Uses[edit]

Specific zones of abnormally high pigmentation such as moles and birthmarks may
be depigmented to match to the surrounding skin. Conversely, in cases of vitilig
o, unaffected skin may be lightened to achieve a more uniform appearance.[1][med
ical citation needed] Long term use of skin whiteners can lead to pigmentation i
ncreasing to the joints of the fingers, toes, buttocks and ears.[medical citatio
n needed] The skin of the face can become thinned and the area around the eyes c
an have increased pigmentation causing a 'bleach panda effect'.[2]
2012 sales of skin lightening creams in India alone totaled 258 tons[3] and the
global market for skin lighteners is projected to reach US $19.8 billion by 2018
based on sales growth primarily in Asia, Africa and the Middle East.[4]
Combination treatments[edit]
Most skin-lightening treatments, which can reduce or block some amount of melani
n production, are aimed at inhibiting tyrosinase. Many treatments use a combinat
ion of topical lotions or gels containing melanin-inhibiting ingredients along w
ith a sunscreen, and a prescription retinoid. Depending on how the skin responds
to these treatments, exfoliants
either in the form of topical cosmetic or chemi
cal peels
and lasers may be used. New development using LED systems are also sho
wing good results.[5][6][7][8][9]
There are various mechanisms described for achieving this. Inhibiting tyrosinase
activity reduces the synthesis of melanin so that as existing skin cells are na
turally exfoliated keratinocytes with less melanin are eventually brought to the
surface, giving the skin a lighter, more even toned complexion.[10]
Pre-melanin synthesis[edit]
Tretinoin[edit]
Research has shown that the use of tretinoin (also known as all-trans retinoic a
cid) can only be somewhat effective in treating skin discolorations.[6][11][12][
13] Users of tretinoin have to avoid sunlight, as the skin can tan. Using tretin
oin always makes the skin more sensitive to UVA and UVB rays.
During melanin synthesis[edit]
Hydroquinone[edit]
Main article: Hydroquinone
In medical literature, hydroquinone is considered the primary topical ingredient
for inhibiting melanin production.[14][15][16][17] Its components have potent a
ntioxidant abilities.[18] Topical hydroquinone comes in 2% (available in cosmeti
cs) to 4% (or more) concentrations (available from a physician or by prescriptio
n), alone or in combination with tretinoin 0.05% to 0.1%. Research has shown hyd
roquinone and tretinoin to prevent sun- or hormone-induced melasma.[6]
Hydroquinone is a strong inhibitor of melanin production, meaning that it preven
ts dark skin from making the substance responsible for skin color.[19] Hydroquin
one does not bleach the skin but lightens it, and can only disrupt the synthesis
and production of melanin hyperpigmentation. It has been banned in some countri
es (e.g. France) because of fears of a cancer risk.
Some concerns about hydroquinone's safety on skin have been expressed, but the r
esearch when it comes to topical application indicates negative reactions are mi
nor or a result of using extremely high concentrations or from other skin-lighte
ning agents such as glucocorticoids or mercury iodine. Any perceived risk is mos
t likely applicable for African women.[20] Hydroquinone has been shown to cause
leukemia in mice and other animals. The European Union banned it from cosmetics
in 2001, but it shows up in bootleg creams in the developing world. It is sold i
n the United States as an over-the-counter drug, but with a concentration of hyd
roquinone not exceeding 2 percent.[21]

