Advances in Pigmentation Management: A Multipronged Approach
November 2022 | Volume 21 | Issue 11 | 1206 | Copyright © November 2022
Published online October 31, 2022
Alan D. Widgerow MBBCh MMed FCS FACSa,b, Jordan V. Wang MD MBE MBAc, Mary E. Ziegler PhDb, Sabrina G. Fabi FAAD FAACSa,d, John A. Garruto BS VPb, Deanne Mraz Robinson MD FAAD CMOf,g, Michaela Bell BS MBAb
aUniversity of California, Irvine, CA
bAlastin Skincare, a Galderma company
cLaser & Skin Surgery Center of New York, New York, NY
dGoldman Butterwick Fitzpatrick Groff & Fabi Cosmetic Laser Dermatology, San Diego, CA
fModern Dermatology, Westport, CT
gYale University of Medicine, New Haven, CT
Abstract
Background: Key cellular players regulating human skin pigmentation include melanocytes in the epidermis that synthesize melanin, neighboring keratinocytes that receive and distribute melanin in the upper layers, and fibroblasts in the dermis that affect overlying melanocytes and keratinocytes. In addition, endocrine factors from the blood supply (endothelial cells) and inflammation-related factors play a role. Thus, new strategies for affecting pigmentation need to consider these multiple cell lines to adequately cover various causes and disease processes associated with hyperpigmentation.
Methods: Pathophysiologic mechanisms and cellular pathways involved in melanogenesis were thoroughly reviewed with particular emphasis on the cellular interplay involved in the process. A complex system of interlinking and independent pathways was defined and described demonstrating differing pathways for altered pigmentary disorders - melasma associated with endothelial cell interactions; post inflammatory hyperpigmentation associated with keratinocyte inflammatory mediators (PGE2 in particular); and photodamage involving all 4 cell types. In vitro validation studies were then undertaken to define differing cell group gene expression profiles with selected peptides and other active agents. Melanocytic production of pigment was then tested with these agents to identify key potential players capable of limiting pigmentation.
Results: Hexapeptide-12 and lactoferrin (melanocytes), Hexapeptide-11 (in keratinocytes), and phosphatidylserine (endothelial cells) were identified as major inhibitors of melanogenesis based on their gene expression profiles. This was confirmed by secondary melanin production tests performed on melanocytic lines. Additional active agents were also identified as inhibitors of melanocytic production of melanin, and together, these constituents formed the basis for a novel formulation for use in pigmentary disorders.
Conclusion: A comprehensive scientific narrative of the various facets relating to pigmentation has been presented including differing pathways affecting varied cell lines that effect pigment production. Based on this concept, actives were tested using gene expression studies as well as in vitro melanogenic model testing in different cell lines. Using this novel multi-faceted approach, we have selected and validated a series of active agents to be used in a formulation targeting the complex problem of hyperpigmentation.
J Drugs Dermatol. 2022;21(11):1206-1220. doi:10.36849/JDD.7013
INTRODUCTION
Skin, hair, and eye color are derived from melanin produced within melanosomes through the process of melanogenesis. The amount of melanin produced depends on genetic, local regulatory, and environmental factors, particularly exposure to ultraviolet (UV) light. Human skin pigmentation may be constitutive or facultative. Facultative pigmentation relates to extrinsic effects on pigmentation, such as UV radiation (UVR), drugs, and hormones, which may lead to abnormal skin hyperpigmentation.2 In contrast, constitutive pigmentation is predetermined intrinsically by gene status, which directs the size, density, and shape of melanosomes, and these can vary significantly among European, African, and Asian populations.2 One of the important roles of melanin is to protect the skin, tissues, and genes from UV-induced skin injury.
MATERIALS AND METHODS
UVA and UVB radiation can result in skin damage with darkening and pigmentation secondary to free oxygen radical formation. These radicals stimulate tyrosine synthesis, which increases the level of melanin. This melanin protects the skin from UVR.
