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