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词条 Skin whitening
释义

  1. Uses

  2. Discovery and design

  3. Mechanisms of action

     Inhibition of the activity of tyrosinase  Inhibition of the expression or activation of tyrosinase  The MC1R receptor and cAMP  Serotonin signaling  Preventing the transfer of melanosomes to keratinocytes  Directly destroying existing melanin  Destroying melanocytes  Non-pharmacological treatments 

  4. Whitening agents

     Pre-melanin synthesis  Tretinoin[68]  During melanin synthesis  Hydroquinone  Resorcinol  Arbutin  Kojic acid  Azelaic acid  Vitamin C  Glutathione  Post-melanin synthesis  Alpha hydroxy acids  Other or ungrouped treatments  Depigmenting agents  Mercury  Tranexamic acid  Other 

  5. Laser treatments

  6. Cryosurgery

  7. Adverse effects

  8. Society and culture

  9. See also

  10. Notes

  11. References

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Skin whitening, also known as lightening, brightening, depigmentation, and bleaching is the use of substances, mixtures, or physical treatments to lighten skin color. Skin whitening treatments work by reducing the skin's melanin content. Many agents have been shown to be effective in skin whitening. Some agents have beneficial side effects, including supplying antioxidants[1] or nutrients or reducing the risk of some types of cancer. Other agents are a significant risk to health, such as mercury-based methods.

Uses

Specific zones of hyperpigmentation such as lentigo spots, moles, and birthmarks may be depigmented to match the surrounding skin. In cases of vitiligo, unaffected skin may be lightened to achieve a more uniform appearance.[2]

Discovery and design

{{Expand section|date=August 2018}}

Melanogenesis inhibitors[3] have been discovered and developed using several methods. One way is through the screening of synthetic chemical libraries. This method occasionally uses high throughput screening. Another way works by screening of plant extracts by computational search[4][5] with off-label use of previously known drugs[6][7][8]{{r|Espín2001}} or exploration of structural analogues of previously known tyrosinase inhibitors.[9][10] These inhibitors are based on knowledge in varying degrees of their structure-activity relationship. The development and discovery of melanogenesis inhibitors illustrates many of the methods used in drug design. Some of the most potent competitive reversible tyrosinase inhibitors are synthetic compounds with a potency a hundreds times more than that of kojic acid.

Mechanisms of action

{{see also|melanocyte|melanin|enzyme inhibitor|skin color|hair color}}

For a review of mechanism of action of skin whitening agents, see Chang (2012){{r|Chang2012}} or Ebanks, Wickett, Boissy (2009).{{r|Ebanks2009}}

Melanin is the main substance responsible for the color of the skin. Melanin is a class of dark polymers generated by the body through the process of melanogenesis. Among the melanin pigmenting the skin and hair, two types can be distinguished based on its chemical composition and biological route of synthesis: the black and brown eumelanin and the red and yellow pheomelanin. The variation of skin color among individuals is mostly caused by variation of the content of melanin in the skin. Skin with little or no melanin is almost white. Other factors influence skin color in a lesser degree, including the amount of blood in blood vessels due to the color of blood, skin thickness, and the content of carotenoids in skin.[11][12]

Melanin in synthesized in melanosomes which are organelles produced in melanocytes, cells dedicated to this function that are present in the skin, hair follicles, and other structures of the body. The synthesis of melanin, also called "melanogenesis" and "melanization", involves a chain of enzyme-catalyzed chemical reactions and non-enzyme-catalyzed reactions.{{refn| group=notes| name=Melanin synthesis| The chemical pathways of the synthesis of melanin has been described by many papers; however, it is often oversimplified. The following references are suggested: Kondo, Hearing (2011),{{r|Kondo2011}} Chang (2009){{r|Chang2009}} and Slominski et al. (2004).{{r|Slominski2004}}}} The main precursor to melanin is L-tyrosine. The first step of melanogenesis is the conversion of L-tyrosine to L-DOPA; this is the first and rate-limiting step and is catalyzed by the enzyme tyrosinase (TYR).{{r|Slominski2004|p=1163}} Other enzymes involved in the synthesis include tyrosinase-related protein 1 (TRP1) and tyrosinase-related protein 2 (TRP2), also known as "dopachrome tautomerase" (DCT). L-tyrosine is taken by the melanocytes from the intercellular medium, then transported to the melanosomes. L-tyrosine is also synthesized within the melanocytes from L-phenylalanine by the enzyme phenylalanine hydroxylase (PAH).{{r|Slominski2004|p=1164}}

Melanosomes are transferred to keratinocytes, the most abundant cell type in the skin and where most melanin of the skin is found. Additionally, melanocytes interact with keratinocytes through chemical signaling. See § Preventing the transfer of melanosomes to keratinocytes.

