packaging such as airless pumps and tubes with a useful shelflife of 2 years. Packaging in jars is a technical hurdle that has been achieved but requires rigorous formulation development and testing.
The biologic effects of all retinoids are dependent on their ability to bind to cytoplasmic and nuclear receptors.21 Within the cytoplasm, retinol and retinaldehyde bind to cellular retinol binding protein (CRBP). Although the role of this cytoplasmic receptor is not completely understood, it is believed that it serves to facilitate the conversion of retinol to retinaldehyde and retinaldehyde to retinoic acid. Retinoic acid binds to cellular retinoic acid binding protein (CRABP), of which there are two isomers, CRABPI and CRABPII. Binding of retinoic acid to CRABPII facilitates translocation of retinoic acid into the nucleus. To regulate gene transcription, retinoic acid must bind to nuclear receptors that are members of the steroid-thyroid hormone superfamily. There are two unique families of nuclear receptors, retinoic acid receptors (RARs), and retinoid X receptors (RXRs). There are three isoforms of RARs and RXRs, α, β, and γ. The epidermis expresses primarily RARγ/RXRα, making this heterodimer important in cutaneous signaling.22 Retinoic acid binds to RARγ within the keratinocyte nucleus, which then forms a heterodimer with RXRα. Once formed, this retinoid-receptor heterodimer complex binds to specific DNA elements known as retinoic acid response elements (RAREs). These elements reside in the promoter region of target genes and stimulate (no 2) transcription of mRNA and ultimately protein synthesis. In addition, retinoids have indirect effects that result from downregulation of genes that do not contain RAREs in their promoter region.23 Retinoic acid is known to antagonize transcription factors activator protein-1 (AP-1) and nuclear factor kappa beta (NF- кβ).24 AP-1 increases synthesis of metalloproteinases that break down collagen and concomitantly causes a reduction in collagen synthesis. NF-кβ triggers production of a variety of inflammatory mediators that contribute to skin aging. The anti-aging benefits of retinoids have been attributed, in part, to their ability to down-regulate these transcription factors.
The cellular and molecular effects of retinol have been studied extensively and confirm its bioactivity in the epidermis and dermis (Figure 4). Topical application of 1.6% retinol under occlusion induces epidermal thickening and enhances expression of CRABPII mRNA like tretinoin 0.025%.25 Retinol treatment resulted in less erythema and skin irritation compared to tretinoin in this study. An ex vivo study using human skin explants demonstrated that 0.1% retinol induced CRABPII and HBEGF gene expression, increased keratinocyte proliferation and epidermal thickness.26 In this study, human
