What is hyperpigmentation

Discoloration is a generalized or limited change in skin color caused by the uneven and excessive accumulation of melanin (pigment) in the cells.

How is the pigment in the skin formed?

Melanin, the skin pigment, is produced in specialized epidermal cells called melanocytes. They make up 1-2% of epidermal cells, and each melanocyte is associated with 36 keratinocytes and 1 Langerhans cell through dendrites. Melanin synthesis occurs in melanosomes – the lysosomal organelles of melanocytes. The process of melanogenesis begins with the hydroxylation of the amino acid phenylalanine to L-tyrosine or directly by L-tyrosine, which is hydroxylated to L-dihydroxyphenylalanine (L-DOPA). Subsequently, L-DOPA is oxidized to L-DOPAquinone (DQ). Both of these reactions are catalyzed by a critical enzyme called tyrosinase (this enzyme contains copper in its structure. Its deficiency will inhibit the process of melanogenesis and thus may lead to premature graying).

Fig.1 Kumari S., Thng  S.T.G, Verma N.K., Gautam H.K, Melanogenesis inhibitors, Acta Derm Venereol 2018; 98(10): 925

The pathway continues in two parts:

  1. The amino group is attached to DQ to form DOPAchrome, which produces the dark eumelanin pigment (brown-black), containing a lot of nitrogen.
  2. DQ reacts with L-cysteine ​​and/or glutathione to form the cysteinyl Dopa, which gives rise to the bright pigment pheomelanin (yellow-red).

There is also a third type of melanin – neuromelanin – a pigment found in neurons that protects against oxidative stress while producing the neurotransmitter dopamine.

The melanin in the skin is a mixture of copolymers containing eumelanin and pheomelanin in various proportions.

What factors determine skin color?

The differences in skin pigmentation do not result from differences in the number of melanocytes but differences in:

  • melanosome activity – they are more active in Asians and African Americans
  • the type of melanin produced in melanosomes (e.g., red hair has higher levels of pheomelanin, the skin of Asians and African Americans have higher levels of eumelanin, but all races have more eumelanin than pheomelanin)
  • size, number, and packing of melanosomes with melanin (the total amount of melanin in Asian skin is 2 times higher than in white skin, and in black skin 3 to 6 times higher. In black skin, there is also the highest amount of melanosomes.

The number of melanocytes in the skin is independent of race, but varies by area, e.g., in the scalp melanocyte density = 2000 mm-2 and in other areas of the body up to 1000 mm2.

Is Melanin Needed?

Melanin has many essential functions in our body. In addition to giving color to our skin, hair, and irises, it has a protective function. Melanin plays a crucial role in protecting the skin from harmful ultraviolet (UV) radiation and the effects of toxic drugs and chemicals (it can bind and neutralize certain heavy metals). Melanin absorbs and disperses solar radiation and converts the absorbed energy into less toxic for the body – heat. Under the influence of UV, the melanogenesis process is activated. Melanocytes synthesize melanin and transport it via granules (melanosomes) to the surrounding keratinocytes, where it accumulates in the perinuclear area, forming “caps”. These “caps” protect the cell’s DNA from damage induced by UV radiation.

As it turns out, a beautiful tan is an effect of protecting our skin against possible photodamage.

Does melanin always protect us?

Eumelanin performs protective functions primarily – it removes free radicals by reducing the superoxide radical to hydrogen peroxide. It is different with pheomelanin. It is susceptible to photodegradation and can generate anions of hydrogen peroxide and superoxides, leading to mutations in melanocytes or other cells. In addition, pheomelanin increases the release of histamine, contributing to sun-induced erythema and swelling in people with fair skin.

What follows from the above?

People with fair skin, dominated by pheomelanin, are more likely to develop various skin lesions, erythema, or swelling than people with a high skin phototype.

What factors stimulate melanogenesis?