Skin whitening agents work by reducing the presence of melanin in the skin. To accomplish this, there are several possible mechanism of actions:{{refn|group=notes|"In addition to inhibition of tyrosinase catalytic activity, other approaches to treat hyperpigmentation include inhibition of tyrosinase mRNA transcription, aberration of tyrosinase glycosylation and maturation, acceleration of tyrosinase degradation, interference with melanosome maturation and transfer, inhibition of inflammation-induced melanogenic response, and acceleration of skin turnover. Accordingly, a huge number of depigmenting agents or whitening agents developed by those alternative approaches have been successfully identified and deeply reviewed in many articles [references omitted]."{{r|Chang2009}}}}{{r|Ebanks2009}}

  • Inhibition of the activity of tyrosinase: The catalytic action of tyrosinase is inhibited by the skin whitening agent.
  • Inhibition of the expression or activation of tyrosinase: The antimelanogenic agent causes less tyrosinase to be generated or prevents tyrosinase from being activated to its functional form.
  • Scavenging of the intermediate products of melanin synthesis.
  • Preventing the transfer of melanosomes to keratinocytes.
  • Directly destroying existing melanin.
  • Destroying melanocytes.

Inhibition of the activity of tyrosinase

{{further|enzyme inhibitor}}

Many tyrosinase inhibitors have been discovered or developed. Many inhibitors of tyrosinase are known; most are of the reversible type.{{refn|group=notes|"In contrast to the huge number of reversible inhibitors has been identified, rarely irreversible inhibitors of tyrosinase were found until now. These irreversible inhibitors, which are also called specific inactivators, can form irreversibly covalent bond with the target enzyme and then inactivate it."{{r|Chang2009}}}} For a review of tyrosinase inhibitors, see Chang (2009).[13] Reviews of patents on tyrosinase inhibitors have been published.[13][14]

The valuation of effectivity{{refn|group=notes|"Inhibitor strength is usually expressed as the inhibitory IC50 value, which is the concentration of an inhibitor needed to inhibit half of the enzyme activity in the tested condition. However, for the tyrosinase inhibitors in the literature, the IC50 values are incomparable due to the varied assay conditions, including different substrate concentrations, varied incubation time, and different batches of commercial tyrosinase. Fortunately, in most studies conducted to discover new tyrosinase inhibitors, a well-known tyrosinase inhibitor such as kojic acid is often used as a positive standard at the same time. Hence, in order to compare the inhibitors described in different literature in a more practical manner, a relative inhibitory activity (RA), which is calculated by dividing the IC50 value of kojic acid with that of a newly found inhibitor in the same report, is used to express and compare the inhibitory strength of an inhibitor with others in this review."{{r|Chang2009}}}} is measured in the potency of reversible inhibitors, usually given in terms of its IC50. The IC50 is highly dependent on assay conditions, making it incomparable among different assays, unless designed to be comparable. It is customary practice in studies of tyrosinase inhibitors to assay one or several well known inhibitors as a positive control and point of comparison. The relative activity (RA) of a compound under investigation is its activity divided by the activity of the positive control; in turn, the activity of a compound is usually defined as 1/IC50. The RA is less dependent on the assay conditions of the IC50 and is suitable to compare the results of different assays, provided that the same positive control was used. The positive control is commonly kojic acid.

Upregulation of tyrosinase caused by tyrosinase inhibitors. Several skin whitening agents, including tyrosinase inhibitors, have been found to cause an increase in the expression of tyrosinase, which by itself would increase melanin synthesis.[15]{{r|Chang2012}}

Irreversible inhibitors of tyrosinase include N-nonyl trans-caffeate;[16] α-Na8SiW11CoO40, a polyoxometalate;[17] a structural analog of aloe emodin;[18] structural analogues of barbituric acid;[19][20][21] structural analogues of chalcone;[22] sodium hydrogen sulfite;[23] structural analogues of coumarin;[24] structural analogues of benzene-1,2-diamine and 2-aminophenol; 2,3-dihydroxybenzoic acid;[25] tetrahydrofolic acid;[26] analogues of pyrimidine and rhodanine;[27] tetrahydropterines;[28] cardol triene, a triene analogue of cardol extracted from cashew;[29] N-(3,5-dihydroxybenzoyl)-6-hydroxytryptamine;[30] aminoethylisothiourea;[31] 8-hydroxynaringenin;[32] NADH;[33] 8-hydroxydaidzein;[34] and captopril.{{r|Espín2001}}

