The vitamin A metabolite retinol is essential for life, and has been shown to exhibit a diverse range of biological functions. Natural as well as synthetic molecules that are structurally related to vitamin A are referred to as retinoids, and typically consist of a polyene chain linking a cyclic end group to a polar end group (see Figure 1). Within the cell, retinoids function as signaling molecules, and play important roles in vision, embryonic development, cell proliferation, cell differentiation and immune functions.1 Vitamin A is stored intracellularly as retinyl esters, which after conversion to retinol, are oxidized to more bioactive retinaldehydes or retinoic acids. The structural abundance of retinoids (see Figure 2) and subsequent bioactivity allow for a variety of therapeutic applications within the pharmaceutical and cosmetic space.
Chemotherapy and Cancer Prevention
In carcinogenesis, the intracellular levels of retinyl esters are greatly reduced, compromising retinoid signaling.2 In relation, extensive work has been conducted to examine the efficacy of retinoids to restore signaling for cancer therapy. These studies show retinoids are both chemopreventive and chemotherapeutic, with their activity attributed to abilities to induce cell differentiation, arrest cell proliferation and promote apoptosis in cancer cells.3
All-trans retinoic acid, or tretinoin, is the most extensively studied retinoid for cancer therapies, and has been evaluated in clinical trials for the treatment of lymphoma, melanoma, lung cancer, neuroblastoma and leukemia.3 Retinoids have shown efficacy at preventing the onset and development of cancer, especially precancerous skin lesions. UV irradiation can cause a deficiency of vitamin A; as such, retinoid treatment can prevent aberrant signaling and skin cancer development.3
Intrinsic skin aging is a natural process, although the majority of changes in skin appearance and health are attributed to sun exposure.4 Natural skin aging is mainly characterized by fine wrinkling and sagging, whereas photoaging causes increased pigmentation, deep wrinkling, sallowness and dryness. Further differences between intrinsic aging and photoaging can be seen at the cellular level. Intrinsically aged skin is thinner, with lower levels of collagen and fibroblasts. Photoaged skin is thicker, with the accumulation of elastin and disorganization of collagen.5
Retinoids can be effective at repairing photodamaged skin by repairing or halting the degradation of collagen, elastin and hyaluronic acid, the main structural constituents of skin. All-trans retinoic acid is commonly prescribed to successfully improve the appearance of aged skin as well as prevent the unfavorable effects of aging. This is accomplished by stimulating dermal collagen production, reducing collagen degradation, and promoting epidermal turnover.6, 7 Non-prescription retinoids such as retinol, retinaldehyde and retinyl propionate also effectively lessen skin wrinkling by stimulating extracellular collagen production.8 In the skin, these derivatives are converted to the more active retinoic acid,9 which results in similar effects to retinoic acid.10
Retinoid efficacy is backed by numerous clinical trials, and thus remains the gold standard for the treatment of skin aging.11
Effective Acne Treatment
The use of retinoids to improve acne has been successful as well.12 Here, retinoids function by exhibiting immunomodulatory and anti-inflammatory responses, in addition to stimulating collagen production and increasing epithelial turnover.13 These activities also treat acne scarring.14
All-trans retinoic acid has repeatedly been proven to significantly reduce mild to moderate inflammatory acne and blackheads, making it a frequently prescribed acne medication.13 The most effective acne therapy, however, is oral 13-cis-retinoic acid, isotretinoin, which typically cures acne when other treatments fail.15 Unfortunately, the use of oral retinoids, which is most commonly isotretinoin, is limited due to side effects such as teratogenicity, caused by increased levels of retinoic acid throughout the body.16 The topical application of retinol, however, has not been shown to affect levels of retinoic acid in blood plasma, therefore avoiding teratogenic risks17—although both tretinoin and isotretinoin treatments have high irritation potential, and are light and air sensitive. Newer generations of synthetic retinoids, including adapalene and tazarotene, represent molecules that are beginning to overcome these limitations (see Figure 3).
