Retinoids

Retinoids such as tretinoin, adapalene, tazarotene and isotretinoin are derivatives of vitamin A. Itis an important nutrient obtained exclusively from the environment having many important and diverse functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of tumor suppressor genes. Research is also being done into their ability to treat skin cancers. retinoids are a common treatment option used to ameliorate acne, photodamage and post inflammatory hyperpigmentation. Retinoids causes inhibition of enzymes from breaking down collagen, acts as penetration enhancers when used with other lightening agents such as hydroquinone.

Mechanism of Action: The mechanisms for reducing pigmentation include inhibition of tyrosinase induction, interference with pigment transfer, and acceleration of epidermal turnover. Tretinoin (retinoic acid) increases keratinocyte proliferation and epidermal cell turnover by impairing glutathione-dependent cytoprotection via inhibition of glutathione S-transferase, which results in accentuation of melanin loss from the epidermis.They also have the ability to disperse pigment granules within keratinocytes.

The most common adverse effects include burning, stinging, erythema, dryness, and scaling. Although the adverse effects are reversible, retinoid dermatitis may itself lead to hyperpigmentation, especially in dark-skinned individuals. Tretinoin is available at different strengths ranging from 0.01% to 0.1%. Adapalene is a viable alternative for patients unable to tolerate tretinoin. It is a synthetic retinoid with greater selectivity than tretinoin.

Phenolic thioethers

N-acetyl-4-S-cysteaminylphenol and N-propionyl-4-S-cysteaminylphenol are derived from homologues of phenols with melanocytotoxic activity. Like Hydroquinone and Monobenzyl Ether of Hydroquinone, these belongs to the phenol/catechols class. N-acetyl-4-S-cysteaminylphenol is a tyrosine-amine derivative analogue that is less irritating than hydroquinone. As an alternative substrate of tyrosinase, it may therefore inhibit tyrosinase activity. By decreasing intracellular glutathione, it favors the pathway of forming pheomelanin rather than eumelanin. A clinical study using 4% preparation of N -acetyl-4-S-cysteaminyphenol for melasma showed marked-to-moderate improvement after 2-4 weeks of application, with minimal adverse effects. N -propionyl-4-S-cysteaminylphenol is more potent and has more cytotoxic properties as compared to the N-acetyl form.

Niacinamide

Niacinamide is the biologically active form of vitamin B-3. It regulates the melanogenesis, suppresses the transfer of melanosomes from melanocytes to keratinocytes. In addition, niacinamide is also a tyrosinase inhibitor. It also promotes acne reduction, increases skin moisture, improves the appearance of aged, hyperpigmented and photodamaged skin. Research shows that it has potential to reduce appearance of wrinkles and fine lines by stimulating collagen & ceramide synthesis, and has soothing activity. Can improve functional & structural integrity of the skin barrier. Combined with vitamin A palmitate shows enhanced skin lightening properties. Niacinamide with retinyl palmitate has been shown to improve hyperpigmentation and increase skin lightening after 4 weeks of treatment compared with vehicle alone.

N-acetyl glucosamine

N-acetyl glucosamine is an amino-monosaccharide that was developed as a pigment-lightening cosmeceutical. It lightens skin by inhibiting the glycosylation of tyrosinase a step necessary for the formation of melanin. NAG is required by fibroblasts which are carpenter cells that synthesize collagen and connective tissue to regenerate body structure. They are highly concentrated in skin to assist the continual process of skin rejuvenation, which slows and becomes inefficient with age. A randomized double-blind study reported that the application of 2% N -acetyl glucosamine twice daily for 5 weeks provided a lightening effect. NAG (3%) applied topically to skin equivalent cell cultures significantly inhibits melanin content in a dose-dependent manner. Clinically, treatment with a 4% niacinamide plus 2% NAG combination for 8 weeks was significantly more effective at reducing hyperpigmentation than niacinamide alone. Thus, it can be an important ingredient in skin lightening products, particularly when combined with niacinamide.

Monobenzone

Monobenzone is the monobenzyl ether of hydroquinone a depigmenting agent. Similar to hydroquinone, monobenzyl ether of hydroquinone (MBEH) belongs to the phenol/catechol class of chemical agents. Genarally monobenzone is used on skin to permanently lighten skin in people with vitiligo. Depigmenting darker skin around the areas of vitiligo helps even out coloring and appearance of the skin. Due to its depigmenting effect, it is also used for skin whitening.