Inhibition of the expression or activation of tyrosinase

{{see also|transcription factor|hormone|receptor (biochemistry)}}Microphthalmia-associated transcription factor (MITF) is the master transcription factor that controls the expression of TYR, TRP1 and TRP2, MART1, PMEL17, and many other important proteins involved in the function of melanocytes.{{refn|group=notes|name=MITF|"The transcriptional level is the first stage by which the expression of tyrosinase and related melanogenic enzymes may be modulated. Influential in this process, the microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor that regulates melanocyte cellular differentiation as well as the transcription of melanogenic enzymes (tyrosinase, TYRP1 and TYRP2) and melanosome structural proteins (MART-1 and PMEL17) [references omitted]."{{r|Ebanks2009}}

"In addition to being involved in the survival, proliferation, and differentiation of melanocytes, MITF is the master regulator of melanogenesis in melanocytes via binding to the M box of a promoter region and regulating the gene expression of tyrosinase, TRP-1, and TRP-2 [references omitted]. The up-regulation of MITF activity activates the expression of the melanogenesis-related enzymes, thus stimulating melanogenesis. In contrast, the down-regulation of MITF activity depresses the expression of the related enzymes, thereby inhibiting melanogenesis."{{r|Chang2012}}}} Downregulation of MITF decreases melanogenesis{{r|group=notes|MITF}} and is a mechanism of action of some skin whitening agents.{{r|Chang2012}}{{r|Smit2009}} As an heuristic rule, agents acting through downregulation of MITF are more likely to have side effects than selective tyrosinase inhibitors.{{refn|group=notes|"Because tyrosinase is produced only by melanocytic cells, tyrosinase inhibitors have highly specific targeting to melanogenesis in the cells without other side effects. In contrast, those melanogenesis inhibitors targeting to the tyrosinase gene expressions or protein degradations are rarely used as clinical hypopigmenting agents, due to their non-specific and global effects via intracellular signaling pathways."{{r|Chang2012}}}} Various signaling pathways and genetic mutations influence the expression of MITF.{{refn|group=notes|name=Signaling pathways|Many papers have described the signaling pathways affecting melanogenesis and other functions of melanocytes. The following reviews are suggested reading (all of which are available online at no cost):

For a description with emphasis on the relation with skin whitening, see Chang (2012){{r|Chang2012}} or Smit, Vicanova, Pavel (2009).{{r|Smit2009}} For a description with emphasis on physiology, see Yamaguchi, Hearing (2009){{r|Yamaguchi2009}} or Kondo (2011).{{r|Kondo2011}} For a description of intra-melanocyte signaling pathways, see Imokawa, Ishida (2014).{{r|Imokawa2014}} An extensive and detailed review was written by Slominski et al. (2004).{{r|Slominski2004}}}}[35][36]

Inhibitors of melanogenesis whose mechanism of action includes reducing the genetic expression of melanogenic enzymes include caffeoylserotonin,[37] AP736,[38] pomegranate extract,[39] and betulinic acid,extracted from Vitis amurensis root.[40]

The MC1R receptor and cAMP

The melanocortin 1 receptor (MC1R) is a transmembrane and G-protein coupled receptor expressed in melanocytes. MC1R is an important target for the regulation of melanogenesis.{{r|Chen2014}}{{r|Rodríguez2014}}{{r|Yamaguchi2009}} Agonism of MC1R increases the ratio of eumelanin to pheomelanin and increases the generation of melanin overall.

