• Users Online: 224
  • Print this page
  • Email this page
  • Email this page
  • Email this page
  • Email this page

Table of Contents
Year : 2021  |  Volume : 39  |  Issue : 1  |  Page : 1-12

Perspective approaches on melanogenesis inhibition

1 School of Biosciences, Faculty of Medical and Health Sciences, Taylor's University, Subang Jaya, Selangor Darul Ehsan, Malaysia
2 Department of Biological Sciences, School of Science and Technology, Sunway University, Petaling Jaya, Selangor, Malaysia

Date of Submission19-May-2020
Date of Decision23-Jul-2020
Date of Acceptance26-Jul-2020
Date of Web Publication24-Mar-2021

Correspondence Address:
Dr. Adeline Yoke Yin Chia
School of Biosciences, Faculty of Health and Sciences, Taylor's University, 1 Jalan Taylor's, Subang Jaya 47500, Selangor
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ds.ds_46_20

Rights and Permissions

Melanogenesis is a melanin-forming process responsible for protecting the skin against ultraviolet radiation damage. An excess production of melanin, however, may result in hyperpigmentation (darkening of the skin) to adverse dermatological effects (freckles, solar lentigines, and melasma) and skin cancer. These hyperpigmentary skin disorders may also have a major effect on a person's appearance and could even result in emotional and mental distress, as well as a diminished quality of life. A large number of melanogenesis inhibitors have been discovered, but most of them appeared to have undesirable side effects. Therefore, in order to better understand the mechanisms of hyperpigmentary skin disorders and to establish effective and safe melanogenesis inhibitors, more fundamental research is needed. Apart from tyrosinase blockers, there are also alternative approaches that involve the manipulation of melanogenesis regulatory pathway such as α-melanocyte-stimulating hormone blockers, melanosome transferase inhibitors, and cytokines. This review abridges data on the different melanogenesis inhibitors and depigmentation agents from both natural and synthetic agents from the last few years.

Keywords: Inhibiting agents, melanogenesis, skin lightening, tyrosinase inhibitor

How to cite this article:
Manap AS, Lum YK, Ong LH, Tang YQ, Gew LT, Chia AY. Perspective approaches on melanogenesis inhibition. Dermatol Sin 2021;39:1-12

How to cite this URL:
Manap AS, Lum YK, Ong LH, Tang YQ, Gew LT, Chia AY. Perspective approaches on melanogenesis inhibition. Dermatol Sin [serial online] 2021 [cited 2022 Dec 2];39:1-12. Available from: https://www.dermsinica.org/text.asp?2021/39/1/1/311819

  Introduction Top

Melanogenesis is defined as a series of process leading to the formation of melanin (dark-brown pigment) by melanocytes,[1] which is found in the basal layer of the interfollicular epidermis.[2] While melanin serves as an antioxidant to protect the skin against harmful ultraviolet (UV) radiation-induced generation of reactive oxygen species (ROS), abnormally high melanin formation and accumulation can lead to hyperpigmentation disorders in the skin.[3] Although hyperpigmentation of the skin is usually harmless, excessive pigmentation, particularly on the face, such as melasma, solar lentigines, and freckles, poses a significant cosmetic nuisance and can cause distress to the person affected.[4],[5] One of the most common hyperpigmentation diseases is melasma,[6] which is an acquired macular brown pigmentation [Figure 1].
Figure 1: Increased epidermal pigmentation is the hallmark of melasma. Fontana-Masson staining shows more pronounced epidermal hyperpigmentation in lesion (L) compared to perilesional normal skin (N). Kang and Ortonne (2010)[7].

Click here to view

Melanogenesis begins with tyrosinase to catalyze in tyrosine oxidation to produce dopaquinone. It is also the rate-limiting step in melanin synthesis as the downstream processes can occur spontaneously at a physiological pH value.[8] Next, when dopaquinone is converted to dopa and dopachrome, auto-oxidation takes place (Dopa may again be oxidized by tyrosinase to dopaquinone). Subsequently, a series of oxidation reaction occurs from eumelanogenesis where dihydroxyindole (DHI) and DHI-2-carboxylic acid are transformed into eumelanin. In the presence of cysteine or glutathione, dopaquinone is converted to cysteinyldopa or glutathionyldopa before the formation of pheomelanin. In addition to eumelanin and pheomelanin, another “melanin” relying on phenolic monomers different from tyrosine is termed allomelanin.[9],[10] [Figure 2] shows the biosynthetic pathway of melanin.
Figure 2: Biosynthetic pathway of melanin. Melanin is present in two main forms: (1) the highly ultraviolet-protective brown/black “eumelanin” pigment, and (2) the ultraviolet-permeable red/blonde “pheomelanin.” Eumelanin and pheomelanin are both synthesized from tyrosine, an amino acid. Tyrosinase, the enzyme that catalyzes the synthetic rate-limiting reaction for both types of melanin, is the deficient enzyme in the most common type of albinism. The incorporation of a cysteine into pheomelanin leads to the retention of a moiety of sulfur into the pigment, which can contribute to oxidative injury caused by ultraviolet. D'Orazio et al.[11] (DOPA: 3,4-dihydroxyphenylalanine, DHI: 5,6-dihydroxyindole, DHICA: 5,6-dihydroxyindole-2-carboxylic acid).

