INTRODUCTION:

Skin Whitening:

Skin whitening, Skin lightening and Skin Bleaching refers to the practice of using chemical substances in an attempt to lighten skin tone or provide an even skin complexion by lessening the concentration of melanin. Several chemicals have been shown to be effective in skin whitening.^[2]

Skin Whitening Agent:

Skin whitening/lightening (agent) use in people of colour is commonplace in many patient and is used for a varieties of skin conditions including the hyper pigmentation associated with photo damage. Skin lightening agent target several point of melanogenesis at either inhibition of melanocytes stimulation (e.g. antioxidants, anti-inflammatory agent), cell receptor antagonism (e.g. α-melanocyte– stimulation hormone antagonist), inhibition of melanin synthesis enzymes [e.g. tyr trp (tyrosinase- related protein)-1,TRP-2], inhibition melanosome transport within the melanocytes and transfer to the keratinocytes (e.g. PAR-2 antagonist and activation of melanin degradation within the keratinocvyte.^[3]

Difference between Skin Whitening and Skin Lightening

There really is no difference between skin whitening and skin lightening. It really depends on what country they are trying to market the product. For example, in Asian countries it is absolutely legitimate to claim that a product has skin whitening effects, however in European countries they try to be more careful with their words and opt to market it as a skin lightening or brightening product. This is simply because the term skin "whitening" may come as a racist comment, and may appear insensitive to some group of people.^[4]

Depigmenting Agents:

Depigmenting agents are commonly prescribed to treat disorders of hyper pigmentation Skin-lightening agents added to product formulations have become increasingly popular. Common depigmenting ingredients include hydroquinone, ascorbic acid (vitamin C), kojic acid, and Licorice extract (glabridin). Recent advances in the field of cosmetic dermatology have developed lasers as another modality for the treatment of hyper pigmentation ^[5]. A growing number of products as follows can be used by physicians as a part of an armamentarium for treating disorders of hyper pigmentation.

ü Alphaquin

ü Benoquin

ü Claripel

ü Clarite

ü Eldopaque

ü Esoterica

ü Fluocinolone/ Tretinoin/ Hydroquinone

ü Hydroquinone .

Mechanism of Skin Depigmenting and Lightening agent.

The type and amount of melanin synthesized by the melanocyte, and its distribution pattern in the surrounding keratinocytes, determines the actual colour of the skin. Melanin forms through a series of oxidative reactions involving the amino acid tyrosine in the presence of the enzyme tyrosinase.

Tyrosinase (A melanin Precursor):

Tyrosinase catalyses three different reactions in the biosynthetic pathway of melanin in melanocytes, the hydroxylation of tyrosine to L-DOPA and the oxidation of L-DOPA to dopaquinone; furthermore, in humans, dopaquinone is converted by a series of complex reactions to melanin. Among the skin-lightening and depigmenting agents, magnesium-L-ascorbyl-2-phosphate (MAP), hydroxyanisole, N-acetyl-4-S-cysteaminylphenol, arbutin (hydroquinone-beta-D-glucopyranoside) and hydroquinone (HQ) are the most widely prescribed worldwide. However, with reports of potential mutagenicity and epidemics of ochronosis, there has been an increasing impetus to find alternative herbal and pharmaceutical depigmenting agents. A review of the literature reveals that numerous other depigmenting or skin lightening agents are either in use or in investigational stages. Some of these, such as kojic, glycolic are well known to most dermatologists. Others have been discovered and reported in the literature more recently.

Targeting Tyrosinase as the Key Enzyme of Melanogenesis:

The tyrosinase inhibitors can be classified as competitive, uncompetitive, mixed type and non-competitive inhibitors. The nature of tyrosinase inhibition can be disclosed by measuring enzyme inhibition kinetics using Line weaver- Burk plots with varying concentrations of l-DOPA as the substrate. This can be seen on example of polyphenol extracts from acerola (West Indian cherry) or a chalcone derivative isolated from Morus nigra (black mulberry). Knowledge of the type of inhibition may be important in order to achieve better skin lightening effects since combined treatments may result in synergistic effects. This has been shown in case of the competitive tyrosinase inhibitor, arbutin and the noncompetitive inhibitor, aloesin. A large majority of tyrosinase inhibitors show reversible inhibition. In irreversible inhibition, covalent binding with the enzyme may cause its inactivation by altering the active site of the enzyme and/or by conformational changes to the protein molecule. Irreversible inhibition may also occur via the so-called suicide inhibition mechanism. The large number of studies using tyrosinase inhibitors from natural sources that have appeared, mostly in the last decade.