The MC1R and cAMP signaling pathway{{r|group=notes|Signaling pathways}}{{r|group=notes|MC1R}}{{r|Chen2014}}{{r|Rodríguez2014}}{{r|Lee2013}} starts with the activation of MC1R, which causes activation of adenylyl cyclase (AC), which produces cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA), which activates by protein phosphorylation cAMP response element-binding protein (CREB), which upregulates MITF, of which CREB is a transcription factor. Whitening agents that interfere with the pathway have been reviewed by Chang (2012).{{r|Chang2012}}

cAMP is degraded by phosphodiesterases (PDE). The PDE5 inhibitors sildenafil and vardenafil, the cAMP-promoter IBMX, and 8-CPT-cGMP, a cyclic guanosine monophosphate (cGMP) analogue, increase melanin synthesis.[41]

Alpha-melanocyte stimulating hormone (α-MSH),{{refn|group=notes|name=MC1R|"Alpha melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), regulates melanogenesis via a cyclic adenosine monophosphate (cAMP)-dependent pathway [references omitted]. When binding to its receptor, melanocortin receptor 1 (MC1R), on the membrane of melanocytes, the hormone activates adenylate cyclase (AC) to produce cAMP as an intracellular second message via a G-protein-coupled receptor (GPCR)-type activation. cAMP activates protein kinase A (PKA), which then activates the gene expression of MITF via phosphorylation of the cAMP response element-binding protein (CREB). Finally, MITF efficiently activates the melanogenesis-related enzymes and stimulates melanogenesis. Once α-MSH binds to MC1R, up to a 100-fold increase in melanogenesis attends. In addition to α-MSH, other POMC-derived peptides, such as β-MSH and adrenocorticotropic hormone (ACTH), also stimulate melanogenesis via the same pathway."{{r|Chang2012}}

"α-MSH binding to melanocortin 1 receptor (MC1R) on melanocytes in the basal epidermis generates the second messenger cAMP via interactions between MC1R and adenylyl cyclase, and leads to activation of protein kinase A and the cAMP responsive binding element (CREB) and microphthalmia (Mitf) transcription factors. CREB and Mitf directly enhance melanin production by raising levels of tyrosinase and other melanin biosynthetic enzymes. Thus, MSH-MC1R signaling leads to enhanced pigment synthesis by melanocytes and accumulation of melanin by epidermal keratinocytes.
[etcetera]
The MC1R is found on the surface of melanocytes where it binds to α-melanocyte stimulating hormone (MSH) and transmits differentiation signals into the cell through activation of adenylyl cyclase and generation of cAMP [references omitted]. cAMP signaling leads to activation of the protein kinase A (PKA) cascade which, in turn, leads to increased levels and/or activity of many melanogenic enzymes to enhance production and export of melanin by melanocytes [references and figure omitted]."{{r|D'Orazio2013}}}} beta-melanocyte stimulating hormone (β-MSH), and adrenocorticotropic hormone are endogenous agonists of MC1R.{{r|Slominski2004|p=1175}} Agouti signaling protein (ASIP) appears to be the only endogenous antagonist of MC1R.{{refn|group=notes|The assertion that ASIP is the only endogenous antagonist is found in Yamaguchi, Hearing (2009).{{r|Yamaguchi2009}}}} Synthetic MC1R agonists have been designed, such as the peptides afamelanotide and melanotan II.{{r|Chen2014}}

Mutations of the MC1R gene correlate and are at least partially responsible for red hair, white skin, and an increased risk for skin cancer in some individuals.{{refn|group=notes|"Loss-of-signaling MC1R polymorphisms are commonly found among fair-skinned, sun-sensitive and skin cancer-prone populations (e.g., Northern Europeans). The most prevalent MC1R mutations (D84E, R151C, R160W and D294H) are commonly referred to as “RHC” (red hair color) alleles because of their association with red hair color, freckling and tendency to burn after UV exposure [references omitted]."{{r|D'Orazio2013}}}}{{r|Chen2014}}[42]{{r|Rodríguez2014}}[43]{{r|Nelson2009}}[44][45][46]{{r|Slominski2004|p=1175}}

Serotonin signaling

Melanocytes express serotonin receptors and are capable of producing serotonin. Pharmacological interference with the serotonin system of melanocytes can result in either increased or decreased melanin synthesis. Serotonin itself is a weak inhibitor of tyrosinase[47] with 0.11 times the potency of kojic acid.{{refn|group=notes|1=Computed from the data reported by Yamazaki et al. (2009):{{r|Yamazaki2009}} IC50(serotonin)=550 µmol/l. IC50(kojic acid)=68 µmol/l.}} Nonetheless, serotonin increases synthesis of melanin when its overall effect on melanocytes, as opposed to isolated tyrosinase, is evaluated.[48] Activation of 5-HT2B receptors with BW-723C86 inhibits melanogenesis,[49] while activation of 5-HT2A receptors with the amphetamine structural analog DOI promotes melanogenesis.[50] The serotonin reuptake inhibitor (SRI) 6-nitroquipazine inhibits melanogenesis in vitro.[51]