  • UV radiation
  • Genetic factors – mutations in the genes coding for proteins that are involved in the process of melanogenesis
  • Hormonal, e.g., pregnancy, menopause, thyroid diseases
  • Medicines, e.g., antibiotics, tetracyclines, anti-inflammatory drugs, antidepressants
  • Systemic diseases, e.g., Addison’s disease, porphyria
  • Injuries, inflammation; Post-Inflammatory Hyperpigmentation PIH can be caused by endogenous factors (e.g., acne or atopic dermatitis) or exogenous (e.g., mechanical skin damage, intense chemical peels, or laser therapy)

Melanogenesis regulation

Melanogenesis is regulated by a series of cascades related to the enzymes: tyrosinase, Tyrp1, Tyrp2.

UV radiation induces melanogenesis via the suppressor protein p53. Activation of the p53 protein results in increased expression of POMC (pioopiomelanocortin) which is cleaved into peptides such as ACTH, α-, β- and γ-MSH. Next, α-MSH (α -melonotropin) stimulates the melanocortin-1 receptor (MC1R) on melanocytes and thus causes an increased synthesis of eumelanin.

UV radiation also enhances the production of reactive oxygen species (ROS) in keratinocytes and melanocytes, and a high concentration of ROS damages DNA, activating p53 and thus stimulating melanogenesis.

Transcription factor associated with MITF microphthalmia (Fig.1)

The MITF factor influences the development, viability, and function of melanocytes. It regulates the most important melanogenesis enzymes: tyrosinase, Tyrp1 and Tyrp2. Many signal pathways are involved in regulating the MITF:

  • cAMP cyclic adenosine-3 ‘, 5’-monophosphate dependent pathway. As a result of α-MSH stimulation of the MC1R receptor, cAMP is released. cAMP activates Protein Kinase A (PKA), which phosphorylates the cAMP response element binding protein (CREB). CREB increases the expression of the MITF factor, which influences melanogenesis by regulating the Tyrp1 and Tyrp2 enzymes.
  • Wnt / β-catenin pathway. Wnts are cysteine-rich glycoproteins that increase the accumulation of β-catenin in the cytosol. β-catenin migrates to the nucleus, where it increases the expression of MITF.
  • Nitric oxide / cyclic guanosine-3 ‘, 5’-monophosphate (NO / cGMP) signaling pathway. NO raises the level of cGMP, which activates protein kinase G (PKG). PKG activates CREB, which increases the expression of MITF. Activating MITF results in increased production of melanin.

How Mitochondria Regulate Melanogenesis

Hereditary or acquired pigmentary diseases, i.e., vitiligo, are associated with mitochondrial dysfunction. Mitochondria interact with melanosomes through fibrillar bridges that are modulated by the mitochondrial membrane protein Mfn2. Mitochondrial cleavage inhibits hyperpigmentation, and mitochondrial fusion increases melanin production. However, the exact mechanism by which mitochondrial fusion enhances melanogenesis is unclear.

Fig.2. Kumari S., Thng  S.T.G, Verma N.K., Gautam H.K, Melanogenesis inhibitors, Acta Derm Venereol 2018; 98(10): 925

Immunological modulation of melanogenesis

Melanocytes are active factors in the skin’s immune system, play a role in immune responses, and have immunomodulatory properties. On the other hand, Melanocytes are regulated by immune mediators.


  • interleukin IL-4 inhibits melanogenesis by activating the JAK2-STAT6 pathways
  • IL-6 inhibits melanogenesis by reducing the expression of tyrosinase and MITF
  • Tumor necrosis factor TNF-α inhibits melanogenesis via nuclear factor kappa B (NF-κB) and also shortens the half-life of tyrosinase
  • Interferon-gamma (IFN-γ) induces melanocyte apoptosis – a role in the pathogenesis of vitiligo. IFN-γ also maintains skin pigmentation homeostasis and mediates hyperpigmentation.

How can I get rid of unwanted hyperpigmentation?

Since tyrosinase is a key enzyme in the melanogenesis pathway, most cosmetics focus on inhibiting the activity of this enzyme and eliminating unwanted discoloration. Some ingredients show additional properties:

  • inhibit the transport of melanosomes from melanocytes to keratinocytes
  • accelerate the epidermal cycle
  • reduce inflammation


Tyrosinase inhibitors slow down the melanogenesis process by reversible or irreversible inhibition of the enzyme activity.

