Melanogenesis is the process for the production of melanin, which is the primary cause of human skin pigmentation. Skin‑whitening agents are commercially available for those who wish to have a lighter skin complexions. To date, although numerous natural compounds have been proposed to alleviate hyperpigmentation, insufficient attention has been focused on potential natural skin‑whitening agents and their mechanism of action from the perspective of compound classification. In the present article, the synthetic process of melanogenesis and associated core signaling pathways are summarized. An overview of the list of natural skin‑lightening agents, along with their compound classifications, is also presented, where their efficacy based on their respective mechanisms of action on melanogenesis is discussed.
Lighter skin tone has long been associated with youth and beauty among a variety of Asian cultures. Investment in skin-whitening agents, boosted by markets in Asian countries, especially those in China, India and Japan, is increasing annually. Skin color is influenced by a number of intrinsic factors, including skin types and genetic background, and extrinsic factors, including the degree of sunlight exposure and environmental pollution. Skin color is determined by the quantity of melanosomes and their extent of dispersion in the skin. Under physiological conditions, pigmentation can protect the skin against harmful UV injury. However, excessive generation of melanin can result in extensive aesthetic problems, including melasma, pigmentation of ephelides and post-inflammatory hyperpigmentation. Traditional pharmacological agents, including corticosteroids, hydroquinone and aminomercuric chloride, lighten skin tone through the inhibition of either melanocyte maturation or interference with the process of melanogenesis. However, most if not all of the aforementioned agents are closely associated with adverse effects including prickling sensation, contact dermatitis, irritation, high toxicity and sensitivity. Therefore, recent research by cosmetic companies and research institutions has been focusing on the development of novel whitening agents that selectively suppress the activity of tyrosinase (TYR) to reduce hyperpigmentation whilst avoiding cytotoxicity to normal, healthy melanocytes. As a result, natural skin whitening compounds are currently garnering significant attention in the cosmetic and medical industry.
The present review summarizes the biosynthetic process of melanogenesis and the associated core regulatory signaling pathways. It also reviews natural skin-whitening agents in terms of their compound classification and discusses their efficacy based on their mechanism of action on melanogenesis. In addition, an overview of the current research methodology applied for the evaluation of compound bioactivity is provided. The aim of the present review is to provide informative guidance for the development of safe and effective depigmenting agents for use in the cosmetic industry.
Melanin is mainly produced by melanocytes that are localized in the epidermis, the outermost layer of the skin; it is also this layer that determines skin color in humans. Melanin is primarily synthesized in melanosomes, which function as specialized organelles in melanocytes. Melanogenesis is a complex process that involves a series of enzymatic and chemical reactions inside the melanosomes, resulting in the production of two types of melanin: Eumelanin and pheomelanin. Eumelanin is an insoluble polymer that is dark brown-black in color, whereas pheomelanin is a soluble polymer light red-yellow in color that also contain sulfur. Both eumelanin and pheomelanin are formed by the conjugation of cysteine or glutathione. To gain an understanding of the mechanism of whitening agents, a summary of the signaling pathways associated with skin melanogenesis is presented. The pigmentation process starts with the oxidation of L-tyrosine to L-dopaquinone (DQ) in the presence of the rate-limiting enzyme TYR. Following DQ formation, the resulting quinone undergoes intramolecular cyclization and oxidation, where it serves as a substrate for the synthesis of eumelanin and pheomelanin. During the process of melanogenesis, hydroxylation of L-tyrosine to form L-3,4-dihydroxyphenylalanine (L-DOPA) is the rate-limiting step of the whole process, which is catalyzed by TYR.