Preventing the transfer of melanosomes to keratinocytes

{{see also|human skin#Structure|epidermis}}

Within the skin, melanocytes are present in the basal layer of the epidermis; from these melanocytes originate dendrites that reach keratinocytes.{{refn|group=notes|name=Keratinocytes|"In the skin, melanocytes are situated on the basal layer which separates dermis and epidermis. One melanocyte is surrounded by approximately 36 keratinocytes. Together, they form the so-called epidermal melanin unit. The melanin produced and stored inside the melanocyte in the melanosomal compartment is transported via dendrites to the overlaying keratinocytes."{{r|Smit2009}}

"Each melanocyte resides in the basal epithelial layer and, by virtue of its dendrites, interacts with approximately 36 keratinocytes to transfer melanosomes and protect the skin from photo-induced carcinogenesis. Furthermore, the amount and type of melanin produced and transferred to the keratinocytes with subsequent incorporation, aggregation and degradation influences skin complexion coloration [reference omitted]."{{r|Ebanks2009}}

Wu, Hammer (2014) describe the number of keratinocytes per melanocyte as above 40.{{r|Wu2014}}}} Keratinocytes are the most abundant cell type in the epidermis.{{refn|group=notes|"Keratinocytes are the most abundant cells in the epidermis and are characterized by their expression of cytokeratins and formation of desmosomes and tight junctions with each other to form an effective physicochemical barrier."{{r|D'Orazio2013}}}} In the skin, there are approximately 36 keratinocytes per melanocyte.{{r|group=notes|Keratinocytes}} Keratinocytes are continuously generated in the basal layer of the epidermis and displace older keratinocytes of the skin towards the surface.

Melanosomes along with the melanin they contain are transferred from melanocytes to keratinocytes when keratinocytes are low in the epidermis.{{refn|group=notes|Research about the mechanism of melanosome transfer has been reviewed by Wu, Hammer (2014).{{r|Wu2014}}}} Keratinocytes carry the melanosomes with them as they move towards the surface. Keratinocytes contribute to skin pigmentation by holding the melanin originated in melanocytes and inducing melanogenesis through chemical signals directed at melanocytes.{{r|group=notes|Signaling pathways}} The transfer of melanosomes to keratinocytes is a necessary condition for the visible pigmentation of the skin.{{r|Wu2014}} Blocking this transfer is a mechanism of action of some skin whitening agents.{{r|Smit2009}}{{r|Ebanks2009}} Skin whitening agents that block melanocyte transfer include niacinamide, heparin,{{r|Makino-Okamura2014}} madecassoside,{{r|Jung2013}} soybean,[52] and Saccharomyces cerevisiae, a species of yeast.[53]

The protease-activated receptor 2 (PAR2) is a transmembrane and G-protein coupled receptor expressed in keratinocytes and involved in melanocyte transfer.{{refn|group=notes|"Protease-activated receptor (PAR)-2 is a member of a novel G-protein-coupled seven-transmembrane receptor family. In epidermis, PAR-2 is expressed in keratinocytes [references omitted], but not melanocytes [references omitted]. A central role for PAR-2 in keratinocyte uptake of melanosomes has been established [references omitted]. PAR-2 has been linked to the upregulation of COX-2 and the release of arachidonic acid and secretion of PGE2 and PGF2α [references omitted]. Several reports have suggested that PAR-2 mediates cutaneous pigmentation through increased uptake of melanosomes by keratinocytes and by the release of PGE2 and PGF2α that stimulate melanocyte dendricity [references omitted]."{{r|Jung2013}}}}{{refn|group=notes|name=PAR2|References about PAR2 and its role in skin pigmentation: Kim et al. (2016),[54] Choi et al. (2014),[55] Makino-Okamura et al. (2014),{{r|Makino-Okamura2014}} Wu, Hammer (2014),{{r|Wu2014}} Ando et al. (2012),[56] Ando et al. (2010).[57]}} Antagonists of PAR2 inhibit the transfer of melanosomes and have skin whitening affects, while agonists of PAR2 have the opposite effect.{{r|group=notes|PAR2}} The common endogenous agonists of PAR2 are serine proteases, which irreversibly activate PAR2 by cleaving a part of the extracellular terminal of this receptor, thereby exposing a part of it that subsequently works as a ligand tethered to the reset of the receptor at the molecular scale. Some synthetic agonists of PAR2 are short peptides that imitate the tethered ligand but do not cleave the extracellular terminal.

