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Retinoic Acid Receptors and Topical Acne Therapy: Establishing the Link Between Gene Expression and Drug Efficacy

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Retinoic Acid Receptors and Topical Acne Therapy: Establishing the Link Between Gene Expression and Drug Efficacy Therapeutics for the Clinician Retinoic Acid Receptors and Topical Acne Therapy: Establishing the Link Between Gene Expression and Drug Efficacy James Q. Del Rosso, DO Topical retinoids have been an integral part of With further knowledge of retinoid cellular mech- the dermatology armamentarium for 3 decades. anisms, researchers perceived the potential for Tretinoin (all-trans-retinoic acid), a naturally developing new effective and safe retinoid com- occurring retinoid compound, was approved and pounds with a better understanding of their selec- released in the United States in 1971 for acne tive activity against specific disease states. therapy. Several strengths and vehicles (cream, gel, solution) of tretinoin became available to titrate Updated Definition: What Is a Retinoid? use based on patient skin type, efficacy, and toler- The term retinoid currently includes both naturally ance. Two synthetic retinoids have been approved occurring and synthetic compounds that may or and released for use in the United States over the may not be structurally related to vitamin A past 5 years. Adapalene, a naphthoic acid deriva- (retinol).1-3 An international joint commission tive with retinoid activity, was released in 1996 for report on biochemical nomenclature in 1982 ini- acne therapy. Tazarotene followed in 1997, with tially stipulated that a retinoid must be related initial approval for psoriasis and more recent chemically/structurally to vitamin A. Since then, approval for acne treatment. Despite the success several compounds exhibiting biologic retinoid and widespread application of prescription-based activity that are not related structurally to vitamin A topical retinoids used for acne and other skin dis- have been synthesized and studied in vitro orders and retinol as a component of various and in vivo, including use in humans. An updated cosmetics, little was known about the mechanism and expanded definition of “retinoid” has been of action of these compounds until the last decade. suggested, taking into account the elicitation of As the use of retinoids (especially systemic agents) specific biologic responses.2 The definition demonstrated significant therapeutic impact for describes a retinoid as “a substance that can elicit several severe diseases in both dermatology and specific biologic responses by binding to or activat- other disciplines (eg, oncology), interest in under- ing a specific receptor or set of receptors. Retinoids standing retinoid cellular mechanisms intensified. are those substances that have a specific molecular In late 1987 and early 1988, researchers identified fit to the receptor; they are defined in terms of specific nuclear retinoic acid receptors (RARs), their interaction with that receptor, rather than suggesting important insights into the cellular/ being restricted to a particular subset of diter- molecular basis of retinoid activity. RARs have penoid, polyene substances.”2 This definition is been found in several organ tissues, including skin. more applicable to modern reality and current directions in retinoid research. “The program for the biological response of target cells for retinoids From the Department of Dermatology, University of Nevada resides in retinoid receptors, rather than in the 2 School of Medicine, Las Vegas. retinoids themselves.” Dr. Del Rosso is in independent private practice with academic affiliations. He has served as a consultant and Retinoic Acid Receptor Genes and on speakers bureaus for the following: Allergan, Inc.; Pathways of Activation Galderma Laboratories; Medicis Pharmaceutical Corporation; and Ortho Dermatological. Retinoic Acid Receptors—In the mid-to-late 1980s, Reprints: James Q. Del Rosso, DO, 4488 S Pecos Rd, independent investigators identified 2 distinct Las Vegas, NV 89121. retinoic acid receptors (RARs), RAR-␣ and RAR-␤, VOLUME 70, AUGUST 2002 127 Therapeutics for the Clinician both of which were found to express low levels of Additional in vivo animal research with recog- the RAR-␣ and RAR-␤ genes in adult human nized models (Rhino mouse and rabbit) using mul- skin.4 This confounded researchers because skin tiple RAR-␥–selective retinoids suggests that was well-known to be highly responsive to the (1) RAR-␥ plays a significant role in retinoid effi- effects of retinoid, especially based on clinical and cacy, and (2) that retinoid-induced skin irritation research experience with topical tretinoin and oral may be mediated at least in part by receptor inter- isotretinoin. The later discovery of RAR-␥ in both action.4,5 In a study of multiple retinoid agents human and murine skin in 1989 appeared to