Click here to view

Hyperpigmentation disorders are currently treated with a broad range of topical hypopigmenting or skin-lightening agents, chemical peels, laser therapy, cryotherapy, and superficial dermabrasion.[5] The preferred mode of treatment for managing these conditions is combination therapy, which allows synergism and reduces the likelihood of inappropriate implications. For example, one of the gold-standard melasma treatments is known to be the most common triple combination, comprising hydroquinone (HQ), tretinoin, and fluocinolone acetonide. This triple combination was also found to significantly reduce melanin levels and the amount of lentigines (marked by the appearance of a small brown patch, a benign lesion often occurring in areas exposed to sunlight).[5] Nonetheless, these treatment modalities do not completely eradicate skin lesions and cause adverse effects. Thus, alternative, more specific, safe, and more effective therapeutic options are increasingly needed. The quest for an effective melanogenesis inhibitor has led to the discovery of hundreds of natural substances with potential anti-melanogenic activity.[12] A better understanding of regulatory pathways to melanogenesis may help to identify certain specific targets for existing or new therapies that could be used to regulate these pathways and control hyperpigmentation disorders.

  Skin Lightening Top

Skin lightening refers to the application of natural or synthetic substances to lighten the skin tone or to provide better complexion by reducing the level of melanin in the skin.[13] The application of the whitening agents can be prompted by dermatological needs in patients with dermatological disorders associated with excessive accumulation of melanin (e.g., melasma and senile lentigo)[14] or merely by culture-specific beauty preferences. Several chemical substances have already been demonstrated to be effective skin whiteners, and some even show beneficial effects (antioxidants,[15],[16] antiproliferative activity,[17],[18] protection of macromolecules such as collagen against harmful radiation,[19] etc.). However, certain safety issues have recently increased, resulting in the prohibition of these chemical substances in some countries.[20],[21] The intense use of whitening agents, therefore, poses a real public health risk and can result in serious pathologies including burns, acne, stretch marks, hypopigmentation, and even cancer.[22],[23] It is important to note that these whitening treatments are often very long term and that their application over weeks or months produces results that are not necessarily definite.[22] The demand for fairness has led in recent years to the discovery of a variety of whiteners with little to no side effects deriving from diverse biological resources. Yet, there is still a long way to go from identifying an active ingredient to incorporating it into cosmetics. [Table 1] lists some examples of skin commercial lighting products and their active biological ingredients.[24]
Table 1: A list of some commercial skin-lightening products

Click here to view

  Skin Lightening by Tyrosinase-Inhibiting Approaches Top

Since tyrosinase is the preliminary enzyme for melanogenesis, the strategy of tyrosinase inhibition to prevent dark spot formation is the most extensively studied approach. A reducing agent such as ascorbic acid can lead to a chemical reduction in dopaquinone due to its ability to reduce o-dopaquinone back to dopa and would then prevent dopachrome and melanin from forming. Many thiol-containing compounds such as o-dopaquinone scavenge are a melanogenesis inhibitor that reacts with dopamine to form colorless products. Thus, the melanogenesis is slowed down until the scavengers are completely consumed. In addition, acids or bases known as nonspecific enzyme inactivators may inhibit melanogenesis activity by denaturing the enzyme which is responsible for melanogenesis. Besides that, suicide inactivators or mechanism-based inhibitors may form a covalent bond with the enzyme that has been catalyzed by tyrosinase. This can contribute to tyrosinase inhibition, and this is known as the “suicide reaction.”[25]

  Quinone-Related Compounds Top

There are three common quinone-related compounds widely used in skincare products: HQ (1,4-dihydroxybenzene), arbutin, and deoxyarbutin (dA).[26] HQ works by binding histidine at the active sites of tyrosinase, therefore, inhibiting the action of tyrosinase.[27] A previous study showed that HQ caused decreased melanosome development, marked changes in the internal structure of melanosomes, increased melanosome degradation, and eventually, destruction of the melanocytes' membranous organelles.[28] Nevertheless, although HQ remains the gold standard for depigmentation agents, the compound has been prohibited by the European Committee (24th Dir 2000/6/EC) since 2000 for general cosmetic purposes and formulation with this compound is only authorized by a doctor or dermatologist prescription.[26] This is because HQ application was shown to induce the generation of ROS and cause the oxidative damage to the membrane lipid, protein, and enzyme such as tyrosinase.[29] HQ was considered as toxic compounds[30] and may cause permanent loss of melanocytes, potentially mutagenic to mammalian cells,[31] and causes skin irritation.[32] Arbutin is a naturally occurring derivative of HQ used extensively for the prevention of dark spots.[33] It is originally developed by Shiseido Company and has been reported to exhibit less melanocyte cytotoxicity compared to HQ. It competitively and reversibly binds to tyrosinase without influencing the mRNA transcription of tyrosinase. A similar effect has been achieved by the synthetically produced arbutin derivative, the dA, which was reported to be effective and safer as a skin-lightening agent.[26]

  Lightening Compounds Originate from Microorganisms Top

Kojic acid produced from several species of fungi (Aspergillus sp. and Penicillium sp.) is one of the naturally occurring compounds used for anti-dark spot formation. It chelates copper atoms in the tyrosinase active sites.[10] However, it only shows moderate effectiveness in the clinical trials and possible to cause contact dermatitis, sensitization, and erythema.[34] Another popular compound is azelaic acid which is a saturated dicarboxylic acid found naturally in wheat, rye, and barley. Besides being used as treatments for acne, rosacea, and skin pigmentation, azelaic acid can also prevent the formation of dark spots by binding to the amino group and carboxyl group, thus preventing tyrosine from interacting in the active tyrosinase site.[35]