Directly destroying existing melanin

Several species of fungi produce enzymes that reduce pigmentation by degrading melanin.[58] These enzymes often require the presence of hydrogen peroxide and sometimes the presence of Mg+2 ions to work.{{r|Nagasaki2008}} They have been proposed as a safer alternative to hydrogen peroxide for cosmetic hair depigmentation.{{r|Nagasaki2008}}

The enzyme lignin peroxidase produced by the fungus phanerochaete chrysosporium has been studied as an ingredient suitable for skin-whitening. A double-blind, placebo-controlled, split-face, randomized study found this enzyme to be effective and superior to hydroquinone in skin whitening.[59] In a non-controlled study, this enzyme was applied to volunteers with facial melasma during 8 weeks; the treatment was found effective in reducing pigmentation in both skin affected by melasma and skin unaffected by melasma.[60]

Destroying melanocytes

Some compounds are known to destroy melanocytes; this mechanism of action is often used to remove the remaining pigmentation in cases of vitiligo.[61][62]

Non-pharmacological treatments

Most skin-lightening treatments, which can reduce or block some amount of melanin production, are aimed at inhibiting tyrosinase. Many treatments use a combination of topical lotions or gels containing melanin-inhibiting ingredients along with a sunscreen, and a prescription retinoid. Depending on how the skin responds to these treatments, exfoliants, either in the form of topical cosmetic or chemical peels, and lasers may be used. New development using LED systems are also showing effectiveness.[64][63][64][65]

Whitening agents

Pre-melanin synthesis

Tretinoin[68]

The use of tretinoin, also known as all-trans retinoic acid, can only be somewhat effective in treating skin discolorations.[66][67][68][69] Users of tretinoin have to avoid sunlight, as the skin can tan. Using tretinoin makes the skin more sensitive to UVA and UVB rays.

During melanin synthesis

Hydroquinone

{{Main|Hydroquinone}}

Hydroquinone is considered the primary topical ingredient for inhibiting melanin production.[70][71][72][73] Its components have potent antioxidant abilities.[74] Topical hydroquinone comes in 2% available in cosmetics, often as monobenzone, to 4% or greater concentrations available from a physician or by prescription, alone or in combination with tretinoin 0.05% to 0.1%. Hydroquinone and tretinoin prevent sun- or hormone-induced melasma.[66]

Hydroquinone is a strong inhibitor of melanin production; it prevents dark skin from making the substance responsible for skin color.[75] Hydroquinone 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 European countries, for example France, because of fears of a cancer risk. However, other European countries, such as Spain, have both prescription and nonprescription formulations.[76]

Some concerns about hydroquinone's safety on skin have been expressed, but the research when it comes to topical application indicates that negative reactions are minor or a result of using extremely high concentrations of hydroquinone or from other skin-lightening agents such as glucocorticoids or mercury iodine. Any perceived risk is most likely applicable for African women.[77] Hydroquinone has been shown to cause leukemia in mice and other animals. The European Union banned it from cosmetics in 2001, but it is found in bootleg creams in the developing world. It is sold in the United States as an over-the-counter drug with the concentration of hydroquinone not exceeding two percent.

Because of hydroquinone's action on the skin, it can be an irritant, particularly in higher concentrations of 4% or greater and when combined with tretinoin. Some medications have created that combine 4% hydroquinone with tretinoin and a form of cortisone, 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 the skin and damage to collagen.[78]

Resorcinol

Resorcinol, or m-hydroquinone, is often used in skin-lightener cosmetics in countries where free hydroquinone is prohibited.

Arbutin

Some alternative skin lighteners are derived from natural sources of hydroquinone. These include Mitracarpus scaber extract, Uva ursi (bearberry) extract, Morus bombycis (mulberry) extract, Morus alba (white mulberry) extract, and Broussonetia papyrifera (paper mulberry) extract. All of these contain arbutin, technically known as hydroquinone-β-D-glucoside, which can inhibit melanin production. Pure forms of arbutin are considered more potent for affecting skin lightening.

Arbutin is derived from the leaves of bearberry, cranberry, mulberry, or blueberry shrubs, and also is present in most types of pears. It can have melanin-inhibiting properties.[79] Arbutin and other plant extracts are considered safe alternatives to commonly used depigmenting agents to make the skin fairer. Medical studies have shown the efficiency of arbutin for skin lightening.[80]{{failed verification|date=December 2013}} Patents exist that control its use for skin lightening. Arbutin exists in two isomers, alpha and beta. The alpha isomer offers higher stability over the beta isomer and is the preferred form for skin lightening indications.