Molecular targets of skin lightening agent^[3]

Molecular targets	Agent Used
1.Tyrosinase Inhibition	Hydroquinone, kojic acid, arbutin, ascorbic acid
1.Tyrosinase Inhibition	Ellagic acid
2.Tyrosinase copper chelation	Glucosamine, N-acetyl glucosamine, tunicamycin
3.Inhibition of tyrosinase glycosylation	Niacin amide, protease inhibitors
3.Inhibition of tyrosinase glycosylation	Retinoid(trans-retinoic acid, retinol
Melanosome transfer	Vitamin C compound , vitamin E, sulfhydryl compound
Down regulation of tyrosinase	Hydrocortisone, phytosterol, glycyrrhetinic acid
Antioxidant	Retinoid, salicylic acid
Anti-inflammatory agent
Increase epidermal turnover

Different Modes of Reducing Melanin Production in Skin and Melanocytes:

All depigmenting agents may be divided on the basis of interference in melanin synthesis, transport and removal by skin turnover. Preventing the maturation or intracellular trafficking of tyrosinase is an alternative way to reduce the effect of the enzyme on pigmentation. Various natural extracts can also influence tyrosinase mRNA at the transcription level; also mRNA of the other tyrosinase-related proteins or microphtalmia transcription factor (MITF) can be affected (see refs. and others in. From the work of Sharlow et al. and Seiberg we learned that the protease activated receptor 2 (PAR-2) is important for melanosomal transfer from melanocytes to keratinocytes and that this transfer can be used as a target for skin lightening. The vitamin B3 derivative niacin amide is one of the agents used for inhibiting melanosomal transfer. Melanocytes express high levels of sAPP, the soluble N-terminal ectodomain of the β-amyloid precursor protein. sAPP may play a role in the release of melanin particles via dendritic tips. Blocking the sAPP signalling could thus be another way to influence melanosome transport.

Melanin can be degraded enzymatically in keratinocytes and application of melanin degrading enzymes could be used to prevent UVB induced pigmentation in human skin. Reduction of ROS levels in melanocytes may prevent activation of melanogenesis. In various studies, extracts from plants or fruit or other species were tested for their antioxidant capacity by using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging assay or the oxygen radical absorbance capacity (ORAC) (e.g., Rangkadilok et al. . It showed that daily oral administration of vitamin C (ascorbic acid) and vitamin E and cysteine to brownish guinea pigs reduced UVB-induced pigmentation. Ascorbic acid is considered a skin whitening agent and more stable derivatives such as ascorbyl glucoside and ascorbyl palmitate are already being used in different skin whitening formulations. As known from many cases of post-inflammatory hyper pigmentation, melanogenesis can be stimulated by some inflammatory mediators. Inhibition of the production of inflammatory mediators (Il1α and TNF-α) was reported for sea grape extracts. Via this indirect way stimulation of melanogenesis in the pigment cells could be prevented

Different natural skin lighting/ whitening agents.

1. Alpha-Arbutin/ Beta Alpha

It is a biosynthetic active ingredient that is pure, water-soluble and is manufactured in a powder form. As one of the most advanced skin lightening ingredients on the market, it has been shown to work effectively on all skin types. It is the epimer of arbutin, and research has proven that it has a stronger inhibitory action than that of (beta) arbutin. Though it is a very expensive ingredient to manufacture, even at very low concentrations, a-arbutin has shown to inhibit the activity of tyrosinase. Alpha Arbutin's inhibitory mechanism is different from that of arbutin and can be up to 10 times more effective. The a-glucosidic bond found in alpha Arbutin offers higher stability and efficancy than the B form found in the related Beta-Arbutin. This leads to a skin whitening active that acts faster and more efficiently than existing single components.^[6].It is best to look for skin lightening products with alpha-arbutin since it has a stronger skin whitening effect than beta-arbutin. Also, beta-arbutin may cause skin irritation in some individuals with sensitive skin.

