et al. (1992) Purification, cloning and PXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell 68: 377–395

    Google Scholar 

  66. Gendimenico GJ, Stim TB, Corbo M, Janssen B, Mezick JA (1994) A pleiotropic response is induced in F9 embryonal carcinoma cells and rhino mouse skin by all-trans retinoic acid a RAR agonist but not by SR11237, a RXR-selective agonist. J Invest Dermatol 102: 676–680

    Google Scholar 

  67. Giguerre V, Lyn S, Yip P, Siu C-H, Amin S (1990) Molecular cloning of cDNA encoding a second cellular retinoic acid binding protein. Proc Natl Acad Sci USA 87: 6233–6237

    Google Scholar 

  68. Astrom A, Tavakkol A, Petterson U, Cromie M, Elder JT, Voorhees JJ (1991) Molecular cloning of two human cellular retinoic acid-binding proteins (CRABP). J Biol Chem 216: 17662–17666

    Google Scholar 

  69. Eller MS, Oleksiak MF, McQuaid TJ, MaAfee SG, Gilchrest BA (1992) The molecular cloning and expression of two CRABP cDNAs from human skin. Exp Cell Res 199: 328–336

    Google Scholar 

  70. Tavakkol A, Griffiths CEM, Keane KM, Palmer RG, Voorhees JJ (1992) Cellular localization of mRNA for cellular retinoic acid-binding protein II and nuclear retinoic acid receptor γ, in retinoic acid treated skin. J Invest Dermatol 99: 146–150

    Google Scholar 

  71. Elder JT, Cromie MA, Griffiths CEM, Chambon P, Voorhees JJ (1993) Stimulus selective induction of CRABP-II mRNA: a marker for retinoic acid action in human skin. J Invest Dermatol 100: 356–359

    Google Scholar 

  72. Griffiths CEM, Elder JT, Bernard BA et al. (1992) Comparison of CD271 (adapalene) and all-trans retinoic acid in human skin: dissociation of epidermal effects and CRABP-II mRNA expression. J Invest Dermatol 101: 325–328

    Google Scholar 

  73. Marks R, Hills S, Barton SP (1990) The effects of an abrasive agent on normal skin and on photoaged skin in comparison with topical tretinoin. Br J Dermatol 123: 457–466

    Google Scholar 

  74. Duell EA, Fishman A, Astrom A, Griffiths CEM, Voorhees JJ (1993) In human epidermis all-trans retinoic acid is metabolised to the less active 4-hydroxy retinoic acid by a unique cytochrome p450 that does not metabolise 9-cis or 13-cis retinoic acid. J Invest Dermatol 100: 578A

    Google Scholar 

  75. Lammer EJ, Chen DT, Hoar RM et al. (1985) Retinoic acid embryopathy. N Engl J Med 313: 837–841

    Google Scholar 

  76. Lipson AH, Collins F, Webster WS (1993) Multiple congenital defects associated with maternal use of topical tretinoin. Lancet 341: 22

    Google Scholar 

  77. Camera G, Pregliasco P (1992) Ear malformation in baby born to mother using tretinoin cream. Lancet 339: 687

    Google Scholar 

  78. Rosa F (1992) Retinoid embryopathy in humans; In: Karen G (ed) Retinoids in clinical practice. Dekker, New York, pp 77–109

    Google Scholar 

  79. Kligman AM (1988) Is topical tretinoin teratogenic? JAMA 259: 2918

    Google Scholar 

  80. Anonymous Scrip (1989) FDA and teratogenic potential of Retin-A. 374/5 : 17

  81. Jick SJ, Terris B, Jick H (1993) First trimester topical tretinoin and congenital disorders. Lancet 341: 1181–1182

    Google Scholar 

  82. Worobec SM, Wong FGA, Tolman EL, Abrams LS, Parker GR, Thorne EG (1991) Percutaneous absorption of 3H-tretinoin in normal volunteers. J Invest Dermatol 96: 574A

    Google Scholar 

  83. Franz TJ, Lehmann PA, Franz SF (1993) Topical use of retinoic acid gel is not teratogenic. J Invest Dermatol 100: 490A

    Google Scholar 

  84. Buchan P, Eckhoff C, Caron D, Nan H, Shroot B, Schaefer H (1994) Repeated topical administration of all-trans retinoic acid and plasma levels of retinoic acid in humans. J Am Acad Dermatol 30: 428–433

    Google Scholar 

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Griffiths, C.E.M., Voorhees, J.J. Human in vivo pharmacology of topical retinoids. Arch Dermatol Res 287, 53–60 (1994). https://doi.org/10.1007/BF00370719

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