Mechanism of Action: Exact mechanisn is unknown but it is theorized that It works by eliminating melanin (pigment molecules) from skin cells by selective melanocytic destruction through free-radical formation and competitive inhibition of the tyrosinase enzyme system. Unlike hydroquinone, MBEH almost always causes nearly irreversible depigmentation of the skin.

It may take up to 4 months to complete the depigmentation of treated skin. It causes uneven pigmentation on skin when applied topically. So users have to use it carefully with expert’s advice. Skin treated with monobenzone makes skin sensitive to sunlight which leads to easy sunburn. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors. In dermatology, MBEH is only used to eliminate residual areas of normally pigmented skin in patients with generalized vitiligo.

Magnesium Ascorbyl Phosphate

Magnesium Ascorbyl Phosphate is a water-soluble, non-irritating, stable derivative of Vitamin C. This form of Vitamin C when used was shown to suppress melanin formation, increase skin’s hydration levels and improve its elasticity. It has the same potential as vitamin C to boost skin collagen synthesis but is effective in significantly lower concentrations, and can be used at concentrations as low as 10% to suppress melanin formation in skin-whitening solutions. It is also important to note that Magnesuim Ascorbyl Phosphate may be better choice than Vitamin C for people with sensitive skin and those wishing to avoid any exfoliating effects since many Vitamin C formulas are highly acidic and therefore produce exfoliating effects. In skin care products, Magnesium Ascorbyl Phosphate (MAP) is also used for UV protection and repair, collagen production, skin lightening and brightening, and as an anti-inflammatory. It is also a potent antioxidant. It is considered an excellent non-irritating skin whitening agent that inhibits skin cells to produce melanin and lightens age spots, and is a great alternative to Quinone. Magnesium Ascorbyl Phosphate is a also a potent anti-oxidant that can protect skin from oxidation and UV rays, and is used as an anti-inflammatory. Furthermore, MAP has been shown to have a protective effect against skin damage induced by UV-B irradiation. The latter protective effect is theorized to be due to the conversion of MAP to ascorbic acid.

Kojic acid

A fungal metabolic product produced by various fungal species such as Aspergillus and Penicillium.. In addition to its skin-lightening abilities, kojic acid is classified as an antioxidant. It has the ability to counteract the effects of particles in the air called free radicals, which have the potential to cause oxidative damage to the skin cells. By limiting the effects of free radicals, kojic acid helps to prevent the formation of signs of aging that occur when the cells that produce the skin's vital structural proteins become damaged. Kojic acid is also an antibacterial agent, meaning. disrupts the processes the processes that bacteria cells must perform to thrive and reproduce, leading to the death of bacteria.

Mechanism of Action: When kojic acid is applied to the skin in concentrated amounts, the chemicals in the ingredient work on the melanocytes, interfering with the production of melanin. It inhibits the catecholase activity of tyrosinase by chelating copper at the active site of the tyrosinase enzyme, which is the rate-limiting, essential enzyme in the biosynthesis of the skin pigment melanin. Melanocytes treated with kojic acid become nondendritic, with a decreased melanin content.

Kojic acid is also consumed widely in the Japanese diet, with the belief that it is of benefit to health. It scavenges reactive oxygen species released excessively from cells or generated in tissue or blood. Kojic acid is used in concentrations ranging from 1-4%. Although effective as a skin-lightening gel, it has been reported to have high sensitizing potential and may cause irritant contact dermatitis. In a study comparing glycolic acid/kojic acid combination with glycolic acid/hydroquinone, no statistical difference in efficacy was reported between kojic acid and hydroquinone; however, the kojic acid preparation was reported to be more irritating. To decrease the irritation from kojic acid, it is combined with a topical corticosteroid. In a comparison study, 2% hydroquinone, 10% glycolic acid, and 2% kojic acid decreased hyperpigmentation in patients with melasma better than the same combination without kojic acid.