2. Kojic Acid

It is a natural substance derived from Japanese Koji mushroom. As a skin lightening agent, kojic acid works by inhibiting melanin production (dark spots and brown pigments). Although not harmful to human health, kojic acid have a few adverse effects on skin, if used excessively. It may cause skin irritation, and continual use after irritation may result in allergic contact dermatitis.^[7]

3. Liqourice Extract

Licorice extract is a very popular skin whitener and has been used for years to effectively lighten skin discolorations. The main compound for skin whitening is glabridin, a potent skin lightener that inhibits pigmentation by preventing tyrosinase activation. Studies have shown that Licorice extract can brighten dull skin while remaining non-toxic to the melanin forming cells. Licorice root also has anti-inflammatory properties and is especially effective at evening out or fading sun tan.^[7]

4. Mulberry

Mulberry, white mulberry and/or paper mulberry are powerful inhibitors of Tyrosinase enzyme than hydroquinone. And, skin irritation with mulberry extract is less than other skin lightener agents. Paper Mulberry extract, is obtained from the root of Broussonetia kazinoki, Siebold. or B. papyrifera, Vent. Tabl. Regn. Veget. or hybrids of both, family Moraceae. Extracts of this root are potent inhibitors of Tyrosinase enzyme. The active constituents present in the extract are Prenylated, polyhydroxylated mono-and bis-phenylderivatives. A 0.4% concentration of paper mulberry extract inhibits tyrosinase by 50% compared to 5.5% for hydroquinone and 10.0% for kojic acid. At 1% paper mulberry extract is not a significant irritant.

5. Glycolic Acid

Glycolic acid, a substance derived from AHA (alpha hydroxy acid) exfoliates skin to allow deeper penetration of other skin lightener ingredients into the skin. By accelerating skin cell turnover, glycolic acid brightens and evens skin tone naturally, and also helps to reduce the appearance of fine lines and wrinkles.

6. Lactic Acid

Lactic acid works similarly to Glycolic acid but is typically better suited for people with sensitive skin. Lactic acid removes dead skin cells to reveal new healthy cells underneath. As a result, the dry flaky skin disappears and skin becomes smoother, fairer and brighter with a youthful glow.

7. Lemon Juice Extract

The citric acid in lemon juice is one of nature's most potent skin bleaching ingredients. However, it can irritate skin and should only be used at small concentrations in skin lighteners. Also, do not expose your skin to sunlight with lemon juice as it could have the opposite effect and make your skin darker. Lemon juice can be extremely drying to the skin if applied directly.

8. Vitamin A

Possesses antioxidant properties and discourages premature aging of the skin. Eliminates dryness and blotchiness and keeps skin healthy and clear. Helps repair skin damage and promote firmer, smoother skin texture.

9. Vitamin C

Vitamin C is a natural antioxidant that occurs in many different forms ((L-ascorbic acid, ascorbic acid, and magnesium ascorbyl phosphate) each with distinct properties. Studies have indicated that Vitamin C has the ability to suppress melanin formation and whiten skin naturally when applied^[7].Vitamin C also protects skin from the damaging effects of ultraviolet (UV) radiation from the sun. Exposure to ultraviolet light (UVA or UVB) can speed up aging by damaging the collagen fibbers of the skin.[7] Vitamin C is widely recognized for its significance in the production of collagen. Application of vitamin C on the skin has also revealed its ability to avert the free radical skin damage exposure to ultraviolet rays from the sun. In recent years, there has been a sudden increase in the number of skin rejuvenation, anti-wrinkle and skin lightening products with vitamin C.

10.EmblicaEmblica is a patented composition extracted from the plant Phyllanthus emblica. The extract uses a multilevel cascade of antioxidant compounds resulting in a long-lasting and stable antioxidant activity. Recent studies have shown that this natural antioxidant also provides significant skin lightening properties when used in moderate concentrations.

11. Aloe Vera Extract

Aloe Vera is a nutritional storehouse, containing vitamins B₁, B₂, B₆, C, niacin amide, choline and 18 amino acids. In addition to many other nutritional substances, aloe provides a refreshing sensation to the skin and serves as a water-binding agent for skin due to its polysaccharide and sterol content. Research has also shown aloe has anti-inflammatory, antioxidant, and antibacterial qualities. Isolated components of aloe vera, such as glycoprotein, also have some effectiveness for tissue repair and wound healing.