Kojic acid

Kojic acid is a by-product in the fermentation process of malting rice for use in the manufacturing of sake, the Japanese rice wine. Some research shows kojic acid to be effective for inhibiting melanin production.[81] However, kojic acid is an unstable ingredient in cosmetic formulations. Upon exposure to air or sunlight, it can turn brown and lose its efficacy. Many cosmetic companies use kojic dipalmitate 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 an antioxidant. Further, some controversial research has suggested that kojic acid may have carcinogenic properties in large doses.[82] Other further studies show that kojic acid is not carcinogenic but can cause allergic contact dermatitis[83] and skin irritation.[84]

Azelaic acid

Azelaic acid is a component of grains, such as wheat, rye, and barley. It is applied 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 skin discolorations.[85] Other research also indicates that azelaic acid may be an option for inhibiting melanin production.[86]

Vitamin C

Vitamin C and its various forms, including ascorbic acid and magnesium ascorbyl phosphate, etc.) are considered an effective antioxidant for the skin and help to lighten skin.{{medcn|date=December 2013}} One study[87] found it raises glutathione levels in the body. Another study found that brownish guinea pigs given vitamin C, vitamin E and L-cysteine, simultaneously, had their skin lightened.[88]

Glutathione

Glutathione is a tripeptide molecule found in mammalian bodies. It is an antioxidant that plays an important role in preventing oxidative damage to the skin. In addition to its many recognized biological functions, glutathione has also been associated with skin lightening ability. Amongst the many mechanisms postulated to contribute to its antimelanogenic properties, inhibition of tyrosinase enzyme, skewing of melanogenesis from the darker eumelanin to the lighter phaeomelanin, and scavenging of free radicals seem to be the most important. While skin whitening reduces melanin which serves as the natural protection from UV exposure, glutathione's antioxidant property also protects the skin from UV radiation.

A double-blind placebo-controlled study found glutathione to be effective as a skin whitening agent and in reducing dark spots; the dose regime was 500 mg per day, split in two equal doses per day, for two to four weeks.[89] In contrast, a study that examined the effect of glutathione and related compounds in vitro found that glutathione monoethyl ester but not glutathione had a depigmenting effect.[90] A review of the use of glutathione for skin whitening was published in 2016.[91]

Glutathione is an ingredient in some cosmetics preparations. [https://thehealthbase.com/glutathione-skin-whitening-soap/ Glutathione for skin whitening] is available in cream, soap, lotion, nasal spray, and [https://www.beskinformed.com/skin-whitening/injections-for-skin-lightening/ injectable form]. Glutathione that is applied on the skin in the form of lotion is not efficiently absorbed by the skin cells as the thiol group undergoes rapid formation of disulfide. When taken orally, glutathione is hydrolyzed by enzymes in the gastrointestinal tract resulting in reduced bioavailability. The level of glutathione is increased in small amounts temporarily when large oral doses are administered.[92] As a result, the effectiveness of externally administered glutathione is slowed down by its inability to cross cell membranes efficiently and its rapid degradation by enzymes in the gastrointestinal tract. On the contrary, intravenous glutathione delivers very high doses directly into the systemic circulation and is the preferred mode of administering glutathione. However, this method of administrating the antioxidant might flood the cells with glutathione, which may cause reductive stress. This might expose the user to potential health risks associated with long-term use of high doses of glutathione. Of all the glutathione products, the glutathione tablet remains the most effective type.

Glutathione can be combined with many other agents like Vitamin C to increase its absorption, N-acetyl cysteine to boost its level, and other antioxidants like Vitamin E. Oral intake of glutathione could be harmful when combined with other skin whitening agents such as hydroquinone, which is a carcinogenic element, and monobenzone, which causes irreversible depigmentation.