Hydroquinone

Hydroquinone is an aromatic organic compound that is a type of phenol, a derivative of benzene. In medical literature Hydroquinone is considered as one of the most effective primary topical ingredient for inhibiting melanin production in melanogenesis. It is considered the golden standard for treatment of hyperpigmentation, with over 50 years of efficacy and safety data. Hydroquinone is also found naturally in many plants, some mushrooms, as well as in wheat, coffee, tea, beer, wine, berries but is detoxified within the liver into inert compounds. Its components have potent antioxidant abilities. Hydroquinone is a strong inhibitor of melanin production, meaning that it prevents dark skin from making the substance responsible for skin color. Hydroquinone does not bleach the skin but lightens it, and can only disrupt the synthesis and production of melanin hyperpigmentation.

Mechanism of action: Hydroquinone produces reversible lightening of the skin by interfering with melanin production by the melanocytes. It works by decreasing the production and increasing the breakdown of melanosomes (melanin pigment granules) in the skin's pigment cells (melanocytes). It does this by inhibiting the activity of tyrosinase, the enzyme needed to make melanin.Specifically, inhibition of the enzymatic conversion of tyrosine to DOPA (dihydroxyphenylalanine) results in the desired chemical reduction of pigment. Ultimately, this causes a decrease in the number of melanocytes and decreased transfer of melanin leading to lighter skin.

The 2% hydroquinone is readily available over the counter in various cosmetic preparations. Evidence of improvement with hydroquinone (monotherapy) is usually observed at 4-6 weeks, with improvement appearing to plateau at approximately 4 months. For better efficacy, hydroquinone is compounded into various mixtures for the treatment of hyperpigmentation. The original Kligman formula involves compounding 5% hydroquinone with 0.1% retinoic acid and 0.1% dexamethasone in a hydrophilic ointment base. Tri-Luma is a popular combination skin-lightening agent that contains 0.01% fluocinolone, 4% hydroquinone, and 0.05% tretinoin in a cream formulation. Despite the remarkable overall safety of hydroquinone, bear in mind the potential adverse effects. Contact dermatitis occurs in a small number of patients and responds promptly to topical steroids. An uncommon, yet important, adverse effect of hydroquinone is exogenous ochronosis. This disorder is characterized by progressive sooty darkening of the skin area exposed to hydroquinone. Histologically, degeneration of collagen and elastic fibers occurs. This degeneration is followed by the appearance of characteristic ochronotic deposits consisting of crescent-shaped, ochre-colored fibers in the dermis. Exogenous ochronosis has generally been observed in black patients who have used high concentrations of hydroquinone for many years. Cases occurring after the use of 2% hydroquinone have also been reported, but assays of some of these products found that they actually contained much higher concentrations. An exogenous ochronosis due to hydroquinone has been reported from South Africa. For this reason, the general recommendation is that hydroquinone should be discontinued if no improvement occurs within 4-6 months. Hydroquinone-induced ochronosis is often difficult to treat, but it may respond to topical steroids and chemical peeling.Tretinoin has been used to enhance the efficacy of hydroquinone. In a large-scale, double-blind, placebo-controlled study, 0.05% tretinoin caused a decrease in melanin content at 6 months.

Glycolic Acid

Glycolic acid is the smallest alpha-hydroxy acid derived from sugar cane and is essentially a fruit acid. This colorless, odorless, and hygroscopic crystalline solid is highly soluble in water. It is used in in food processing as a flavoring agent and as a preservative, and in the pharmaceutical industry as a skin care agent. Due to its excellent capability to penetrate skin, glycolic acid finds applications in skin care products, most often as a chemical peel performed by a dermatologist, plastic surgeon or licensed aesthetician. It is used to improve the skin's appearance and texture. It may reduce wrinkles, acne scarring, hyperpigmentation and improve many otherskin conditions, including actinic keratosis, hyperkeratosis, and seborrheic keratosis. Glycolic acid works as an exfoliant. Once applied, glycolic acid reacts with the upper layer of the epidermis, weakening the binding properties of the lipids that hold the dead skin cells together. By removing that top layer of skin, the newer (healthier) skin below the acne layer can be revealed, resulting in less oily and acne-prone skin.

