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Skin Lightening and Depigmenting Agents กระบวนการทำงานของกลูตาไทโอน
Skin Lightening and Depigmenting Agents
Author: Bernardita Policarpio, MD,, Consultant, Department of Dermatology, University of Santo Tomas Hospital; Visiting Staff, Division of Dermatology, The Medical City Hospital, Manila, Philippines
Coauthor(s): Harvey Lui, MD, FRCPC, Professor and Head, Department of Dermatology and Skin Science, Vancouver General Hospital, University of British Columbia; Medical Director, The Skin Centre, Lions Laser Skin Centre and Psoriasis and Phototherapy Clinic, Vancouver General Hospital
Contributor Information and Disclosures
Updated: Oct 26, 2009

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Depigmenting agents are commonly prescribed to treat disorders of hyperpigmentation. In this article, a review is presented of several notable depigmenting agents reported in the literature. Although some of these topical agents are available only in certain research institutions, a growing number of products can be used by physicians as part of an armamentarium for treating disorders of hyperpigmentation. Recent advances in the field of cosmetic dermatology have developed lasers as another modality for the treatment of hyperpigmentation.

A basic understanding of the pigmentation pathway is helpful prior to a discussion of various skin-lightening agents and their known mechanisms of action. The type and amount of melanin synthesized by the melanocyte and its distribution pattern in the epidermis determines the actual color of the skin. Melanin forms through a series of oxidative reactions involving the amino acid tyrosine and the enzyme tyrosinase.

The first step is the most critical because the remainder of the reaction sequence can proceed spontaneously at physiological pH. Here, tyrosinase converts tyrosine to dihydroxyphenylalanine (DOPA) and then to dopaquinone. Subsequently, dopaquinone is converted to dopachrome through auto-oxidation, and, finally, to dihydroxyindole or dihydroxyindole-2-carboxylic acid (DHICA) to form eumelanin (black-brown pigment). The latter reaction occurs in the presence of dopachrome tautomerase and DHICA oxidase. In the presence of cysteine or glutathione, dopaquinone is converted to cysteinyl DOPA or glutathione DOPA. Subsequently, pheomelanin, a yellow-red pigment, is formed.

One study suggests a novel method of testing multiple topical skin-lightening methods prior to initiating therapy, using UV-induced skin tanning.1

Concern has been raised regarding some commercial lightening products, related to mercury content. Allergic contact dermatitis was attributed to mercury in one report,2 and another described high concentrations of mercury in the ovaries of mice exposed to the skin-lightening cream.3 Further study is warranted before conclusions can be made.


Determining the cause of the hyperpigmentation is important in selecting the best approach for treatment. Based on the history and clinical findings of the patient, the etiology of the hyperpigmentation may include postinflammatory hyperpigmentation, drugs, photosensitizing agents, ultraviolet light, or systemic disease (eg, Addison disease, liver disease, pregnancy, pituitary tumors). In order to adequately treat the pigmentary disorder, the causative agent should be determined and managed.

Hyperpigmentation is treated with the application of topical agents and/or with laser treatments. Therapy with topical skin-lightening products and laser treatments may take weeks to several months before any significant difference is noted. During the treatment phase, patients should avoid the sun by using sun-protective clothing and sunscreen to decrease the likelihood of pigmentary changes induced by UV light.

Common Topical Treatments


An important industrial chemical, hydroquinone is also a ubiquitous chemical readily available in cosmetic and nonprescription forms for skin lightening. It is considered one of the most effective inhibitors of melanogenesis in vitro and in vivo. Hydroquinone causes reversible inhibition of cellular metabolism by affecting both DNA and RNA synthesis. The cytotoxic effects of hydroquinone are not limited to melanocytes, but the dose required to inhibit cellular metabolism is much higher for nonmelanotic cells than for melanocytes. Thus, hydroquinone can be considered a potent melanocyte cytotoxic agent with relatively high melanocyte-specific cytotoxicity. Hydroquinone is also a poor substrate of tyrosinase, thereby competing for tyrosine oxidation in active melanocytes.

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. Concentrations as high as 10% can be compounded extemporaneously for refractory cases. 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. Two known inhibitors of glutathione, cystamine and buthionine sulfoximine, have also been reported useful for their enhancement of the inhibitory effect of hydroquinone on pigmentation. The authors of the study reported a synergistic decrease in hair pigmentation when a combination of hydroquinone (2% or 4%) and buthionine sulfoximine (5%) was applied to the dorsal skin of mice.