  Flavonoids Top

Flavonoids are a large group of polyphenolic compounds, which can be derived from herbs and vegetables. Flavonoids are categorized into five major groups with the shared core backbone structure of flavan: flavones, flavonols (3-hydroxyflavone), flavanols, isoflavones, and anthocyanidines[36] [Figure 3]. The effects of flavonoids in melanogenesis have been studied extensively, and to date, there are more than 8000 flavonoids identified.[37] The main function of this pigment-reducing compound is that it acts as a ROS scavenger to interact with free radicals generated at the active site of tyrosinase. In addition, they also work as metal chelators to the copper, thus forming the copper-flavonoid complex and rendering them inactive to participate in free radical generating reactions.[38],[39] According to previous studies, flavonoid compounds may have a stimulating and inhibitory effect on melanogenesis.[40],[41] In a recent study conduced by Promden et al., of the 27 types of flavonoids tested for inhibitory activity and melanin synthesis in melanocytes, only cajanin and (6aR, 11aR) 3,8 dihydroxy 9 methoxy pterocarpan were shown to inhibit murine tyrosinase activity.
Figure 3: (a) Six main types of flavonoid which have been tested in melanoma models and their major dietary sources. (b) Structure comparison of luteolin, apigenin, and quercetin. The different side groups are circled in luteolin structure. The boxed side groups in apigenin show a typical structure that is able to bind metal ions. Comparing these three popular compounds which sometimes show opposite effects on melanogenesis may provide some hints on how each side group functions biologically.

Click here to view

Various studies revealed that flavonoids that stimulate melanogenic effects are cyanidin, hesperetin, apigenin, and fisetin. In addition, flavonoids that exhibit anti-melanogenic effects include epigallocatechin gallate (EGCG), hesperidin, luteolin, baicalein, and kaempferol. Cyanidin exhibits melanogenic effects by induces B16 differentiation by upregulating cAMP, expression of tyrosinase, and differentiation marker MART-1. Hesperetin will enhance the accumulation of melanocyte-inducing transcription factor (MITF) and lead to melanogenesis. Apigenin induces melanogenic effect by targeting tyrosinase-related protein-2/dopachrome tautomerase (TYRP-2/DCT) and TYRP-1 by p38 mitogen-activating protein kinase (PK). Fisetin plays a role in anti-melanogenesis by inhibiting melanoma cell invasion via inhibition of epithelial-to-mesenchymal transition in a three-dimensional skin model and in a xenografted mouse model. On the other hand, MITF protein accumulation can be inhibited by hesperidin and catechins, including EGCG, as well as inhibit tyrosinase accumulation. Baicalein, which is an anti-melanogenesis agent, plays a role in inhibiting accumulation of MITF via ERK1/2-phosphorylation-mediated degradation. Luteolin and kaempferol will inhibit melanogenesis by targeting tyrosinase directly or indirectly.[40]

Another well-known flavonoid till date is licorice roots (Glycyrrhiza glabra), which have been found to play a role in skin whitening treatment.[42] A previous study has shown that glabridin, a chemical compound that is found in the root extract of licorice, acts as a tyrosinase inhibitor which inhibits melanogenesis.[43] Moreover, 70% of skin-whitening cosmetic products containing glabridin molecules.[44] A previous study which investigated the inhibitory effect of melanogenesis and inflammation by glabridin using B16 murine melanoma cells and guinea pig skins had shown that glabridin successfully inhibited the enzyme tyrosinase activity at the concentration of 0.1–1.0 μg/ml.[45] In addition, the study also showed that it successfully prevented UVB-induced pigmentation and erythema when 0.5% glabridin was added topically to the skin of the guinea pig. However, glabridin has a limited skin-whitening efficacy as well as the instability in formulation.[45]

In order to encounter the limitation of glabridin application, the effort of discovering new compound for anti-melanogenesis continues. Another compound, glabrene was then isolated by Nerya et al. which has two hydroxyl groups at the 2' and 7' position with a 2,2-dimethyl-ç-pyran ring connected to the B ring as well as a double bond between carbon atoms 3 and 4 in the C ring. This configuration provides the maximum conjugation of the double bonds on the glabrene molecule. This study showed that both glabrene and another compound, isoliquiritigenin, can inhibit mushroom tyrosinase by inhibiting this enzyme's mono- and diphenolase activities. Moreover, both of these compounds are proven to be able to inhibit the biosynthesis of melanin in melanocytes. Apart from that, another report postulated that glabrene and isoliquiritigenin are the inhibitors of tyrosinase instead of its inactivators. This is because they demonstrated that preincubation of tyrosinase with both of the compounds in the absence of substrate did not show a reduction in tyrosinase enzyme activity significantly.[46] In 2005, glycyrrhisoflavone and glyasperin C were reported as two new potential tyrosinase inhibitors from the root extract of licorice with glyasperin C exhibits a higher tyrosinase inhibitory activity than the well-known glabridin.[47]

Another work carried out where the total content of the licorice plant was isolated was found to contain more flavonoids than its root component in the licorice leaves. The most abundant flavonoid in the liquorice leaves is pinocembrin, with strong antioxidant activity and nitrile scavenging potential and mild ability to inhibit mushroom tyrosinase. Besides, the main flavonoid compound found in licorice root is the liquiritin which exhibits a strong inhibitory effect on mushroom tyrosinase.[48] This finding, however, contradicts another study reported in which four separate flavonoid compounds, namely liquiritin, licuraside, isoliquiritin, and licochalcone A, are isolated from the root of licorice. The result showed that liquiritin displayed no enzyme-inhibiting activity in mushroom tyrosinase relative to licuraside, isoliquiritin, and licochalcone A with IC50 values of 0.072, 0.038, and 0.0258 mM respectively for monophenolase activity.[49]

  Skin Lightening by Nontyrosinase-Inhibiting Approaches Top

While most studies focus on compounds' ability to inhibit tyrosinase, other mechanisms are also available to inhibit melanogenesis, as tyrosinase development or melanogenesis initiation is also regulated by many other components including hormones and cytokines. Therefore, it is important to identify the melanogenesis regulatory pathway. [Figure 4] shows the selected pathways for melanogenesis regulation.
Figure 4: Selected signaling pathways regulating melanogenesis. Park et al.[50] ER: endoplasmic reticulum; P: Phosphate group; RACK-I: Receptors for activated C-kinase.