Plant-derived tyrosinase inhibitors

  • Hydroquinone – occurs in plant and animal organisms as well as microorganisms. It has been widely used as a skin whitening agent for over 40 years; In the EU, its use in cosmetics is prohibited due to its irritating, mutagenic, and cytotoxic properties.
  • Arbutin and methylarbutin (bearberry extracts) – glycosides, hydroquinone derivatives, but with fewer side effects. They have a reversible effect on the activity of tyrosinase.
  • Glabradine (licorice extract) / Glycyrrhiza glabra (licorice) root extract / – is up to 16 times more effective than hydroquinone (strongly inhibits tyrosinase) but is not cytotoxic.
  • Aloesin and feruloylaloesin, – compounds obtained from aloe, safe ingredients that competitively inhibit tyrosinase. Additionally, they have anti-inflammatory, bactericidal, and photoprotective properties.
  • Soy isoflavones daidzein, genistein, glicytein/ Soy isoflavones e.g., Daidzein, Genistein / – obtained from soybeans, inhibit the transport of melanosomes from melanocytes to epidermal cells, provide photoprotective and antioxidant properties.
  • Belides / Bellis perennis (daisy) flower extract / – a patented compound from the Common Daisy, strongly reduces tyrosinase activity.
  • Green tea polyphenols /Camellia Sinensis Leaf Extract/– inhibit tyrosinase activity and affect the process of transporting melanosomes to keratinocytes.
  • Linoleic acid – a compound obtained mainly from vegetable oils, e.g., grape seed oil, sunflower oil, corn oil, or soybean oil. It reduces the availability and degrades tyrosinase.
  • Lipoic acid /Alpha Lipoic Acid/– the main sources are plant and animal products such as broccoli, spinach, and offal. It inhibits tyrosinase activity and counteracts UV radiation’s harmful effects.
  • Acerola polyphenols /Acerola Cherry Extract/– obtained from Acerola cherries. They effectively lighten discoloration caused by UVB action.
  • Hesperidin /Hesperetin/– obtained, for example, from the citrus skin or peppermint leaves. It inhibits the activity of tyrosinase and also protects against harmful UV radiation.
  • Resveratrol (polyphenol) – reduces the expression of tyrosinase, Tyrp1, Tyrp2 and MITF.

Tyrosinase inhibitors derived from microorganisms

  • Kojic acid – a metabolite obtained from Acetobacter, Aspergillus and Penicillium. It chelates Cu2 + in the active site of tyrosinase and inhibits dopachrome tautomerization. It is a substance with high allergenic potential.
  • Azelaic acid – a metabolite produced by Pityrosporum Ovale. It competently inhibits tyrosinase. In addition, it exfoliates the epidermis, thus accelerating the removal of unwanted discoloration.

Animal derived tyrosinase inhibitors

  • Collagen – a natural compound of animal origin: beef, pork, fish, squid, octopus. Clinical studies have shown that the supply of collagen for 6 weeks resulted in a partial reduction of pigmented lesions. The mechanism has not been fully explained.

Synthetic tyrosinase inhibitors.

  • Vitamin C – reduces the activity of tyrosinase through cooperation with copper ions. In addition, it has anti-radical properties and protects the skin against solar radiation. The most stable forms of Vitamin C are:
    • Ascorbyl palmitate – low biological activity,
    • Ascorbyl glucoside
    • Magnesium Ascorbyl Phosphate (MAP)
    • Sodium Ascorbyl Phospate (SAP)
    • Ascorbyl tetraisopalmitate / Tetrahexyldecyl Ascorbate / – fat-soluble, oily, stable form of vitamin C
  • Retinoids / e.g. adapalene or tertinoin – inhibit the transfer of pigment to keratinocytes, affect cell renewal and differentiation, and exfoliate the epidermis, thus accelerating the removal of unwanted discoloration.
  • Vitamin E /Tocopherol/– a strong lipophilic antioxidant, inhibits tyrosinase and prevents oxidation of pigment cell membranes.
  • 4-Butylresorcinol – a strong tyrosinase inhibitor. It has a stronger effect than hydroquinone, arbutin, or kojic acid.
  • Niacinamide (a form of vitamine B3) – inhibits the transport of melanosomes from melanocytes to keratinocytes.
  • N-acetylglucosamine – a chemical compound from a group of modified monosaccharides. It inhibits the conversion of protyrosinase to tyrosinase.
  • Synthetic resveratrol analogs (replacing the CH group with a nitrogen atom) have an increased tyrosinase inhibitory effect.
  • Cinnamic acid derivatives, e.g., p-coumaric acid and ferulic acid (p-Coumaric acid, Ferulic acid), reversibly inhibit tyrosinase’s activity.
  • Polyphenol derivatives, e.g., benzyl benzoate – have a tyrosinase inhibitory effect.
  • Methanol derivatives, e.g., Tranexamic Acid, bind to the tyrosinase’s active site and competitively inhibit its activity.