Glutathione

Glutathione is an antioxidant made from glycine, glutamic acid and cysteine. It is a strong antioxidant for cleaning of the liver, removal of toxic substances from the body and sharpening of the brains. Like any other drug side effects glutathione inhibits production of melanin hence lightens the skin and many people have used as an advantage in getting a fair skin. Glutathione lightens skin in several ways. It works by

• Direct inactivation of the enzyme tyrosinase by binding and chelating copper within the enzyme’s active site
• Mediating the switch mechanism from eumelanogenesis to pheomelanogenesis, as glutathione participates in the conversion of dopaquinone to pheomelanin. The observed differences in the glutathione and glutathione-related enzyme content between black and yellow (or red) skin provide evidence that the increase of glutathione-reductase activity in the environment of the melanocytes may stimulate the pigment cells to produce phaeomelanin instead of eumelanin pigment. As expected, the lowest levels of reduced glutathione (GSH) were found associated with eumelanin type pigmentation, whereas the highest ones were found in the skin with phaeomelanin producing melanocytes;
• Quenching of free radicals and peroxides that contribute to tyrosinase activation and melanin formation;
• Modulation of depigmenting abilities of melanocytotoxic agents.
• Research results also indicate that glutathione inhibits the synthesis and agglutination of melanin by interrupting the function of L-DOPA. The balance between CysH and GSH, which is partly determined by the rate of utilization of CysH for GSH biosynthesis, regulates not only the levels of 5-S-CD and DOPA but also the melanogenic activity of pigment cells. Since DOPA functions as a cofactor in the monophenolase reaction of tyrosinase, it is proposed that the ratio of 5-S-CD to DOPA may be an important factor in the regulation of tyrosinase activity.

These concepts supported by the various experimental evidence presented form basis for future research in the use of glutathione in the treatment of pigmentary disorders. The presence of Glutathione is required by the body to maintain normal function of the immune system. Glutathione is involved in detoxification by binding to toxins like heavy metals, solvents, pesticides and transforms them into a form that can be excreted in urine. It neutralizes the harmful effects of free radicals. Glutathione can be found in many healthy foods that people eat on a regular basis like walnuts, avocados, tomatoes and oranges can all help to keep Glutathione levels high in the bloodstream. Glutathione is commonly taken in pill form, and Glutathione pills are hugely successful in Japan, particularly for women that just want to have lighter skin than they were born with without the side effects that some topical treatments have. Glutathione works to clear the body of free radicals and toxins that can lead to serious skin problems like hyperpigmentation and melasma, as well as more common ones like sun spots. Glutathione can be extremely beneficial for people that would just prefer a slightly lighter complexion. In fact, many women that have flawless skin use Glutathione on a regular basis to help maintain their excellent complexion.

Glabridin(licorice extract)

Glabridin is the main ingredient in licorice extract. Licorice, the root of the glycyrrhiza plant species, which contains glabridin has been used medicinally for more than 4000 years. The genus glycyrrhiza consists of approximately 30 species, in which six species produce a sweet saponin glycyrrhizic acid (GA), and they are widely used in Asia countries. These medicinal plants were used as flavorings, sweeteners and as herbal medicine, and they were also used for improving health, detoxification and cures for injury. Glabridin is an isoflavane, a type of isoflavonoid. This product is part of a larger family of plant-derived molecules, the natural phenols. Glabridin has been reported to exhibit multiple pharmacological activities, such as cytotoxic activity, antimicrobial activity, estrogenic and anti-proliferative activity against human breast cancer cells. It also affects melanogenesis, inflammation, low-density lipoprotein oxidation and protection of mitochondrial functions from oxidative stresses. The authors investigated glabridin for its inhibitory effect on pigmentation and reported that glabridin inhibited tyrosinase activity of melanocytes without cytotoxicity. They further showed that UV-B–induced pigmentation and erythema were inhibited by topical application of 0.5% glabridin. The anti-inflammatory properties of glabridin were attributed to inhibition of superoxide anion production and cyclooxygenase activity.

