You are in: eMedicine Specialties > Dermatology > COSMETICS Skin Lightening and Depigmenting AgentsArticle Last Updated: Jun 28, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 7
  Author: Alaina J James, MD, PhD, Staff Physician, Department of Dermatology, University of Pennsylvania Medical Center Coauthor(s): Cherie M Ditre, MD, Assistant Professor, Director, Cosmetic Dermatology and The Skin Enhancement Center, Department of Dermatology, Penn Medicine at Radnor, University of Pennsylvania School of Medicine; P Michael Tabibian, MD, Consulting Staff, Department of Dermatology, Daniel Freedman Hospital, Marina Hospital Editors: Zoe Diana Draelos, MD, Clinical Associate Professor, Department of Dermatology, Wake Forest University School of Medicine; Primary Investigator, Dermatology Consulting Services; Private Practice; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Christen M Mowad, MD, Assistant Professor, Department of Dermatology, Geisinger Medical Center; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center Author and Editor Disclosure Synonyms and related keywords: 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 INTRODUCTIONSection 2 of 7
  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. ETIOLOGYSection 3 of 7
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 TREATMENTSSection 4 of 7
Hydroquinone An important industrial chemical, hydroquinone (HQ) 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. HQ causes reversible inhibition of cellular metabolism by affecting both DNA and RNA synthesis. The cytotoxic effects of HQ are not limited to melanocytes, but the dose required to inhibit cellular metabolism is much higher for nonmelanotic cells than for melanocytes. Thus, HQ can be considered a potent melanocyte cytotoxic agent with relatively high melanocyte-specific cytotoxicity. HQ is also a poor substrate of tyrosinase, thereby competing for tyrosine oxidation in active melanocytes. The 2% HQ is readily available over the counter in various cosmetic preparations. Evidence of improvement with HQ (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, HQ is compounded into various mixtures for the treatment of hyperpigmentation. The original Kligman formula involves compounding 5% HQ 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% HQ, and 0.05% tretinoin in a cream formulation. Despite the remarkable overall safety of HQ, 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 HQ is exogenous ochronosis. This disorder is characterized by progressive sooty darkening of the skin area exposed to HQ. 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 HQ for many years. However, cases occurring after the use of 2% HQ have also been reported. An exogenous ochronosis due to HQ has been reported from South Africa. For this reason, the general recommendation is that HQ should be discontinued if no improvement occurs within 4-6 months. HQ-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 HQ. 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 HQ on pigmentation. The authors of the study reported a synergistic decrease in hair pigmentation when a combination of HQ (2% or 4%) and buthionine sulfoximine (5%) was applied to the dorsal skin of mice. Monobenzyl ether of HQ Similar to HQ, monobenzyl ether of HQ (MBEH) belongs to the phenol/catechol class of chemical agents. Unlike HQ, 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 HQ 4% in the treatment of facial hyperpigmentation in dark-skinned patients. The combination formula reportedly was as effective as HQ 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/HQ, no statistical difference in efficacy was reported between kojic acid and HQ; 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% HQ, 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 HQ, 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. ALTERNATIVE TREATMENTSSection 5 of 7
Arbutin (HQ-beta-D-glucopyranoside) A glycosylated HQ 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 HQ, 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. 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 HQ reveal that the IC50 (ie, the concentration causing 50% inhibition of the activity of tyrosinase) is 0.396%, compared with 5.5% for HQ and 10.0% 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. 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. 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. 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. PHOTOTHERAPYSection 6 of 7
Lasers 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. 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. Intense pulsed light A recent derivative of laser treatment is intense pulsed light (IPL), in which high-intensity pulses of a broad wavelength (515-1200 nm) of light deliver energy to the skin. The energy of IPL is delivered to the dermis and is absorbed by the chromophores. IPL 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. Adverse effects of IPL treatment include pain, local irritation, and postinflammatory hyperpigmentation. 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. 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. 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. REFERENCESSection 7 of 7
Skin Lightening and Depigmenting Agents excerpt Article Last Updated: Jun 28, 2006 |