Click here to view

The binding of alpha-melanocyte-stimulating hormone (α-MSH) to melanocortin 1 receptor (MC1R) will lead to activation of adenylate cyclase which in turn increases cAMP levels and activates PKA. This will then induce gene transcription of MITF and cause the production of melanogenic enzyme tyrosinase. Besides, the releases of diacylglycerol (DAG) from the cell membrane due to UV radiation will activate PKC-β, which then activates tyrosinase enzyme through phosphorylation at the serine residue on enzyme. In addition, DAG also phosphorylates the diacylglycerol kinase-ζ, which regulates tyrosinase degradation. The UV radiation also damages cellular DNA, initiating a cascade of DNA damage responses including p53 activation, and leading to increased tyrosinase transcription. UV irradiation, by decreasing the level of bone morphogenetic protein (BMP) receptors, prevents BMP-4-mediated inhibition on melanogenesis.[51]

  Alpha-Melanocyte-Stimulating Hormone Blockers Top

α-MSH is an endogenous tridecapeptide neurohormone originating from proopiomelanocortin (POMC) that modulates inflammatory cutaneous and immune responses in normal human keratinocytes, Langerhans, melanocytes, and dermal fibroblasts. It is the most important hormone which stimulates melanocytes in melanogenesis. α-MSH binds to the MC1R, a particular G-coupled protein receptor that induces adenylyl cyclase activation, accompanied by the increase of intracellular cAMP.[52] A previous study showed that Piperlongumine from Piper longum L. successfully inhibited melanogenesis although it does not have the ability to inhibit tyrosinase. Its anti-melanogenesis is achieved by inhibiting the α-MSH-induced melanogenesis where α-MSH acts via cAMP to cAMP response element-binding (CREB), which in turn regulates the expression of MITF and tyrosinase.[34] Another report showed that sophoraflavanone G is also able to inhibit α-MSH-induced melanogenesis despite its capability in tyrosinase inhibition.[34]

  Melanosome Transferase Inhibitor Top

Soybean extract was found to contain small serine proteases such as Bowman–Birk inhibitor and soybean trypsin inhibitor which could inhibit the protease-activated receptor-2 pathway expressed on keratinocytes. Subsequently, it induced the depigmentation of skin as the phagocytosis of melanosomes by keratinocyte has been reduced.[53] Apart from that, a flowering plant, yarrow, was found to contain a flavonoid glucoside, centaureidin, which reduced in melanosome transfer and melanocyte dendrites outgrowth.[54] Melanogenesis can also be blocked by preventing the transfer of melanosomes from melanocytes to keratinocytes by niacinamide (from Vitamin B3), despite simultaneously being a tyrosinase inhibitor. Ginsenoside F1 could also disrupt the synthesis of melanin in melanocytes by inhibiting melanin transfer via dendrite retraction of melanocytes in the basal layer.[55]

  Cytokines Inhibitors Top

Another approach reported to perform anti-melanogenesis effect is by inhibiting the cytokines. A previous study demonstrated that UV-induced skin pigmentation in brown guinea pigs and human melanoma cell cultures is reduced, likely through downregulation of the keratinocyte-associated MITF mediated by interleukin (IL)-6.[56] Pax 3 gene, a transcription factor that regulated MITF, thus induces melanogenic activity. IL-6-mediated signaling can suppress the production of Pax 3 gene. Suppression of Pax 3 gene can lead to loss of MITF and tyrosinase expression and thus decrease in melanogenesis.[56] On the other hand, IL-4 can affect melanogenesis in epidermal melanocytes and various functions of epidermal keratinocytes, dermal fibroblasts, dendritic cells, and other pro-inflammatory infiltrating lymphocytes. IL-4 induces JAK2-STAT6 signaling, which inhibits melanogenic activity by decreasing protein expression of MITF, TRP-1, and DCT1. These genes are melanogenesis-associated genes that play an important role in skin pigmentation.[57]

  Evaluation of in vivo and in vitro Depigmenting Activity Top

Research on the inhibition of melanogenesis by natural compounds as a potent inhibitor of tyrosinase has been widely studied by using an in vivo and in vitro. A recent study by Hseu et al. found that Coenzyme CoQ10 (CoQ10), a ubiquinone compound, is capable to inhibit tyrosinase activity and melanin production through suppression on p53/POMC, α-MSH production as well as ROS generation in UVA-irradiated keratinocyte HaCaT cells. In addition, CoQ10 downregulated the melanin synthesis in α-MSH-stimulated murine B16-F10 cells by suppressing the MITF expression by downregulating the cAMP-mediated CREB protein signaling cascades. With these results, CoQ10 is believed to be a promising depigmentation or skin-whitening agent and could be used in cosmetics for topical application.[58]

Novel amide derivatives (3a-e and 5a-e) as new potent tyrosinase inhibitors were identified. From in vitro study, 15 μg/ml of 5c is able to attenuate 36% tyrosinase and 24% reduction in melanin content of B16F10 cells without significant cytotoxicity. Furthermore, 5c effectively reduces melanogenesis without perceptible toxicity in zebrafish. These observations are believed due to interaction of 5c with copper ions and multiple amino acids in the active site of tyrosinase with the strongest glide score (−5.387 kcal/mol) via computational docking study. Based on their valuable results, 5c has been proposed as a new potent candidate to inhibit tyrosinase in hyperpigmentation.[59]