  • Synthetic pyridinyl-imidazole compound
  • Cardamom extracted from Alpinia katsumadai
  • Acetylsalicylic acid (ASA), a synthetic derivative of salicylic acid
  • Shogaol is the active ingredient in ginger
  • Gallic acid – naturally present in galls, witch hazel


  • Alpha-hydroxy acids (AHA), e.g., glycolic, mandelic, lactic acid / lactic acid /, azelaic acid
  • Beta – hydroxy acids (BHA) – salicylic acid
  • Polyhydroxy acids (PHA) lactobionic acid, gluconolactone / Gluconolactone /


Selected cosmetics for discoloration and their active ingredients that brighten hyperpigmentation.

  1. Arkana Acid Cleansing Gel
  • glycolic acid, lactic acid, aloe leaf juice, green tea extract
  1. Biologique Recherche Lotion P50 PIGM 400 / tonic
  • niacinamide, lactic acid, mandelic acid, gluconolactone, ascorbic acid, citric acid, fig acid, salicylic acid
  1. Sesderma Azelac RU liposomal serum / liposomal serum
  • 4-Butylresorcinol, ascorbyl glucoside, azelaic acid, retinol, niacin, glycyrrhetinic acid,
  1. Image Skincare Iluma Intense Brightening Eye Creme / eye cream
  • Daisy Extract, Vitamin E, Ascorbyl Tetraisopalmitate, Licorice Root Extract, Cucumber Extract, Haloxyl (a mixture of ingredients that is able to absorb and eliminate blood pigments in the skin; thus reducing dark circles under the eyes)
  1. Dermaquest SkinBrite Cream / day and night cream
  • ascorbyl tetraisopalmitate, kojic acid dipalmitate, hexylresorcinol, arbutin, vitamin C, licorice root extract, Canadian sorrel extract, bakuchiol (vegetable equivalent of retinol)
  1. PCA Skin Pigment Gel Pro / day and night gel
  • niacinamide, tranexamic acid, hexylorcinol, 4-Butylresorcinol, licorice root extract, lactic acid, gluconolactone
  1. Image MD Restoring Brightening Creme / night cream
  • daisy extract, ascorbyl tetraisopalmitate, glycolic acid, linoleic acid, kojic acid, oxalic extract, arbutin
  1. Mesoestetic Cosmelan 2 / cream to be used 3 times a day
  • azelaic acid, kojic acid, phytic acid, alpha-arbutin, retinol palmitate, ascorbic acid, salicylic acid, niacinamide, aloe juice
  1. Juice Beauty Peel Full Streght Exfoliating Mask / peeling
  • malic acid, glycolic acid, lactic acid, tartaric acid, citric acid, vitamin C, vitamin E
  1. DR.BELTER Lumination Secret radiance performance mask / mask
  • Biowhite (extract from Baikal skullcap, white mulberry, saxifrage and grapes), Magnesium ascorbyl phosphate, common daisy extract, tartaric acid
It should also be remembered that some of the above-mentioned ingredients, e.g. retinol or hydroxy acids, require the use of a sun protector. Cream with filter will not only protect the skin against unwanted reactions in our skin, but also prevent the formation of new discoloration.

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