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AT-A-GLANCE

AT-A-GLANCE

  • A retinoid is any molecule that by itself or through metabolic conversion binds to and activates retinoic acid receptors.

  • Retinoid receptors are ligand-dependent transcription factors.

  • The predominant retinoid receptors in human skin are retinoic acid receptor α (RAR-α), RAR-γ, retinoid X receptor α (RXR-α), and RXR-β. RAR-γ/RXR-α heterodimers bind to retinoic acid–responsive elements and are responsible for retinoid signaling.

  • Clinical use of topical retinoids:

    • Approved indications: acne, psoriasis, cutaneous T-cell lymphoma, Kaposi sarcoma, melasma, photoaged skin

    • Unapproved indications with clinical studies supporting benefit: postinflammatory hyperpigmentation, and early stretch marks

  • Clinical use of oral retinoids:

    • Approved indications: acne, chronic hand eczema, psoriasis, and cutaneous T-cell lymphoma

    • Unapproved indications with clinical studies supporting benefit: pityriasis rubra pilaris, premalignancies, photoaging, ichthyosis, and Darier White disease

  • Teratogenicity is the most concerning side effect. Mucocutaneous (cheilitis, xerosis, skin peeling, conjunctivitis) involvements are common, as are reversible abnormal results on laboratory tests (hyperlipidemia, increased liver enzyme levels, and hypothyroidism [bexarotene/alitretinoin]). Musculoskeletal and central nervous system side effects are rare.

INTRODUCTION AND BACKGROUND

Retinoids are widely used as prescription drugs as well as cosmeceuticals. They are able to elicit skin responses by mediating their effects through their intranuclear retinoid receptors, acting as transcription factors. Indeed, the discovery of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) have been pivotal to our understanding of the retinoid action mechanism.1,2 In 1976, Michael Sporn and his colleagues originally defined retinoids as both the naturally occurring compounds with vitamin A activity and the synthetic analogs of retinol. This concept is no longer adequate. Now, retinoid is defined as any molecule that, by itself or through metabolic conversion, binds to and activates the RARs, thereby eliciting transcriptional activation of retinoic acid–responsive genes, resulting in specific biologic responses. Our understanding of retinoid mechanism, as highlighted in this chapter, is primarily based on action of topical natural retinoids in vivo. Mechanism for oral retinoids is less clear, and further elucidation is needed.

PHARMACOLOGY AND MECHANISM OF ACTION

STRUCTURE

NOMENCLATURE

All-trans-retinoic acid (tretinoin), which binds to and activates RARs, is derived from sequential oxidation of all-trans-retinol (or vitamin A) and all-trans-retinaldehyde. It is a 20-carbon molecule that consists of a cyclohexenyl ring, a side chain with four double bonds (all arranged in trans-configuration), and a carboxylic-acid end group (Fig. 185-1). The numbering of the carbon atoms is as shown in Fig. 185-1. The terms 9-cis- (alitretinoin) and 13-cis-retinoic acid (isotretinoin) refer to stereoisomers of all-trans-retinoic acid in which the double bond that begins with the 9th and 13th carbon atoms, respectively, is in the cis- rather than trans-configuration. The fourth carbon atom is located in the cyclohexenyl ring of retinoic acid and is involved in a hydroxylation reaction to generate 4-hydroxy-retinoic acid (see Fig. 185-1...

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