The anti-melanogenic properties of the rhizoma of Ligustrum sinense, a Chinese medicinal plant, have gained an intense interest recently. Twenty-four compounds from the ethyl acetate surface of L. sinense methanolic extracts were isolated and identified.[60] All the pure isolates from L. sinense were subjected to anti-melanogenesis assay using murine melanoma B16-F10 cells. Their results demonstrated that the compound isolates, 5-[3-(4-hydroxy-3-methoxyphenyl) allyl] ferulic acid and (3S,3aR)-neocnidilide, displayed anti-melanogenesis activities with IC50 values of 78.9 and 31.1 μM, respectively, without cytotoxicity. They investigated further using zebrafish embryo and found (3S,3aR)-neocnidilide at 10–20 μM and also demonstrated significant anti-pigmentation activity on zebrafish embryos compared to arbutin (20 μM). They suggested that (3S,3aR)-neocnidilide (8) is a potent anti-melanogenic and noncytotoxic natural compound and may be developed potentially as a skin-whitening agent for cosmetic uses.[60]

A bioactive compound, T1, bis (4-hydroxybenzyl) sulfide, isolated from the Chinese herbal plant, Gastrodia elata, has been demonstrated as a strong competitive inhibitor against mushroom tyrosinase. When the melanocyte cell lines were treated with 50 μM of T1, bis sulfide, a 20% reduction in melanin content without significant cell toxicity was noticed. Moreover, through the zebrafish model, T1, bis sulfide also inhibits melanogenesis effectively without any toxicity observed. Interestingly, computational molecular modeling indicated that coordination of the sulfur atom of T1, bis sulfide with the copper ions in the active site of tyrosinase is crucial for mushroom tyrosinase inhibition and the ability of lessening the synthesis of melanin in human.[61]

A study by Lin et al. using Raspberry Ketone (RK) as a melanogenesis inhibitor found that RK inhibited melanin formation through reduction of tyrosinase activity in zebrafish. They showed that in B16 melanoma cells, all RK treatments significantly decreased the melanin content of the treated cells compared with that of the isobutylmethylxanthine-stimulated cells. RK also inhibited melanogenesis by reduction of tyrosinase activity in zebrafish. While in mice, application of 0.2% or 2% gel preparation of RK to mice skin significantly raised the degree of skin whitening within 7 days of treatment. They suggested that RK would appear to have high potential for utilization in the cosmetic industry.[62]

The study conducted by Boissy et al. using in vivo pigmented guinea pig model demonstrated that the newly developed tyrosinase inhibitor, dA, was able to demonstrate a rapid and sustained skin lightening that was completely reversible within 2 months of cessation for topical application. In contrast, HQ has developed a short but impersistence skin-lightening effect, whereas kojic acid and arbutin have no skin-lightening effect. They also performed a human clinical trial, where the panel of safety test results supported the overall establishment of dA as a tyrosinase inhibitor. It showed that there was a significant reduction in overall skin lightness as well as improvement of solar lentigines in population of light skin or dark skin individuals, respectively, after topical treatment of dA for 3 months.[63]

  Potential Therapeutic Effects: clinical-based Evidence Study Top

As aforementioned in the previous section, skin-whitening agents from natural ingredients derived from natural compounds exhibit capability as potent tyrosinase and nontyrosinase inhibitors by modulating various pathways in melanogenesis. These botanical or natural compounds provide an alternative to the current gold standard, HQ. Nevertheless, how safe and effective of the natural compounds in the management of hyperpigmentation? Here, we provide information on evidence-based clinical studies involving wide range of synthetic[64] as well as natural compounds such as azelaic acid, aloesin, mulberry, licorice extracts, lignin peroxidase, kojic acid, niacinamide, ellagic acid, arbutin, green tea, turmeric, soy, and ascorbic acid, extracted from systematic research on 30 chosen clinical trials.[65] Unlike some of the synthetic chemicals such as HQ, and tretinoin that has been suspended and terminated in clinical trials, natural ingredients from natural sources have demonstrated potential therapeutic effects and may provide clinicians and researchers a better insight on clinical practice in the future. The summary of clinical trials done previously is shown in [Table 2].
Table 2: Summary of clinical trials for synthetic and natural compounds

Click here to view

  Conclusions Top

Despite more serious clinical disorders like melasma, excessive melanogenesis will cause problems such as darker, uneven skin tone, hyperpigmentation, and other facial implications. Among the studies, it was shown that tyrosinase is the key and preliminary enzyme of melanogenesis, and therefore, most of the skin lightening approaches target the tyrosinase inhibition mechanism to downregulate melanogenesis. Both synthetic and natural compounds are found to be applied in the skin lightening products such as HQ, kojic acid, and flavonoid compounds. It is noted that synthetic compounds such as HQ are effective tyrosinase inhibitors, but they can cause serious adverse effects such as permanent melanosome loss. Kojic acid was shown to only portrait moderate effectiveness while bringing the threat of dermatitis and other complications. Up to now, the use of flavonoid-derived compounds such as glabridin has been shown to be very effective as a skin-lightening agent and relatively safer for human skin application. Nevertheless, more studies needed to be carried out to overcome the drawback of the flavonoid compounds such as its low stability when formulated in topical application cream.

Financial support and sponsorship

This study was supported by Taylor's Research Grant Scheme (TRGS/MFS/1/2017/SBS/006) for funding and facilities provided by Taylor's University.

Conflicts of interest

There are no conflicts of interest.

