INTRODUCTION

Traditionally, retinoids have been classified as compounds that have the basic core structure of vitamin A and its oxidized metabolites. More recently, this structural classification has been broadened to include newer series of synthetic compounds that share similar mechanisms of action as naturally occurring retinoids. The discovery of these novel retinoid analogs has been facilitated in large part by mechanistic understanding of the role of retinoids in molecular biology, gene expression profiling, and basic metabolic research. While the current knowledge of vitamin A metabolism and activity profiles can be further grouped via the two different delivery routes, oral and topical, this chapter will focus primarily upon pharmacologic profiles and metabolic rates as per topical delivery in humans. Also, this chapter will highlight key understandings of current topically used retinoids both in the dermatologic field as well as in the over-the-counter (OTC) and cosmetic marketplace.

MOLECULAR BIOLOGY OF RETINOIDS

Retinoids are naturally occurring derivatives of beta-carotene and ascribed as vitamin A and its direct metabolites. These include retinol, retinaldehyde, retinyl esters, and retinoic acid (Fig. 6.1). These compounds have an essential role in such processes in higher order mammals as development (including ocular), angiogenesis, and dermatologic homeostasis. One of the key biologically relevant retinoids is retinoic acid, which exists as several isomeric forms (e.g. all-trans, 9-cis and 13-cis) and is essentially an oxidized form of retinol. This molecule has been shown at the molecular level to function as an agonist for the retinoic acid receptors (RAR) and retinoid X receptors (RXR), a specific subgroup from the broader family of nuclear receptors. In this subclass, there exist three isoforms of respective receptors, labeled α, β, and γ. Upon binding of the retinoic acid ligand, RAR and RXR will form a heterodimer that then is capable of interacting with specific DNA sequences located in the promoter regions of retinoid-regulated genes. These nucleic acid sequences are termed retinoic acid response elements (RARE). More recently, it has become apparent that the transcription factor AP-1 also has a significant effect upon regulating activation of genes through its interactions at the RARE site.

Fig. 6.1 Chemical structures of key retinoids

In summary, retinoic acid can influence the function of a cell by altering gene expression patterns through its facilitated binding to RAREs of a dimerized RAR/RXR complex (Fig. 6.2). This knowledge of the mechanistic role in retinoid regulation of gene expression patterns allowed for the synthesis of novel pharmacologic classes of compounds that have a broader structural diversity with varying pharmacologic properties than natural retinoids. Additionally, it appears that the majority of biologic effects observed from topical delivery of various retinoids are mediated by interaction through the RAR/RXR complex, including in some cases any obligatory metabolic conversion to retinoic acid.

Fig. 6.2 Retinoic acid regulation of gene expression

METABOLISM OF CUTANEOUSLY DELIVERED RETINOIDS

The metabolic pathways that have been identified as involved in retinoid metabolism in the digestive system have been confirmed in large part as existing in human skin (Fig. 6.3). While much of free retinol is esterified via lecithin:retinol acyltransferase (LRAT) or acyl CoA:retinol acyltransferase (ARAT) to retinyl palmitate for storage, a small percentage is further oxidized to the active acid form. The oxidation of free retinol to retinoic acid is the limiting step in the generation of active retinoid metabolites within cells. This process is begun when free retinol associates with a specific cytoplasmic retinol-binding protein (CRBP). The retinol-CRBP complex is a substrate for retinol dehydrogenase, a microsomal enzyme uniquely capable of catalyzing the conversion of retinol to retinaldehyde. Retinaldehyde is then rapidly and quantitatively oxidized to retinoic acid by retinaldehyde oxidase. Once converted, retinoic acid regulates gene expression profiles via RAR/RXR for skin keratinocyte growth and differentiation.

