How Do Retinoids Work?
Topical retinoids (for example, tretinoin) and retinoid analogues (for example, adapalene and tazarotene) help normalize hyperkeratinization and have demonstrated significant anti-inflammatory effects. Retinoids are potent agents that can normalize abnormal growth and differentiation in keratinocytes (American Academy of Dermatology [AAD], 2003). Topical retinoids also demonstrate inhibition of various immune factors, including the activity of leukocytes, the release of pro-inflammatory cytokines and other mediators, and the expression of transcription factors and toll receptors involved in immunomodulation (Wolf, 2002). These various mechanisms may be advantageous to clinicians in managing numerous inflammatory and keratotic dermatoses. Topical retinoids have the potential of indirectly reducing the risk of antibiotic resistance by controlling and maintaining remission of inflammatory and noninflammatory lesions (Rizova, Pagnoni, Stoudemayer, Poncet, & Kligman, 2001). all-trans retinol is considered to be a parent form of vitamin A and the addition of this compound in over-the-counter (OTC) products is not considered to be a drug. Due to substantial structural differences, the newest generation of retinoids have limited similarity to retinol (Baumann, 2003).
Retinoids and retinoid analogues exert their activities by interacting with nuclear receptors (RARs [retinoic acid receptors] or RXRs [retinoic X receptors]) on cells and by activating genes that contain RARE (retinoic acid response elements) or RXRE (retinoic X response elements) in their promoters (Michel, Jombard, & Démarchez, 1998). Additionally, they can regulate gene expression by inhibiting the activity of other transcription factors, such as AP-1. The AP-1 transcription complex controls the expression of a subset of genes that are expressed early in response to extracellular mitogenic stimuli or to stress. It has been hypothesized that the AP-1 may play a substantial role in the inflammation and immune response (Michel et al., 1998).
Keep in mind, all-trans retinol is a weaker form of the prescription all-trans retinoic acid, also known as tretinoin. all-trans retinol can be readily found in today's abundant selection of OTC beauty products. The first to market all-trans retinol in cosmetic products was Avon, in 1984 (Prystowsky, 2001). Today's marketing strategies often focus on obtaining a more "youthful" appearance, stressing the ability to soften wrinkles, firm the skin, and counteract photoaging. These "anti-aging" products are not regulated (Leyden, 2003). The implied benefits of some OTC products could potentially occur because all-trans retinol is oxidized to form tretinoin, after absorption into skin cells (Prystowsky, 2001). It is difficult, however, to determine the actual amount of the active agent these unregulated products contain. Many of today's products contain biologically inactive forms (Baumann, 2003). Prescription topical retinoids can provide favorable, evidenced-based results (see Table 1 ).
Tretinoin is endogenously formed in the skin from all-trans retinol by basal keratinocytes. Both all-trans retinoic acid (tretinoin) and all-trans retinol are naturally occurring retinoids. The human body is armed with the proper binding proteins and enzymatic machinery to metabolize these retinoids appropriately (Prystowsky, 2001). Metabolism of synthetic retinoids, however, is somewhat unpredictable, due to the significant structural differences of adapalene and tazarotene, which are not naturally occurring retinoids (Prystowsky, 2001). Retinoids promote a reversal of comedogenesis, leading to a reduction in microcomedos, which is a precursor of both inflammatory and noninflammatory acne lesions (Leyden, 2001). Retinoic acid (tretinoin) reverses thickening of the stratum corneum and the abnormal desquamation of keratinocytes, and has been a mainstay for the treatment of acne for more than 30 years (Verschoore et al., 1993). Topical retinoids reduce hyperkeratinization and allow enhanced penetration of adjunctive topical agents (Berson, 1999). For over 25 years, topical tretinoin has been studied for numerous other conditions. The modulation of epidermal differentiation by retinoids led to its use in premalignant lesions, such as actinic keratoses (Verschoore et al., 1993).
Adapalene is considered to be a second-generation retinoid and the first of its kind. It contains retinoid properties by reason of a synthetic naphtholic acid derivative. It targets abnormal desquamation of the skin, modulates cellular differentiation, and possesses anti-inflammatory properties (Leyden, 2001). Adapalene contains unique pharmacologic properties, which are characterized by a selectivity for the nuclear retinoic acid receptor RAR β/γ, and a potent activity on cell differentiation. This selectivity may contribute to an improved tolerance, associated with adapalene (Michel et al., 1998).
Tazarotene (Tazorac®) is pharmacologically inactive until metabolic conversion to the active drug transpires (Wolverton, 2001). This prodrug is hydrolyzed rapidly in tissues to the active metabolite tazarotenic acid. The RAR-γ nuclear receptor is the predominant receptor present in the epidermis, for which tazarotenic acid has a high affinity. Additionally, tazarotenic acid has the ability to bind with RAR-α and RAR-γ, but not to RXRs. Tazarotenic acid modulates the expression of retinoid-responsive genes, including those that regulate cell proliferation, cell differentiation, and inflammation, in view of these binding capacities to various RAR receptors. Tazarotene down-regulates the abnormal expression of keratinocytes, epidermal growth factor receptor, and hyperproliferative keratins (Prystowsky, 2001).
Dermatology Nursing. 2003;15(5) © 2003 Jannetti Publications, Inc.
Cite this: Clinical Review: Topical Retinoids - Medscape - Oct 01, 2003.
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