Because of hydroquinone's action on the skin, it can be irritant, particularly i

n higher concentrations of 4% or greater and predictably when combined with tret
inoin. Some medications have been created that combine 4% hydroquinone with tret
inoin and a form of cortisone. The cortisone is included as an anti-inflammatory
. The negative side effect of repeated application of cortisone is countered by
the positive effect of the tretinoin so that it does not cause thinning of skin
and damage to collagen.[22] Safer alternatives are more expensive but are availa
ble.
Arbutin[edit]
Some of alternative lighteners are derived from natural sources of hydroquinone.
These include Mitracarpus scaber extract, Uva ursi (bearberry) extract, Morus b
ombycis (mulberry), Morus alba (white mulberry), and Broussonetia papyrifera (pa
per mulberry). All of these contain arbutin (technically known as hydroquinone--D
-glucoside), which can inhibit melanin production. Pure forms of arbutin are con
sidered more potent for affecting skin lightening.
Arbutin is derived from the leaves of bearberry, cranberry, mulberry or blueberr
y shrubs, and also is present in most types of pears. It can have melanin-inhibi
ting properties.[23] Arbutin and other plant extracts are considered safe altern
atives to commonly used depigmenting agents to make the skin fairer. Medical stu
dies have shown the efficiency of arbutin for skin lightening.[24][not in citati
on given] There are patents controlling its use for skin lightening. Arbutin act
ually exists in two isomers, alpha and beta. The alpha isomer offers higher stab
ility over the beta isomer and is the preferred form for skin lightening indicat
ions.[citation needed]
Kojic acid[edit]
Kojic acid is a by-product in the fermentation process of malting rice for use i
n the manufacturing of sake, the Japanese rice wine. Some research shows kojic a
cid to be effective for inhibiting melanin production.[25] However, kojic acid i
s an unstable ingredient in cosmetic formulations. Upon exposure to air or sunli
ght it can turn brown and lose its efficacy. Many cosmetic companies use kojic d
ipalmitate as an alternative because it is more stable in formulations. However,
there is no research showing kojic dipalmitate to be as effective as kojic acid
, although it is a good antioxidant. Further, some controversial research has su
ggested that kojic acid may have carcinogenic properties in large doses.[26] Oth
er further studies show that kojic acid is not carcinogenic, but can cause aller
gic contact dermatitis[27] and skin irritation.[28][29]
Azelaic acid[edit]
Azelaic acid is a component of grains, such as wheat, rye, and barley. It is app
lied topically in a cream formulation at a 10-20% concentration. Azelaic acid is
used to treat acne, but there also is research showing it to be effective for s
kin discolorations.[30] Other research also indicates azelaic acid may be an opt
ion for inhibiting melanin production.[5]
Vitamin C[edit]
Vitamin C and its various forms (ascorbic acid, magnesium ascorbyl phosphate, et
c.) are considered an effective antioxidant for the skin and help to lighten ski
n.[medical citation needed] One study[31] found it raises glutathione levels in
the body. Another study found that brownish guinea pigs given vitamin C, vitamin
E and L-cysteine, simultaneously, led to lighter skin.[32]
Glutathione[edit]
Glutathione is a tripeptide molecule found in mammalian bodies. It is an antioxi
dant that plays an important role in preventing oxidative damage to the skin.[33
] In addition to its many recognized biological functions, glutathione has also
been associated with skin lightening ability.[34] The role of glutathione as a s
kin whitening was discovered as a side effect of large doses of glutathione.[35]

Glutathione utilizes different mechanisms to exert its action as skin whitening

agent at various levels of melanogenesis. It inhibits melanin synthesis by mean
s of stopping L-DOPA s ability to interact with tyrosinase in the process of melan
in production.[36] Research result from a study [36] shows that glutathione inhi
bits the actual production as well as agglutination of melanin by interrupting t
he function of L-DOPA. Another study found that glutathione inhibits melanin for
mation by direct inactivation of the enzyme tyrosinase by binding and chelating
copper within the enzyme s active site.[37] Glutathione s antioxidant property allow
s it to inhibit melanin synthesis by quenching of free radicals and peroxides th
at contribute to tyrosinase activation and melanin formation.[38] Its antioxidan
t property also protects the skin from UV radiation and other environmental as w
ell as internal stressors that generate free radicals that cause skin damage and
hyper-pigmentation.[39] In most mammals, melanin formation consists of eumelani
n (brown-black pigment) and pheomelanin ( yellow-red pigment) as either mixtures
or co-polymers.[40] Increase in glutathione level may induce the pigment cell t
o produce pheomelanin instead of eumelanin pigments.[41] A research by Te-Sheng
Chang found lowest levels of reduced glutathione to be associated with eumelanin
type pigmentation, whereas the highest ones were associated with the pheomelani
n.[42] As a result, it is reasonable to assume that depletion of glutathione wou
ld result in eumelanin formation. Prota [43] observed that decreased glutathione
concentration lead to in the conversation of L-dopaqunione to L-dopachrome incr
easing the formation of brown-black pigment (eumelanin).