Monobenzyl ether of hydroquinone

Similar to hydroquinone, monobenzyl ether of hydroquinone (MBEH) belongs to the phenol/catechol class of chemical agents. Unlike hydroquinone, MBEH almost always causes nearly irreversible depigmentation of the skin. Traces of MBEH have been found in disinfectants, germicides, rubber-covered dish trays, adhesive tape, powdered rubber condoms, and rubber aprons. In dermatology, MBEH should only be used to eliminate residual areas of normally pigmented skin in patients with refractory and generalized vitiligo. The suggested mechanism of depigmentation of MBEH is selective melanocytic destruction through free-radical formation and competitive inhibition of the tyrosinase enzyme system.

Azelaic acid

A naturally occurring, saturated dicarboxylic acid originally isolated from Pityrosporum ovale, azelaic acid is a rather weak competitive inhibitor of tyrosinase in vitro. 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, it has been successfully used in the treatment of lentigines, rosacea, and postinflammatory hyperpigmentation. It is prescribed topically as a 20% cream and has been combined with glycolic acid (15% and 20%). 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.

Kojic acid (5-hydroxy-4-pyran-4-one-2-methyl)

A fungal metabolic product, kojic acid inhibits the catecholase activity of tyrosinase, which is the rate-limiting, essential enzyme in the biosynthesis of the skin pigment melanin. Kojic acid is also consumed widely in the Japanese diet, with the belief that it is of benefit to health. Indeed, it has been shown to significantly enhance neutrophil phagocytosis and lymphocyte proliferation stimulated by phytohemagglutinin. Melanocytes treated with kojic acid become nondendritic, with a decreased melanin content. Additionally, 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.

Mequinol (4-hydroxyanisole)

Similar to hydroquinone, 4-hydroxyanisole (4HA) is cytotoxic to melanocytes. Reports indicate it is clinically effective in inhibiting melanogenesis when used as a combination of 2% 4HA cream and 0.01% retinoic acid. The authors reported minimal local skin irritation with this combination. Two percent 4HA alone did not produce significant hypopigmentation. Mequinol is used in Europe in concentrations ranging from 5-20% and is approved in the United States for the treatment of solar lentigines.


Retinoids such as tretinoin and adapalene are derivatives of vitamin A. The mechanisms for reducing pigmentation include inhibition of tyrosinase induction, interference with pigment transfer, and acceleration of epidermal turnover. They also have the ability to disperse pigment granules within keratinocytes. Retinoids may act as penetration enhancers when used with other lightening agents such as hydroquinone and mequinol. 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%. In a study on a white population, 0.1% tretinoin used as monotherapy reduced the over all severity of melasma by 36% compared with its vehicle.4,5


Niacinamide is the biologically active form of vitamin B-3. It suppresses the transfer of melanosomes to the epidermal keratinocytes. Early studies show 35-68% inhibition of melanosomes in culture models with 1 mmol L-1 niacinamide for 12 days. Niacinamide with retinyl palmitate has been shown to improve hyperpigmentation and increase skin lightening after 4 weeks of treatment compared with vehicle alone.6,7


Soy proteins contain serine protease inhibitors that inhibit the activation of the protease activated receptor–2 pathway (PAR-2). The PAR-2 pathway is important for keratinocyte phagocytosis of melanosomes and melanosome transfer. By inhibiting this pathway, reduction of melanin transfer produces a lightening effect. Improvement of hyperpigmentation was seen after 12 weeks of twice-daily application of unpasteurized soy milk, with minimal adverse effects.5,8,9

Chemical peels

The mechanism of action of chemical peels agents is to accelerate epidermal turnover and remove melanized keratinocytes, leading to loss of melanin granules. Postinflammatory hyperpigmentation is the most common complication, especially in dark-skinned individuals. Other adverse reactions include postpeel erythema, infection, and aggravation of melasma.

Exfoliants such as alpha-hydroxy acids have been shown to lighten melasma, solar lentigines, and postinflammatory hyperpigmentation. Glycolic acid is derived from sugar cane and 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.10,11

Other chemical peels include 50% trichloroacetic acid (TCA) peels and 20-30% salicylic acid peels used for various pigmentary disorders, including melasma, on darker skin types. A clinical trial on TCA peels in 20 patients with melasma reported 55% of patients experienced good clinical response, with no significant complications reported.12 Superficial and medium-depth peels with salicylic acid have shown efficacy and were well tolerated in darker skin types when combined with hydroquinone.10,13

Alternative Treatments

Arbutin (hydroquinone-beta-D-glucopyranoside)

A glycosylated hydroquinone found at high concentrations in certain plants and capable of surviving extreme and sustained dehydration, 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. Because arbutin does not hydrolyze to liberate hydroquinone, the latter agent is not responsible for the inhibitory effect of arbutin on melanogenesis. Inhibition of melanin synthesis (approximately 39%) occurs at a concentration of 5 X 105 mol/L.