Post-melanin synthesis

Alpha hydroxy acids

Alpha hydroxy acids (AHAs) are primarily in the form of lactic acid and glycolic acid and are the most researched forms of AHAs because they have a molecular size that allows effective penetration into the top layers of skin. It is generally assumed that in and of themselves AHAs in concentrations of 4% to 15% are not effective for inhibiting melanin production and will not lighten skin discolorations in that manner. It is believed that their benefit is in helping cell turnover rates and removing unhealthy or abnormal layers of superficial exfoliant skin cells where hyperpigmented cells can accumulate. However, other research has shown that lactic and glycolic acids can indeed inhibit melanin production separate from their actions as an exfoliant on skin.[93]Alpha hydroxy acid peels using concentrations of 50% or greater may remove skin discolorations.[94]

Other or ungrouped treatments

Depigmenting agents

{{Unreferenced section|date=August 2018}}

Most commonly, depigmentation of the skin is linked to people born with vitiligo, which produces differing areas of light and dark skin. These individuals, if they so decide to use a lightening process to even out their skin tone, can apply a topical cream containing the organic compound monobenzone to lessen the remaining pigment. Monobenzone may cause destruction of melanocytes and permanent depigmentation. An alternate method of lightening is to use the chemical mequinol over an extended period of time. Increasingly, people who are not afflicted with the vitiligo experiment with lower concentrations of monobenzone creams in the hope of lightening their skin tone evenly. However, monobenzone is not recommended for skin conditions other than vitiligo.

Mercury

Many skin whiteners contain a form of toxic mercury as the active ingredient, such as mercury(II) chloride or ammoniated mercury. However, mercury has been banned in most countries for use in skin whitening because it accumulates on the skin and can have the opposite results in the long term. As late as January 2016, the FDA published a warning not to use a particular brand of whitener, Viansilk's Crema Piel De Seda (Silky Skin Cream), sold in the United States due to its mercury content.[95]

Tranexamic acid

Tranexamic acid is sometimes used in skin whitening as a topical agent, injected into a lesion, and taken by mouth, both alone and as an adjunct to laser therapy; as of 2017 its safety seemed reasonable but its efficacy for this purpose was uncertain because there had been neither large scale randomized controlled studies nor long term follow-up studies.[96][97]

Other

Other options with some amount of research regarding their potential skin lightening abilities are licorice extract, specifically glabridin.

There is also some research showing that oral supplements of pomegranate extract, ellagic acid, vitamin E, and ferulic acid can inhibit melanin production.[98]

Laser treatments

Both ablative and nonablative lasers can have a profound effect on melasma{{Citation needed|date=June 2010}}. However, the results are not always consistent, and problems have been reported, such as hypopigmentation or hyperpigmentation. Laser treatments of this kind are more likely to result in problems for those with darker skin tones.[99]

Cryosurgery

Another alternative to laser treatment is cryosurgery using liquid nitrogen. Controlled destruction of skin cells causes the skin to naturally regenerate itself. Excess melanin comes to the surface and peels off in a few days. This is particularly useful in sensitive areas like the genitals where laser treatment could leave a scar. Efficacy of the treatment depends on the depth of the pigment.[100]

Adverse effects

There is evidence to suggest that some types of skin-whitening products use active ingredients, such as mercurous chloride and hydroquinone, which can be harmful. Hydroquinone is not available without a prescription in Europe. This is also the case in many other countries where hydroquinone can only be prescribed by a doctor for certain skin conditions.

A test of common skin lightening creams available in Nigeria showed that they caused mutations in bacteria and were possibly carcinogenic.[101] A study that examined skin whitening creams in Mexico found a high concentration of mercury in several of them.[102]

Society and culture

In India, the sales of skin lightening creams in 2012 totaled around 258 tons, and in 2013 sales were about US$300 million.[103][104] As of 2013, the global market for skin lighteners was projected to reach $19.8 billion by 2018 based on sales growth primarily in Africa, Indian-Asia, and the Middle East.[105]

In the United Kingdom, many skin whiteners are illegal due to possible adverse effects. Such products are frequently still sold even after shops have been prosecuted. Trading standards departments lack resources to deal with the problem effectively.[106]

See also

  • Procedures
    • Anal bleaching
    • Ethnic plastic surgery
    • Tooth bleaching
    • Depigmentation
    • Taxifolin
    • Facial
    • Sun tanning
    • Xeesal
  • Diseases
    • Vitiligo
    • Albinism
    • Hypopigmentation
    • Hyperpigmentation
  • Culture
    • White skin
    • Colorism
    • Shadism
    • Venetian Ceruse{{snd}} white lead based cosmetic worn by Elizabeth I of England
    • Racial whitening
    • Whiteness in Japanese culture
    • Colonial mentality

Notes

Italics have been preserved whenever they appear in quotations. Text between square brackets are additional notes not present in the source.

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References

{{reflist|refs=[107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122][123]
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