  References Top

Rescigno A, Sollai F, Pisu B, Rinaldi A, Sanjust E. Tyrosinase inhibition: General and applied aspects. J Enzyme Inhib Med Chem 2002;17:207-18.  Back to cited text no. 1
Tsatmali M, Ancans J, Thody AJ. Melanocyte function and its control by melanocortin peptides. J Histochem Cytochem 2002;50:125-33.  Back to cited text no. 2
Denat L, Kadekaro AL, Marrot L, Leachman SA, Abdel-Malek ZA. Melanocytes as instigators and victims of oxidative stress. J Invest Dermatol 2014;134:1512-8.  Back to cited text no. 3
Borovansky J, Riley PA. Melanins and Melanosomes: Biosynthesis, Structure, Physiological and Pathological Functions. U.S. John Wiley & Sons; 2011.  Back to cited text no. 4
Kumari S, Tien Guan Thng S, Kumar Verma N, Gautam HK. Melanogenesis inhibitors. Acta Derm Venereol 2018;98:924-31.  Back to cited text no. 5
Tzouveka E. Epidemiology and risk factors of melasma. Pigmentary Disorders S. 2014;1:2376-0427.  Back to cited text no. 6
Kang HY, Ortonne JP. What should be considered in treatment of melasma. Ann Dermatol 2010;22:373-8.  Back to cited text no. 7
Halaban R, Patton RS, Cheng E, Svedine S, Trombetta ES, Wahl ML, et al. Abnormal acidification of melanoma cells induces tyrosinase retention in the early secretory pathway. J Biol Chem 2002;277:14821-8.  Back to cited text no. 8
Schallreuter KU, Kothari S, Chavan B, Spencer JD. Regulation of melanogenesis-controversies and new concepts. Exp Dermatol 2008;17:395-404.  Back to cited text no. 9
Chang TS. An updated review of tyrosinase inhibitors. Int J Mol Sci 2009;10:2440-75.  Back to cited text no. 10
D'Orazio JA, Marsch A, Veith JL. Skin pigmentation and melanoma risk. Advances in malignant melanoma-clinical research perspective 2011. p. 39-68.  Back to cited text no. 11
Pillaiyar T, Manickam M, Jung SH. Downregulation of melanogenesis: Drug discovery and therapeutic options. Drug Discov Today 2017;22:282-98.  Back to cited text no. 12
Bum-Ho, B.I.N., Eun-Gyung, C.H.O., Choi, E.J., Kim, S., Suhyeon, C.H.O.I. and Taeryong, L.E.E., Amorepacific Corp, 2019. Skin whitening composition, and method for screening for materials having skin whitening effect. U.S. Patent 10,350,152.  Back to cited text no. 13
Grimes P, Nordlund JJ, Pandya AG, Taylor S, Rendon M, Ortonne JP. Increasing our understanding of pigmentary disorders. J Am Acad Dermatol 2006;54:S255-61.  Back to cited text no. 14
Chou TH, Ding HY, Hung WJ, Liang CH. Antioxidative characteristics and inhibition of α-melanocyte-stimulating hormone-stimulated melanogenesis of vanillin and vanillic acid from Origanum vulgare. Exp Dermatol 2010;19:742-50.  Back to cited text no. 15
Lee HJ, Lee WJ, Chang SE, Lee GY. Hesperidin, A popular antioxidant inhibits melanogenesis via Erk1/2 mediated MITF degradation. Int J Mol Sci 2015;16:18384-95.  Back to cited text no. 16
Iwai K, Kishimoto N, Kakino Y, Mochida K, Fujita T. In vitro antioxidative effects and tyrosinase inhibitory activities of seven hydroxycinnamoyl derivatives in green coffee beans. J Agric Food Chem 2004;52:4893-8.  Back to cited text no. 17
Jiang F, Li W, Huang Y, Chen Y, Jin B, Chen N, et al. Antioxidant, antityrosinase and antitumor activity comparison: The potential utilization of fibrous root part of Bletilla striata (Thunb.) Reichb F PloS One 2013;8:e58004.  Back to cited text no. 18
Zhu W, Gao J. The use of botanical extracts as topical skin-lightening agents for the improvement of skin pigmentation disorders. J Investig Dermatol Symp Proc 2008;13:20-4.  Back to cited text no. 19
Hu ZM, Zhou Q, Lei TC, Ding SF, Xu SZ. Effects of hydroquinone and its glucoside derivatives on melanogenesis and antioxidation: Biosafety as skin whitening agents. J Dermatol Sci 2009;55:179-84.  Back to cited text no. 20
Desmedt B, Courselle P, de Beer JO, Rogiers V, Grosber M, Deconinck E, et al. Overview of skin whitening agents with an insight into the illegal cosmetic market in Europe. J Eur Acad Dermatol Venereol 2016;30:943-50.  Back to cited text no. 21
FERNANDEZ, Xavier, Thomas MICHEL, and Stéphane AZOULAY. Cosmetic active ingredients with whitening effect-Nature, efficacy and risks. Techniques de l'Ingenieur. 2015. J2300 v1.  Back to cited text no. 22
Burger P, Landreau A, Azoulay S, Michel T and Fernandez X. Skin whitening cosmetics: Feedback and challenges in the development of natural skin lighteners. Cosmetics. 2016 Dec;3:36.  Back to cited text no. 23
Couteau C, Coiffard L. Overview of skin whitening agents: Drugs and cosmetic products. Cosmetics. 2016;3:27.  Back to cited text no. 24
Zolghadri S, Bahrami A, Hassan Khan MT, Munoz-Munoz J, Garcia-Molina F, Garcia-Canovas F, et al. A comprehensive review on tyrosinase inhibitors. J Enzyme Inhib Med Chem 2019;34:279-309.  Back to cited text no. 25
Gillbro J, Olsson M. The melanogenesis and mechanisms of skin-lightening agents–existing and new approaches. Int J Cosmetic Sci 2011;33:210-21.  Back to cited text no. 26
Masum MN, Yamauchi K, Mitsunaga T. Tyrosinase inhibitors from natural and synthetic sources as skin-lightening agents. Rev Agricult Sci 2019;7:41-58.  Back to cited text no. 27
Jimbow K, Obata H, Pathak MA, Fitzpatrick TB. Mechanism of depigmentation by hydroquinone. J Invest Dermatol 1974;62:436-49.  Back to cited text no. 28
Schwartz C, Jan A. Hydroquinone. StatPearl. U.S. StatPearls Publishing; 2019.  Back to cited text no. 29
Ahmad Nasrollahi S, Sabet Nematzadeh M, Samadi A, Ayatollahi A, Yadangi S, Abels C, et al. Evaluation of the safety and efficacy of a triple combination cream (hydroquinone, tretinoin, and fluocinolone) for treatment of melasma in Middle Eastern skin. Clin Cosmet Investig Dermatol 2019;12:437-44.  Back to cited text no. 30
Curto EV, Kwong C, Hermersdörfer H, Glatt H, Santis C, Virador V, et al. Inhibitors of mammalian melanocyte tyrosinase: In vitro comparisons of alkyl esters of gentisic acid with other putative inhibitors. Biochem Pharmacol 1999;57:663-72.  Back to cited text no. 31
Parvez S, Kang M, Chung HS, Cho C, Hong MC, Shin MK, et al. Survey and mechanism of skin depigmenting and lightening agents. Phytother Res 2006;20:921-34.  Back to cited text no. 32
Zhou H, Zhao J, Li A, Reetz MT. Chemical and biocatalytic routes to arbutin. Molecules 2019;24:3303.  Back to cited text no. 33
Lin JW, Chiang HM, Lin YC, Wen KC. Natural products with skin-whitening effects. J Food Drug Analysis 2008;16.  Back to cited text no. 34