A New Retinoid for Cosmetics
The pharmaceutical and cosmetic utility of retinoids is impressive, but recent work aims to push the skin care benefits even further. One common goal is to avert the skin irritation and dryness commonly associated with topical retinoid treatments. Structural alterations to vitamin A—such as molecular alterations to the cyclic group, polar group or linker—have enabled the construction of synthetic retinoids that harness the desired activities while simultaneously reducing adverse side effects.18 Taking inspiration from stored retinyl esters, novel esterified forms of retinoic acid are also being investigated. Typically, natural retinyl esters, such as retinyl propionate, are less active than retinol.8 However, new synthetic esters, such as hydroxypinacolone retinoate, are proving to be viable alternatives (see Figure 3).
Hydroxypinacolone retinoate is of great interest because it is capable of interacting with retinoid receptors without first being converted to retinol or retinoic acid.19 This allows for the effective treatment of skin while eliminating the irritation and dryness caused by acidic retinoids. Furthermore, topically applied hydroxypinacolone retinoate effectively diffuses into skin, comparable to topically applied retinoic acid, again without elevating the levels of retinoic acid in blood plasma, thus eliminating the risk of teratogenicity.19
Clearly, retinoids possess a wide spectrum of functions. For skin cancer, skin aging and acne, they have proven both preventive and therapeutic. Successful efforts to create more bioavailable vitamin A derivatives and retinoid formulations have increased the industry’s reliance on them for cosmetic benefits. Recent work to further optimize retinoids and reduce their side effects for cosmetic applications has yielded a new generation of promising molecules.
- R Blomhoff, M Green, T Berg and K Norum, Transport and storage of vitamin A, Science 250 399–404 (1990)
- X-H Tang and LJ Gudas, Retinoids, retinoic acid receptors and cancer, Annual Review of Pathology: Mechanisms of Disease 6 345–364 (2011)
- N Bushue and Y-JY Wan, Retinoid pathway and cancer therapeutics, Advanced Drug Delivery Reviews 62 1285–1298 (2010)
- MCB Hughes, GM Williams, P Baker and AIC Green, Sunscreen and prevention of skin aging, a randomized trial, Annals of Internal Medicine 158, 781 (2013)
- YR Helfrich, DL Sachs and JJ Voorhees, Overview of skin aging and photoaging, Dermatology Nursing 20 177–184 (2008)
- C Griffiths, AN Russman, G Majmudar, RS Singer, TA Hamilton and JJ Voorhees, Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid), New England J Med 329 530–535 (1993)
- GJ Fisher, Z Wang, SC Datta, J Varani, S Kang and JJ Voorhees, Pathophysiology of premature skin aging induced by ultraviolet light, New England J Med 337 1419–1429 (1997)
- ZD Draelos, The latest cosmeceutical approaches for antiaging, J Cos Derm 6 2–6 (2007)
- CK Huang and TA Miller, The truth about over-the-counter topical anti-aging products: A comprehensive review, Aesthetic Surgery Journal 27 402–412 (2007)
- J Varani et al, Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin 1, J Inves Derm 114 480–486 (2000)
- S Mukherjee et al, Retinoids in the treatment of skin aging: An overview of clinical efficacy and safety, Clinical Interventions in Aging 1 327–348 (2006)
- LF Sandoval, JK Hartel and SR Feldman, Current and future evidence-based acne treatment: A review, Expert Opinion on Pharmacotherapy 15 173–192 (2014)
- A Thielitz and H Gollnick, Topical retinoids in Acne vulgaris: Update on efficacy and safety, Amer J Clin Derm 9 369–381 (2008)
- AE Rivera, Acne scarring: A review and current treatment modalities, J Amer Acad Derm 59 659–676 (2008)
- A Shalita, The integral role of topical and oral retinoids in the early treatment of acne, J Eur Acad Derm and Venereol 15 43–49 (2001)
- FW Rosa, AL Wilk and FO Kelsey, Vitamin A congeners, Teratology 33 355–364 (1986)
- GJ Nohynek et al, Repeated topical treatment, in contrast to single oral doses, with Vitamin A-containing preparations does not affect plasma concentrations of retinol, retinyl esters or retinoic acids in female subjects of child-bearing age, Toxicology Letters 163 65–76 (2006)
- JH Barnard, JC Collings, A Whiting, SA Przyborski and TB Marder, Synthetic retinoids: Structure–activity relationships, Chemistry–A European Journal 15 11430–11442 (2009)
- J Gormley, Topical hydroxypinacolone retinoate: Skin diffusion, receptor activity, metabolism and mildness, Grant Industries Inc. (2008)