Although the effective topical concentration for treating disorders of hyperpigmentation has not been formally evaluated and published, several manufacturers are marketing arbutin as a depigmenting agent. Several studies have shown that arbutin is less effective than kojic acid for the treatment of hyperpigmentation. Some manufacturers report arbutin as an effective depigmenting agent at a 1% concentration.14,15

Paper mulberry

This tyrosinase inhibitor was isolated from a plant herbal extract. The plant roots from which paper mulberry was isolated were collected in Korea. A comparison of the tyrosinase inhibition of paper mulberry with kojic acid and hydroquinone reveals that the IC50 (ie, the concentration causing 50% inhibition of the activity of tyrosinase) is 0.396%, compared with 5.5% for hydroquinone and 10% for kojic acid. The authors also performed a patch test using 1% paper mulberry extract and found no significant irritation at either 24 hours or 28 hours.16

Glabridin (licorice extract)

Glabridin is the main ingredient in licorice extract. 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. A combination product of 0.4% licorice extract, 0.05% betamethasone, and 0.05% retinoic acid was effective in the treatment of melasma. This treatment is not currently available in the United States.17

Arctostaphylos patula and Arctostaphylos viscida

The leaves of these 2 Arctostaphylos plants have been reported to be potent inhibitors of tyrosinase. These 2 extracts not only inhibited the production of melanin from dopachrome, but also exhibited superoxide dismutaselike activity. The effective topical concentration of these 2 plants in disorders of hyperpigmentation is not currently known.

Magnesium ascorbyl phosphate

Magnesium-L -ascorbyl-2-phosphate (MAP) is a stable derivative of ascorbic acid. When used as a 10% cream, MAP was shown to suppress melanin formation. A significant lightening effect was seen clinically in 19 of 34 patients with melasma and solar lentigines.18 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. In a Japanese study of 110 patients, a 25% decrease in hyperpigmentation was noted after 6 months of using a 3% MAP skin-lightening moisturizer.19


A hydroquinone derivative, 4- isopropylcatechol has been used to treat hypermelanosis in concentrations ranging from 1-3%. Through its melanocytotoxic effect, it produces loss of functional melanocytes causing depigmentation.10 Like other phenolic compounds, it is a known irritant and may cause contact allergy. It also causes confettilike areas of depigmentation on the treatment site.


Aleosin is a low-molecular weight glycoprotein and a natural derivative of aloe vera. It inhibits tyrosinase by competitive inhibition and does not show cell cytotoxicity, unlike hydroquinone.8 Because of its hydrophilic nature, it has a decreased ability to penetrate the skin. An experimental product, it has been used in combination with arbutin or deoxyarbutin to lessen tyrosinase activity.

Phenolic thioethers

N -acetyl-4-S-cysteaminylphenol and N -propionyl-4-S-cysteaminylphenol are derived from homologues of phenols with melanocytotoxic activity. 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.10 By decreasing intracellular glutathione, it favors the pathway of forming pheomelanin rather than eumelanin.6 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.20 N -propionyl-4-S-cysteaminylphenol is more potent and has more cytotoxic properties as compared to the N -acetyl form.

N-acetyl glucosamine

N -acetyl glucosamine is an amino-monosaccharide that was developed as a pigment-lightening cosmeceutical. It decreases melanin production by inhibiting tyrosinase glycosylation. A randomized double-blind study reported that the application of 2% N -acetyl glucosamine twice daily for 5 weeks provided a lightening effect.21

Tranexamic acid

Tranexamic acid (trans -4-aminomethylcyclohexanecarboxylic acid) is a lysine analog that has been shown to prevent UV-induced pigmentation. It decreases melanocyte tyrosinase activity by preventing the binding of plasminogen to the keratinocytes, which results in reduction of prostaglandins and arachidonic acid, which are inflammatory mediators involved in melanogenesis.

In an open pilot study, intradermal microinjection of tranexamic acid was given to 100 women with melasma for 12 weeks. The treatment was well tolerated, and 76.5% of the subjects reported fair lightening of their melasma.21



The treatment of hyperpigmentation with laser (light amplification by stimulated emission of radiation) techniques is a fast-growing field. Lasers function by emitting a monochromic, high-intensity, coherent energy source that is absorbed by water, hemoglobin, and melanin in the skin, referred to as chromophores. The absorption of energy destroys the chromophores. The wavelength of the laser dictates the depth of laser penetration and the chromophores targeted.