Gunia-Krzyżak A, Popiol J, Marona H. Melanogenesis inhibitors: Strategies for searching for and evaluation of active compounds. Curr Med Chem 2016;23:3548-74.  Back to cited text no. 35
Rasouli H, Hosseini Ghazvini SM, Khodarahmi R. Therapeutic Potentials of the Most Studied Flavonoids: Highlighting Antibacterial and Antidiabetic Functionalities. Studies in Natural Products Chemistry. U.K Elsevier; 2019. p. 85 122.  Back to cited text no. 36
Bulea, M., Khanb, F., & Niazd, K. (2015). Flavonoids (flavones, flavonols, flavanones, flavanonols, flavanols or flavan-3-ols, isoflavones, anthocyanins, chalcones/coumestans). Recent Advances in Natural Products Analysis. (pp. 42-56).  Back to cited text no. 37
van Acker SA, van den Berg DJ, Tromp MN, Griffioen DH, van Bennekom WP, van der Vijgh WJ, et al. Structural aspects of antioxidant activity of flavonoids. Free Radic Biol Med 1996;20:331-42.  Back to cited text no. 38
Jacob V, Hagai T, Soliman K. Structure-activity relationships of flavonoids. Curr Organ Chem 2011;15:2641-57.  Back to cited text no. 39
Liu-Smith F, Meyskens FL. Molecular mechanisms of flavonoids in melanin synthesis and the potential for the prevention and treatment of melanoma. Mol Nutr Food Res 2016;60:1264-74.  Back to cited text no. 40
Promden W, Viriyabancha W, Monthakantirat O, Umehara K, Noguchi H, De-Eknamkul W. Correlation between the potency of flavonoids on mushroom tyrosinase inhibitory activity and melanin synthesis in melanocytes. Molecules 2018;23:1403.  Back to cited text no. 41
Van Den Nest, W., BIELSA, K.R., Laporta, O., Sanz, N.G. and DOMÈNECH, N.A., Compounds useful for the treatment and/or care of the skin, hair, nails and/or mucous membranes. U.S. Lubrizol Advanced Materials Inc, 2020. Patent Application 16/465,410.  Back to cited text no. 42
Kanlayavattanakul M, Lourith N. Plants and Natural Products for the Treatment of Skin Hyperpigmentation-A Review. Planta Med 2018;84:988-1006.  Back to cited text no. 43
Simmler C, Pauli GF, Chen SN. Phytochemistry and biological properties of glabridin. Fitoterapia 2013;90:160-84.  Back to cited text no. 44
Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigment Cell Res 1998;11:355-61.  Back to cited text no. 45
Nerya O, Vaya J, Musa R, Izrael S, Ben-Arie R, Tamir S. Glabrene and isoliquiritigenin as tyrosinase inhibitors from licorice roots. J Agric Food Chem 2003;51:1201-7.  Back to cited text no. 46
Kim HJ, Seo SH, Lee BG, Lee YS. Identification of tyrosinase inhibitors from Glycyrrhiza uralensis. Planta Med 2005;71:785-7.  Back to cited text no. 47
Dong Y, Zhao M, Zhao T, Feng M, Chen H, Zhuang M, et al. Bioactive profiles, antioxidant activities, nitrite scavenging capacities and protective effects on H2O2-injured PC12 cells of Glycyrrhiza glabra L. leaf and root extracts. Molecules 2014;19:9101-13.  Back to cited text no. 48
Fu B, Li H, Wang X, Lee FS, Cui S. Isolation and identification of flavonoids in licorice and a study of their inhibitory effects on tyrosinase. J Agric Food Chem 2005;53:7408-14.  Back to cited text no. 49
Park HY, Kosmadaki M, Yaar M, Gilchrest BA. Cellular mechanisms regulating human melanogenesis. Cell Mol Life Sci 2009;66:1493-506.  Back to cited text no. 50
Bae-Harboe YS, Park HY. Tyrosinase: A central regulatory protein for cutaneous pigmentation. J Invest Dermatol 2012;132:2678-80.  Back to cited text no. 51
Wolf Horrell EM, Boulanger MC, D'Orazio JA. Melanocortin 1 Receptor: Structure, Function, and Regulation. Front Genet 2016;7:95.  Back to cited text no. 52
Minwalla L, Zhao Y, Cornelius J, Babcock GF, Wickett RR, Le Poole IC, et al. Inhibition of melanosome transfer from melanocytes to keratinocytes by lectins and neoglycoproteins in an in vitro model system. Pigment Cell Res 2001;14:185-94.  Back to cited text no. 53
Ito Y, Kanamaru A, Tada A. Centaureidin promotes dendrite retraction of melanocytes by activating Rho. Biochim Biophys Acta 2006;1760:487-94.  Back to cited text no. 54
Lee CS, Nam G, Bae IH, Park J. Whitening efficacy of ginsenoside F1 through inhibition of melanin transfer in cocultured human melanocytes-keratinocytes and three-dimensional human skin equivalent. J Ginseng Res 2019;43:300-4.  Back to cited text no. 55
Choi H, Ahn S, Lee BG, Chang I, Hwang JS, et al. Inhibition of skin pigmentation by an extract of Lepidium apetalum and its possible implication in IL-6 mediated signaling. Pigment Cell Res 2005;18:439-46.  Back to cited text no. 56
Choi H, Choi H, Han J, Jin SH, Park JY, Shin DW, et al. IL-4 inhibits the melanogenesis of normal human melanocytes through the JAK2-STAT6 signaling pathway. J Invest Dermatol 2013;133:528-36.  Back to cited text no. 57
Hseu YC, Ho YG, Mathew DC, Yen HR, Chen XZ, Yang HL, et al. The in vitro and in vivo depigmenting activity of Coenzyme Q10 through the down-regulation of α-MSH signaling pathways and induction of Nrf2/ARE-mediated antioxidant genes in UVA-irradiated skin keratinocytes. Biochem Pharmacol 2019;164:299-310.  Back to cited text no. 58
Ali A, Ashraf Z, Rafiq M, Kumar A, Jabeen F, Lee GJ, et al. Novel amide derivatives as potent tyrosinase inhibitors; in vitro, in vivo antimelanogenic activity and computational studies. Med Chem 2019;15:715-28.  Back to cited text no. 59
Cheng MC, Lee TH, Chu YT, Syu LL, Hsu SJ, Cheng CH, et al. Melanogenesis inhibitors from the rhizoma of Ligusticum sinense in B16-F10 melanoma cells In vitro and Zebrafish In vivo. Int J Mol Sci 2018;19:3994.  Back to cited text no. 60
Chen WC, Tseng TS, Hsiao NW, Lin YL, Wen ZH, Tsai CC, et al. Discovery of highly potent tyrosinase inhibitor, T1, with significant anti-melanogenesis ability by Zebrafish in vivo assay and computational molecular modeling. Sci Rep 2015;5:7995.  Back to cited text no. 61
Lin CH, Ding HY, Kuo SY, Chin LW, Wu JY, Chang TS. Evaluation of in vitro and in vivo depigmenting activity of raspberry ketone from Rheum officinale. Int J Mol Sci 2011;12:4819-35.  Back to cited text no. 62
Boissy RE, Visscher M, DeLong MA. DeoxyArbutin: A novel reversible tyrosinase inhibitor with effective in vivo skin lightening potency. Exp Dermatol 2005;14:601-8.  Back to cited text no. 63
Zarin DA, Fain KM, Dobbins HD, Tse T, Williams RJ. 10-Year update on study results submitted to clinicaltrials.gov. N Engl J Med 2019;381:1966-74.  Back to cited text no. 64
Hollinger JC, Angra K, Halder RM. Are natural ingredients effective in the management of hyperpigmentation? A systematic review. J Clin Aesthet Dermatol 2018;11:28-37.  Back to cited text no. 65