clarify using a mouse model, retinoid-induced skin irrita- the controversy, as this specific receptor gene was tion was correlated directly to receptor-binding expressed in skin at high levels.4,5 affinity for RAR-␤, RAR-␥, or both.9 Cutaneous RAR-␣, RAR-␤, and RAR-␥ are the 3 distinct irritation was not related to RAR-␣ agonist activ- RAR genes identified in humans. Gene transcripts ity. The study also reported that in regard to skin for RAR-␣ are relatively ubiquitous in adult and irritation, a distinction could not be made between embryonic tissues.1,4 The RAR-␣ gene is expressed the relative contributions of RAR-␤ and RAR-␥ at a higher degree in fetal skin than adult skin in receptor binding.9 vivo and in human neonatal keratinocytes in Retinoid X Receptors—In 1990, another receptor vitro. Such findings suggest that RAR-␣ most type, the retinoid X receptor (RXR), was discov- likely plays an important role in overall cellular ered.1,4 Three types appear to exist: RXR-␣, RXR-␤, growth and differentiation.1,4 and RXR-␥. Of the RXRs, RXR-␣ expression appears The RAR-␤ gene appears to play a limited role to be predominant in human epidermis. None of the in adult skin.1,4 To date, studies suggest that RAR-␤ currently available prescription or over-the-counter gene expression has been dependent on the cell retinoids bind directly to RXRs. However, conversion type analyzed. Induction of RAR-␤ by retinoic acid to 9-cis-retinoic acid is one of the intracellular has been demonstrated in dermal fibroblasts, with a metabolic pathways of all-trans-retinoic acid; up to delayed kinetic pattern and with more rapid onset 5% epidermal recovery of 9-cis-retinoic acid has been in both hepatoma and teratocarcinoma cell lines, reported after application of a topical retinoic acid. 9- but not in keratinocytes.4,6 cis-Retinoic acid may bind with high affinity to RARs The most abundant and readily detectable RAR and also serves as a ligand for RXR binding.1,3,4 type in adult skin is RAR-␥.4,5 Based on in vitro RARs and RXRs exhibit considerable coopera- and in vivo data, including data from studies in tive activity in binding to DNA.3 After retinoid human skin, the RAR-␥ gene appears to be abun- binding and activation, RARs require the formation dantly expressed in human skin as compared with of a heterodimer complex with a bound RXR before RAR-␣ and RAR-␤ and is expressed in both interaction with DNA. To the contrary, RXRs may human keratinocytes and dermal fibroblasts.4,5 behave as homodimers or form complexes with Retinoid binding and agonist activation of RARs other nonretinoid hormone receptors (eg, thyroid). have been demonstrated to modulate gene expres- Other than the role of RXR in RAR-RXR het- sion through retinoid (retinoic acid) response ele- erodimer formation required for DNA interaction ments (RAREs) of DNA.3 The specific products of and gene expression, the direct role of RXRs in the such gene modulation/expression, apparently influ- therapeutic or adverse effects of topical retinoids is enced by the role of individual RARs (and proba- unknown. An in vivo study in the hairless mouse bly other yet-to-be-discovered receptors), create model comparing topically applied RAR-specific the varied biologic effects of retinoids. and RXR-selective retinoids suggests that RXRs Different topical retinoids may vary in their behave primarily as “silent partners,” functioning route of cellular transport; use of cellular-binding passively in the RAR-RXR heterodimer com- proteins, such as cellular (cytoplasmic) retinoic plex.10 In contrast to RAR-specific retinoids, acid-binding protein (CRABP); RAR binding pat- RXR-selective retinoids produced only very mild terns; and RAR binding affinity.4,7,8 The nature of evidence of skin irritation (flaking) and demon- both therapeutic and adverse retinoid effects pro- strated weak potency in induction of epidermal duced by a specific topical retinoid depends on the hyperplasia. Further research is needed to better pattern and affinity of receptor binding and the define the cellular and biologic activities of RXRs. multiplicity of pathways for receptor-gene activa- tion. In addition, as isoforms of RARs have been Cellular Pathways of Activity: identified, this also may relate to specific functions Topical Retinoids and resultant clinical effects. At least 7 isoforms of The receptor-binding activities of topical retinoids RAR-␥ have been described.4,6 currently approved for use in the United States 128 CUTIS® Therapeutics for the Clinician RAR Binding Properties of Topical Retinoids*1,7,11 Drug CRABP RAR-␣ RAR-␤ RAR-␥ RXR Tretinoin (all-trans-retinoic acid) ϩϩ ϩϩϪ† Adapalene Ϫϩ/ϪϩϩϪ Tazarotene‡ ? ϩ/ϪϩϩϪ *RAR indicates retinoic acid receptor; CRABP, cellular (cytoplasmic) retinoic acid-binding protein; RXR, retinoid X receptor; ϩ/Ϫ, weak binding. †Tretinoin does not exhibit direct binding to RXR; isomerase enzymatic conversion of tretinoin
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