Fig. 6.3 Retinoid metabolism in skin

This multistep processing of retinyl esters serves as a point of regulation to control the level of active retinoid in the skin and may thus contribute to the lower irritation potential of these derivatives. Ultimately, retinoic acid can be metabolized irreversibly via hydroxylation to 4-hydroxy-retinoic acid and 4-oxo-retinoic acid via various cytochrome P450. It is important to note that the majority of retinoid metabolism that occurs is mediated via retinoid bound to cytosolic lipid binding proteins. This family of proteins with high retinoid specificity includes CRBP and cytoplasmic retinoic acid-binding protein (CRABP), of which there are two isoforms, I and II.

Topical usage of retinoids has shown a high degree of efficacy against acne, photodamage, and psoriasis. These effects can be ascribed on some level as being a normalization of altered skin conditions. However, two of the key negatives associated with topical retinoids are:

Thus, a significant effort has been expended to identify retinoids that are efficacious and have an overall lower irritation profile and lessened teratogenic safety concerns.

To minimize these negatives and yet still alter photodamaged skin, retinoic acid precursors such as retinol, retinaldehyde, and retinyl esters (e.g. retinyl propionate and retinyl palmitate) have been used widely in the skin care industry. It is hypothesized that the acyl chain length of retinyl esters plays a key role in determining the activity and irritation profiles. It may therefore be possible to identify an acyl chain length retinol that provides robust retinoid activity yet has minimal irritation.

• Retinyl esters

Retinyl esters serve a primary role of storage of vitamin A in cellular locations, primarily lipids, with retinyl palmitate being the predominant form. The conversion of retinol from retinyl palmitate is believed to occur via retinyl esterase activities residing in a number of subcellular locations and through nonspecific esterases, which are abundant in the skin.

RETINYL PROPIONATE

Retinyl propionate has been reported to be active in human skin and to have less irritation than other active retinoid options. More recently, it has been observed that this particular ester is capable of eliciting retinoid-like effects in human skin via both histologic assessments and clinical measures of photodamage changes (Fig. 6.4). Furthermore, retinoid-induced irritation appears to be less evident from retinyl propionate in comparison with retinol or retinyl acetate (Table 6.1). As with the palmitate ester of retinol, retinyl propionate must be hydrolyzed to free retinol, a process that occurs via skin esterases. Additionally, it has been reported that the propionate ester has an improved stability profile relative to other esters, thereby increasing half-life upon skin during topical delivery.

Fig. 6.4 Effect of retinyl propionate upon photodamaged skin. 0.2% retinyl propionate in a stable skin care emulsion system was applied twice daily for 12 weeks. Images were taken at baseline, and weeks 4, 8, and 12, showing impact upon fine lines/wrinkles (A) baseline image; (B) week 12 image, and impact upon hyperpigmented age spots (C) baseline image; (D) week 12 image

Table 6.1 Back irritation measures for retinol and its esters

RETINYL PALMITATE

The primary role of endogenous retinyl palmitate is to provide a stored form of dietary retinol, thereby serving as a control point. Although topical application of retinyl palmitate may be considered a nonphysiologic route of exposure, there is ample evidence to support the view that the skin possesses all of the enzymatic machinery necessary to convert retinyl palmitate to retinol. Accordingly, the small amount of retinyl palmitate that actually penetrates the skin would be expected and has been indirectly demonstrated to enter the normal physiologic pathways controlling vitamin A homeostasis. Based on published information and historical cosmetic usage, it is accepted that retinyl palmitate has, at best, an overall weak activity profile and is nonirritating.

CONCLUSION

Retinoids are a broad family of molecules whose primary function is to serve as agonists for members of the RAR and RXR nuclear receptor family. In turn, this denotes their role in regulating gene expression profiles via RAR/RXR binding to RAREs. In dermatology, retinoids have been shown to have beneficial effects upon acne, psoriasis, actinic keratosis, and photodamaged/aging skin attributes. The ability of synthetic retinoid analogs to mimic the effects of endogenous ligands such as retinoic acid is based in part on similar mechanisms of action but with variant pharmacokinetic properties that renders them as more functional for specific purposes, based on the disease state being targeted. Future research directions in better understanding the connections between efficacy and retinoid-induced irritation should allow for the identification of analogs or optimized therapies that decouple these two phenomena.