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]

This article has been cited by
1 Melanin of fungi: from classification to application
Ruofan Liu, Xianfu Meng, Cuiyuan Mo, Xuetuan Wei, Aimin Ma
World Journal of Microbiology and Biotechnology. 2022; 38(12)
[Pubmed] | [DOI]
2 Plant polyphenols as green sunscreen ingredients: A systematic review
Ng Shin Yi, Lai Ti Gew, Vicit Rizal Eh Suk
Journal of Cosmetic Dermatology. 2022;
[Pubmed] | [DOI]
3 Potential application of natural bioactive compounds as skin-whitening agents: A review
Wei Zhao, Anquan Yang, Jing Wang, Dan Huang, Yankang Deng, Xiaoli Zhang, Qingli Qu, Wenjing Ma, Ranhua Xiong, Miaomiao Zhu, Chaobo Huang
Journal of Cosmetic Dermatology. 2022;
[Pubmed] | [DOI]
4 Inhibitory Effect of Curcumin-Inspired Derivatives on Tyrosinase Activity and Melanogenesis
Gaia Rocchitta, Carla Rozzo, Marina Pisano, Davide Fabbri, Maria Antonietta Dettori, Paolo Ruzza, Claudia Honisch, Roberto Dallocchio, Alessandro Desś, Rossana Migheli, PierAndrea Serra, Giovanna Delogu
Molecules. 2022; 27(22): 7942
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
Skin Lightening
Skin Lightening ...
Quinone-Related ...
Lightening Compo...
Skin Lightening ...
Melanosome Trans...
Cytokines Inhibitors
Evaluation of
Potential Therap...
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded410    
    Comments [Add]    
    Cited by others 4    

Recommend this journal