12. Grape Seed Extract

Grape seed polyphenols help slow down aging of the skin by exerting very strong free radical- scavenging effect on the skin. Reduces adverse allergic and inflammatory responses and promotes healing. Aids in maintaining skin elasticity by stabilizing the collagen and elastin in the skin so that their chemical structures are not disrupted ^[9].

13. Green Tea Extract

Reputed to contain the highest concentration of polyphenols, Green Tea is well known for its antioxidant, anti-inflammatory, and astringent properties. Considering their well-documented antioxidant and anti-inflammatory activities, topical green tea polyphenols help slow down the development of some signs of aging and helps repair skin damage by quenching free radicals and reducing inflammation ^[9].

14. Alfalfa Extract

Great source of protein, minerals and vitamins C, D, E and K for the skin. Conditions and increases skin metabolism to promote skin healing ^[9].

15. Caviar Extract

The Caviar is loaded with proteins, vitamins and minerals to nourish the skin, speed up cell renewal and increase natural production of collagen for a healthier, firmer appearance ^[9].

16. Cucumber Fruit Extract

A natural anti-inflammatory substance with extremely high skin soothing and moisture binding properties. Has mild cell renewal properties and helps tighten the skin ^[9]

17. Glycerine

Natural humectants to keep skin soft and moisturized. Derived from natural substances by hydrolysis of fats and by fermentation of sugars. It can also be synthetically manufactured. Glycerine shores up the skin’s natural protection by filling in the area known as the intercellular matrix and by attracting just the right amount of water to maintain the skin’s homeostasis. There is also research indicating that the presence of glycerine in the intercellular layer helps other skin lipids do their jobs better ^[9].

18. Hydrolyzed Soya Protein

A naturally derived protein of vegetable origin that is produced from Soya flour. It moisturizes, softens and smoothens the skin and helps minimize the appearances of wrinkles and fine lines ^[9].

19. Niacin amide

It is commonly known as Vitamin B3 and is an effective skin lightening compound that works by inhibiting melanosome transfer from melanocytes to keratinocytes. Often this ingredient works best when combined with other skin lightening treatments. Niacin amide (Vitamin B₃) is also known to be effective in reducingacne ^[9].

20. Sugar Cane Extract

Contains Glycolic Acid to help exfoliate and renew the skin by loosening up dead cells to reveal newer, healthier, skin cells. Promotes penetration of the skin lightening actives ^[9].

21. Safflower Seed Oil

Rich in essential fatty acids. Deeply moisturizes and re-conditions, restores skin moisture balance and prevents skin dryness ^[9].

22. Salicylic Acid

A Beta Hydroxy Acid derived from the bark of the willow tree. Penetrates and exfoliates within the pores. Causes the cells of the epidermis to slough off more rapidly preventing pores from clogging up, and allowing room for new cell growth. Excellent exfoliant for acne-prone skin ^[9].

23. Squalane

Refined oil derived from olive and found to be extremely compatible with the natural oils of the skin. Squalane is very silky to the touch and easily absorbs into the skin to soften and moisturize the skin ^[9].

24. Vitamin E

Possesses strong moisturizing properties. Discourages premature aging of the skin with its strong anti-oxidant properties ^[9].

25. Watercress Extract

A perennial found near streams and springs to help regulate sebum production and regulate moisture balance have no risk of skin irritation ^[9].

Advantage of Natural Whitening Agent over Synthetic Whitening Agent

(1)Safer:

Safer alternative to using creams containing harsh chemical bleaches, AHA skin peels, or other potentially dangerous ingredients and safer for animals too since our creams do not contain animal by-products and are not tested on animals^[7-9].

(2) More Effective

More effective and more gentle on your skin than creams containing mineral oil or other substances that block skin pores ^[7-9].

(3)More Affordable

They are comparably equally priced compared to other leading brands containing the same or similar active ingredients ^[7-9].