Azelaic acid

A naturally occurring, saturated dicarboxylic acid originally isolated from Pityrosporum ovale, azelaic acid is a rather weak competitive inhibitor of tyrosinase. It is found in grains, such as wheat, rye, and barley In addition, azelaic acid has an antiproliferative and cytotoxic effect on melanocytes. The latter effect occurs because of a rather potent inhibition of thioredoxin reductase, an enzyme involved in mitochondrial oxidoreductase activation and DNA synthesis. Although azelaic acid was initially prescribed for the treatment of acne which works by killing acne bacteria that infect skin pores, and decreases the production of keratin, which is a natural substance that promotes the growth of acne bacteria later it was found that azelaic acid reduces synthesis of melanin. Its efficacy has been compared with hydroquinone 4% in the treatment of facial hyperpigmentation in dark-skinned patients. The combination formula reportedly was as effective as hydroquinone 4% cream, although with a slightly higher rate of local irritation.

Arbutin

Arbutin is a molecule that is derived from natural sources of hydroquinone. It is a glycosylated hydroquinone found at high concentrations in certain plants and capable of surviving extreme and sustained dehydration. Arbutin is found in leaves of bearberry, cranberry, mulberry or blueberry shrubs, and also is present in most types of pears, which is found to have skin lightening properties. Arbutin has been shown to inhibit melanin synthesis by inhibition of tyrosinase activity. Inhibition of melanosomal tyrosinase activity, rather than suppression of the synthesis and expression of this enzyme, appears to be the mechanism of action. It prevents the formation of melanin and was effective in the topical treatment of various cutaneous hyperpigmentations characterized by hyperactive melanocyte function. Structurally related to hydroquinone, arbutin is a glycoside(a glycosylated derivative of hydroquinone) relatively simple chemical, with a glucose attached to a hydroquinone. Both hydroquinone and arbutin have skin lightening properties, primarily because they inhibit synthesis of melanin. But the glucose residue makes a difference which makes arbutin special, not having the side effects that hydroquinone seems to have. Arbutin also has anti-cancer activity on melanoma cells. Arbutin and other plant extracts are considered safe alternatives to commonly used depigmenting agents to make the skin fairer

Aloesin

Aloesin, a natural hydroxymethyl chromone compound, a low-molecular weight glycoprotein and a natural derivative of aloe vera, obtained from the aloe vera plant with structure is rather similar to flavonols. It has been proven to competitively inhibit tyrosinase from human, mushroom, and murine sources. It inhibits tyrosinase by competitive inhibition at DOPA oxidation site and does not show cell cytotoxicity, unlike hydroquinone. Because of its hydrophilic nature, it has a decreased ability to penetrate the skin. Hence, combination treatment of aloesin with arbutin has been observed to synergistically inhibit melanin production. Testing of aloesin revealed no cytotoxicity, which makes it a good alternative to HQ

Alpha Hydroxyacids

Alpha Hydroxyacids (AHA) are weak organic acids found in fruits, plants and milk sugars. Most researched forms, and commonly, widely used AHAs are primarily in the form of lactic acid and glycolic acid because they have a molecular size that allows effective penetration into the top layers of skin. For centuries, alpha hydroxyacids have been one of the most commonly utilized peeling agents used to treat dry skin, acne, actinic damage and to improve skin color/texture. At low concentrations AHAs promotes exfoliation by decreasing corneocyte cohesion and stimulating new growth in the basal layer, while at higher concentrations AHAs promote epidermolysis and dispersed basal layer melanin. Lactic acid and glycolic acid are AHAs derived from sour milk and sugarcane juice, respectively. Alpha-hydroxy acids have been shown to lighten melasma, solar lentigines, and postinflammatory hyperpigmentation. Glycolic acid which acts as exfoliant is used as an ingredient in skin-lightening products in low concentrations. It may also be used as a peeling agent in concentrations of 30-70% to increase the efficacy of other lightening agents such as hydroquinone by removal of the epidermis, thus enhancing the penetration of hydroquinone. Repeated peels every 2-3 weeks are necessary to attain significant lightening. In an Indian study of 40 patients with skin types III-IV with moderate-to-severe melasma, glycolic acid peels were used in addition to a modified Kligman hydroquinone formula in a 21-week open pilot study. Eighty percent of patients in the peel group noted excellent improvement, while only 60% of the control group had the same improvement.