Based on the absorption spectrum of melanin, the Q-switched ruby laser (694 nm) and the Q-switched Nd:YAG laser (1064 nm) are the lasers of choice for the treatment of hyperpigmented lesions such as lentigines and postinflammatory hyperpigmentation. In a randomized controlled trial of 27 patients with solar lentigines on the dorsal hand, the best treatment was with the Q-switched Nd:YAG laser compared with a krypton laser, 532-nm diode pumped laser, or liquid nitrogen.

In a Chinese study, a Q-switched laser (755 nm) was used to treat 602 patients with nevus of Ota.22 It was reported to achieve good results with minimal adverse effects. Adverse effects were transient hyperpigmentation and aggravation of preexisting melasma. The rate of success was dependent on the number of treatments. More treatments achieved better response rates in the majority of the patients.

Adverse effects from laser treatment include discomfort, redness, mild swelling, and postinflammatory hyperpigmentation. Patients should always have a test spot performed before a full treatment.


For more refractory hyperpigmentation disorders, ablative lasers (pulsed/scanned carbon dioxide or Er:YAG laser) were reported to ablate superficial portions of the skin, including abnormal melanocytes. However, this therapeutic approach is not considered a first-line treatment because of the adverse effects of hyperpigmentation, scarring, and rapid recurrence of the primary hyperpigmentation.

A split-face study of 6 patients with refractory dermal-type melasma showed complete resolution using combination treatment of pulsed carbon dioxide laser and Q-switched alexandrite laser compared with pulsed carbon dioxide laser alone. Although effective, this approach is unpredictable and may cause scarring and infection.23

The Er:YAG laser (2490 nm) ablates skin and disrupts melanin granules in the upper dermis. It has been shown to produce marked improvement in refractory melasma; however, most cases develop transient postinflammatory hyperpigmentation, making this approach useful only for selected patients with refractory/recalcitrant melasma.24

Intense pulsed light

A recent derivative of laser treatment is intense pulsed light, in which high-intensity pulses of a broad wavelength (515-1200 nm) of light deliver energy to the skin. The energy of intense pulsed light is delivered to the dermis and is absorbed by the chromophores. Intense pulsed light has been shown to work well for the treatment of lentigines, but the therapy has not been optimized for the treatment of melasma. A Japanese study showed a 50% improvement of solar lentigines and ephelides in 48% of patients after 3-5 treatments and a 75% improvement in 20% of the patients.26 Adverse effects of intense pulsed light treatment include pain, local irritation, and postinflammatory hyperpigmentation.25

Fractional photothermolysis

Fractional photothermolysis (Fraxel) is a recent development in laser technology. It was approved by the US Food and Drug Administration for the treatment of dyspigmentation in 2005. Fraxel works by thermal damage to microscopic zones of the epidermis and dermis. With a single Fraxel treatment, an estimated 15-20% of the skin undergoes laser resurfacing, and the surrounding normal skin is postulated to help in the healing process. Based on the fraction of skin that experiences thermal damage, it is hypothesized that the skin will have less damage and thus will require less healing ("downtime") between treatments.

A case report describing Fraxel treatment showed a marked reduction in hyperpigmentation in a white woman after 2 treatments, and no adverse effects were reported.27 Furthermore, a case series of 10 patients with melasma documented a 75-100% improvement of melasma in 5 of 10 patients based on physician and patient assessments.28 Patients with skin type V showed little-to-no improvement with treatment. One patient experienced postinflammatory hyperpigmentation from the Fraxel treatment, and, overall, patients reported pain of 6.3 on a scale of 0-10.

Further comparison studies of the laser treatments and depigmenting agents will determine the optimal treatment for patients of varying skin tones with hyperpigmentation.



Although not a standard treatment modality for melasma, dermabrasion has been reported as a possible alternative treatment for recalcitrant melasma. In an Asian study, 97% of 410 patients had clearance of melasma without recurrence. Adverse reactions include postinflammatory hyperpigmentation, erythema, pruritus, milia formation, loss of skin texture, and scarring.29,30


skin lightening agents, skin-lightening agents, depigmenting agents, cosmetic lightening, cosmetic depigmentation, cosmetics, skin bleaching, hyperpigmentation treatment, hyperpigmentation, depigmentation agents, depigmenting agents, topical depigmentation, topical lightening, topical depigmentation agents, topical lightening agents, hydroquinone, monobenzyl ether of hydroquinone, azelaic acid, kojic acid, mequinol, arbutin, paper mulberry, glabridin, licorice extract, Arctostaphylos patula, Arctostaphylos viscida, magnesium ascorbyl phosphate, laser depigmentation, intense pulsed light depigmentation, fractional photothermolysis

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors, Alaina J. James, MD, PhD, P. Michael Tabibian, MD, and Cherie M. Ditre, MD, to the development and writing of this article.

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