(4) All Natural

Many of the natural skin whitening product available in the market contains nearly 100% natural base s, formulated from the ground up with a luxurious aromatherapy base that is very gentle on the skin, with added ingredients that nurture and protect the skin. Active ingredients are herbal extracts of bearberry and mitracarpe that are effective melanin inhibitors.

Application:

ü Enhances the appearance and feel of your skin.

ü Gives your skin a brighter look.

ü Makes your skin tone lighter.

ü Gives your skin a healthier look.

ü Makes your skin glow again.

ü Protects against discoloration and uneven skin tone.

In cases of vitiligo, unaffected skin may be lightened to achieve a more uniform appearance.

An additional application is genital or anal bleaching, intended to reduce the typically darker pigmentation of the genital and perianal area.

CONCLUSION:

Skin whitening products are commercially available for cosmetic purposes in order to obtain a lighter skin appearance. They are also utilized for clinical treatment of pigmentary disorders such as melasma or post inflammatory hyper pigmentation. Whitening agents act at various levels of melanin production in the skin. Many of them are known as competitive inhibitors of tyrosinase, the key enzyme in melanogenesis. Others inhibit the maturation of this enzyme or the transport of pigment granules (melanosomes) from melanocytes to surrounding keratinocytes. It was an overview of (natural) whitening and skin nourishing agents that may decrease skin pigmentation by their interference with the pigmentary processes. There are too many skin whitening agents which are capable of inhibiting tyrosinase activity but they impart harmful effects on skin and health of person so it was the need to formulate the skin whitening agent in natural form so thus the natural skin whitening agent formulated Now a days the Natural skin whitening nourishing agent becoming popular instead of synthetic whitening product, it is due to the absence of harmful chemicals and their least toxic effect. A major cosmetic industrial sector orienting towards the use of natural skin whitening agent in the formulation and thus the skin whitening pharmaceutical product are popular brands in their cosmetic market. The use of Natural skin whitening agent preventing the environment from the pollution because of less dependence and ignorance of people in using synthetic and harmful product. It provide little piece of perfection by beatifying the people specially women all over the world.

REFERENCE:

1) Jin YH, Lee SJ, Chung MH, Park JH, Park YI, Cho TH, Lee SK. Aloesin and arbutin inhibit tyrosinase activity in a synergistic manner via a different action mechanism. Arch. Pharm. Res. 1999 Jan;22(3): 232–6.

2) Muizzuddin N, Marenus KD, Mammone T, Maes DH. A novel method to study the skin-lightening effect of topical materials. J Cosmet Sci. Sep-Oct 2009; 60(5):501-8.

3) Cooksey CJ, Garratt PJ, Land EJ, Pavel S, Ramsden CA, Riley PA, Smit NP. Evidence of the indirect formation of the catecholic intermediate substrate responsible for the autoactivation kinetics of tyrosinase. J. Biol. Chem. 1997; 272: 26226–35

4) Fu B, Li H, Wang X, Lee FS, Cui S. Isolation and identification of flavonoids in Liquorice and a study of their inhibitory effects on tyrosinase. J. Agric. Food Chem. 2005; 53: 7408–14.

5) Smit NP, Peters K, Menko W, Westerhof W, Pavel S, Riley PA. Cytotoxicity of a selected series of substituted phenols towards cultured melanoma cells. Melanoma Res. 1992; 2: 295–304.

6) Friedman M. Food browning and its prevention: An overview. J. Agric. Food Chem. 1996; 44: 631–53.

7) Kim Y J, Uyama H. Tyrosinase inhibitors from natural and synthetic sources: Structure, inhibition mechanism and perspective for the future. Cell Mol. Life Sci. 2005; 62: 1707–23

8) Parvez S, Kang M, Chung HS, Bae H. Naturally occurring tyrosinase inhibitors: Mechanism and applications in skin health, cosmetics and agriculture industries. Phytother. Res. 2007; 21: 805–16.

9) Hanamura T, Uchida E, Aoki H. Skin-lightening effect of a polyphenol extract from Acerola (Malpighia emarginata DC.) fruit on UV-induced pigmentation. Biosci. Biotechnol. Biochem. 2008; 72: 3211–18.

Received on 04.03.2013 Accepted on 12.4.2013

Res. J. Topical and Cosmetic Sci. 4(1): Jan. –June 2013 page 21-25