Melanin bio-synthesis and biological pathway

The oxidation of L-Tyrosine to L-DOPA is catalysed by the action of tyrosinase enzymes within the melanocyte's melanosome. In the next step L-DOPA is oxidized to DOPAquinone.
From DOPAquinone, the melanin synthesis pathways diverge to produce either eumelanin or pheomelanin.

Eumelanin: Firstly, DOPAquinone is converted to DOPAchrome through auto-oxidation, and subsequently in the presence of DOPAchrome tautomerase and dihydroxyindole-2-carboxylic acid oxidase, DOPAchrome is converted to 5,6-dihydroxyindole. Finally, the oxidation of 5,6-dihydroxyindole (DHI) to indole-5,6-quinone by tyrosinase leads to the formation of eumelanin (brown-black pigment).

Pheomelanin: In the presence of cysteine or glutathione, dopaquinone is converted to cysteinyl DOPA Subsequently, pheomelanin, a yellow-red pigment, is formed through the oxidative polymerization of cysteinyldopa via 1,4-benzothiazinylalanine intermediates.

About Melanin and Skin color

Melanin is a biological pigment that can be found in hair, the eyes, the ear, the brain and other parts of the human body. Melanin is water-insoluble polymer of various compounds derived from the amino acid tyrosine. Skin color comes from a pigment called melanin. This pigment is made by melanocytes, a type of cell deep within the skin. It is one of two pigments found in human skin and hair and adds brown to skin color; the other pigment is carotene, which contributes yellow coloring. The synthesis of melanin reactions is catalyzed by the enzyme tyrosinase.Tyrosinase is found in only one specialized type of cell, the melanocyte, and in this cell melanin is found in membrane-bound bodies called melanosomes. Melanosomes can be transferred from their site of synthesis in the melanocytes to other cell types. The various hues and degrees of skin tone or color found in the skin of human beings are directly related to the number, size, and composition of melanosomes within the melanocytes and distribution of melanocytes or activity of melanogenic enzymes. Besides it role in pigmentation, melanin, which absorbs ultraviolet light, plays a protective role when skin is exposed to the damaging rays of the sun. Melanocytes convert an amino acid called tyrosine into melanin. It uses an enzyme called tyrosinase to do this.These pigments are then transported to the upper layers of the skin where they are deposited. The more melanin is produced, the darker your skin gets.There are three main types of melanin. Eumelanin, pheomelanin and neuromelanin. In context to the human skin color, Melanin comes mainly in two forms. It can be a lighter, yellowish Pheomelanin or a darker brown Eumelanin.

Eumelanin is the most abundant type of melanin in humans. It can be found in two variations. Black eumelanin and brown eumelanin.

Pheomelanin is a red-yellow pigment found both in lighter-skinned humans and darker skinned humans. it contains sulphur and is alkali soluble.

Neuromelanin can be found in the medulla, the adrenal gland and pigment bearing neurons (locus coeruleus, substantia nigra, etc.) in the brain.

Melanin possesses photochemical qualities that makes it an excellent photoprotectant. The protective qualities of melanin rely upon its ability to absorb harmful UV-radiation and transform the solar energy into harmless heat. Melanin can dissipate the absorbed UV radiation as heat. This prevents the indirect DNA damage that is responsible for the formation of malignant melanoma and other skin cancers.

Interestingly UV radiation, when it comes in contact with pheomelanin, it possesses the ability of inducing the release of free radicals in the skin, thus intensifying skin damage rather than protecting the skin.

Upon exposure to UV radiation, DNA damage triggers cytokines, growth factors and other inflammatory factors to stimulate melanin production. Melanin forms in specialised cells called melanocytes. Melanocytes are especially abundant in the basal layer of the epidermis and underlying dermis and are responsible for the pigmentation of the skin. The melanocytes, by increasing the production of intracellular nitric oxide (NO), they trigger signal transduction cascades to initiate melanogenesis through a series of oxidative reactions involving the amino acid tyrosine in the presence of the enzyme tyrosinase. This leads to the production of melanin. Melanin granules synthesized in the melanocytes are then transferred from the cytoplasm of the melanocytes to the basal cytoplasm of the keratinocytes. In the human epidermis, melanocytes work in close harmony with their neighbouring cells such as keratinocytes via their dendrites. They thus form a protective covering in the inner layers of the epidermis, absorbing UV rays and inhibiting their penetration.