Melanogenesis is a complex process that is modulated by a network of pivotal signaling cascades and transcription factors, which is controlled at different levels. In particular, modulation of TYR activity is the most commonly applied strategy for the clinical intervention of pigmentation disorders. Since naturally occurring inhibitors of melanogenesis usually garner more attention compared with chemically synthesized compounds due to the cosmetic demands of consumers, the present review focuses on natural compounds that have been documented to exhibit skin-whitening effects through the inhibition of TYR activity. The three core signal pathways involved in the regulation of melanogenesis are: i) melanocortin-1 receptor (MC1R) signaling; ii) the Wnt/β-catenin signaling pathway; and iii) the tyrosine kinase receptor KIT/stem cell factor (SCF) pathway, all of which converge downstream to activate the master regulator-microphthalmia-associated transcription factor (MITF). The following sections will describe the genetic and molecular modulators that are involved in the control of melanogenesis by these three key pathways.
α-MSH is a precursor polypeptide derived from pro-opiomelanocortin that can modulate pigmentation through paracrine action, whilst MC1R is a member of the G-protein-coupled receptor family. α-MSH binding to MC1R results in the activation of adenylyl cyclase, increasing the intracellular levels of cAMP and subsequently upregulating TYR, tyrosinase related protein-1 (TRP-1) and tyrosinase related protein-2 (TRP-2) expression. The biological effects downstream of cAMP elevation have been previously demonstrated to be predominately mediated by cAMP-dependent protein kinase (PKA), which phosphorylates cAMP-response element (CRE) binding protein (CREB). However, it has also been suggested that neither TRP-1 nor TRP-2 have cAMP response elements in their respective promoter regions. Evidence has indicated that regulating the gene expression of TRP-1 and TRP-2 by cAMP is directly associated with MITF, which binds to the M-box sequence (AGTCATGTGCT) located in the tyrosinase distal elements (TDEs) after its activation. Since the promoter region of MITF contains the consensus CRE sequence, the expression of MITF can also be increased by α-MSH stimulation in a cAMP-dependent manner. This demonstrated that the α-MSH-MC1R signaling pathway induces melanin production predominantly by elevating intracellular cAMP levels, and the inhibition of which can exert inhibitory effects on melanogenesis.
The Wnt signaling pathway has been previously reported to serve an important role in melanogenesis. Wnt ligands bind to Frizzled receptors on the cell surface, resulting in the increased stability of cytoplasmic β-catenin, and its subsequent translocation into the nucleus, where it activates the transcription of MITF by interplay with lymphoid enhancer-binding factor 1 (LEF1)/T-cell factor (LEF1/TCF). Previous studies on melanocytes suggest that β-catenin and LEF1 synergistically regulate the M promoter activity of MITF via LEF1 binding sites, which upregulate MITF expression in melanoma. By regulating MITF transcription, the Wnt/β-catenin signaling pathway can control the expression of TYR and other pigmentation enzymes.
Recent studies have verified the important roles of the SCF-KIT signaling pathway in melanocyte proliferation and differentiation, and the process of melanogenesis. SCF is a paracrine factor that is secreted by fibroblasts, whereas c-KIT, its receptor, is expressed on melanocytes. When SCF binding to its receptor-c-KIT, it stimulates tyrosine kinase activity, resulting in receptor auto-phosphorylation to initiate signal transduction. c-KIT phosphorylation directly activates p38 mitogen-activated protein kinase (MAPK), a member of the MAP kinase family, which in turn phosphorylates CREB and subsequently activates MITF to promote TYR transcription. c-KIT can also activate ERK. c-KIT-mediated ERK signaling pathway can induces CREB phosphorylation to activate melanin synthesis on one hand, and on the other hand, the activation of ERK signaling has been demonstrated to phosphorylate MITF at the serine 73 residue, which leads to the ubiquitination and degradation of MITF, this is the feedback mechanism of the ERK pathway to regulate melanin production. In addition to p38 MAPK and ERK, c-KIT activation is associated with the phosphoinositide 3-kinase (PI3K) signaling pathway, which not only regulates cell survival but also causes pigmentation by activating the serine/threonine-specific protein kinase AKT. Downstream, PI3K activation leads to the phosphorylation of glycogen synthase kinase 3β (GSK-3β) to increase MITF activity. Therefore, inhibitors of the SCF-KIT signaling pathway can potentially exhibit anti-melanogenesis act
