Dermatologic Therapy, Vol.

20, 2007, 308313 Printed in the United States All rights reserved

Copyright Blackwell Publishing, Inc., 2007

DERMATOLOGIC THERAPY
ISSN 1396-0296

Blackwell Publishing Inc

Skin lightening preparations and the hydroquinone controversy

ZOE DIANA DRAELOS

Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina and Dermatology Consulting Services, High Point, North Ccarolina

ABSTRACT: Skin lightening preparations are widely used in dermatology by persons of all Fitzpatrick skin types. Fitzpatrick skin types IIII require local pigment lightening for the treatment of hormonally induced melasma and postinammatory hyperpigmentation caused by acne and trauma. Fitzpatrick skin types IV and darker have an even greater need for skin lightening for social reasons, as well as pigmentary changes that occur around the eyes, in the intertriginous areas, following dermatitis, or with acne and trauma. The gold standard dermatologic agent for skin lightening was hydroquinone, until regulatory agencies in Japan, Europe, and most recently in the United States questioned the safety of this substance. This has encouraged research into alternative agents to inhibit skin pigmentation such as retinoids, mequinol, azelaic acid, arbutin, kojic acid, aleosin, licorice extract, ascorbic acid, soy proteins, and N-acetyl glucosamine. The efcacy and safety of each of these ingredients is examined as possible topical alternatives to hydroquinone. KEYWORDS: hydroquinone safety, pigment lightening, topical skin-lightening cosmeceuticals

Introduction
Even skin color is considered a universal sign of youth and beauty. Pigmentation problems typically do not arise without injury and/or advancing age, creating a tremendous market for products designed to lighten skin. These products exist in the prescription, over-the-counter (OTC) drug, cosmeceutical, and cosmetic realm. Yet, the perfect skin-lightening ingredient has yet to be developed. There is a ne line between substances that are toxic to the melanocyte and agents that interrupt one of the key steps in melanogenesis. Many chemicals induce decreased pigment production in a Petri dish, but few can translate this in vitro observation into clinical efcacy. The stratum corneum and supercial epidermis present formidable barriers protecting the fragile melanocytes from toxic substances. After all, injury to the melanocytes

Address correspondence and reprint requests to: Zoe Diana Draelos, MD, 2444 North Main Street, High Point, North Carolina 27262, or email: zdraelos@northstate.net.

results in the pigmentary abnormalities requiring dermatologic intervention. Pigmentary abnormalities can take several forms, depending on skin type. The most common abnormal pigmentation results from mild to moderately photodamaged skin characterized by dyspigmentation, in addition to ne wrinkles and tactile roughness (1,2). Individuals with Fitzpatrick skin types IIII demonstrate this photoinduced change. The irregular pigmentation is labeled freckling in young persons and lentigenes in more mature individuals. Although this type of clonal proliferation of melanin is seen in fair-complected individuals, it may also be seen in Fitzpatrick skin types IV and darker. In addition to photodamage, there are some types of familial dyspigmentation that can be observed in all skin types. These conditions include melasma, hormonal effects of estrogen on pigment production, and periorbital darkening, which is particularly common in persons whose gene pool can be traced to India. Acquired forms of pigment darkening are termed postinammatory hyperpigmentation and may be the result of acne, trauma, thermal burns, etc. This is the most common

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form of abnormal pigmentation in all skin types. This diversity of causes accounts for the tremendous popularity of skin-lightening agents. The most effective pigment-lightening agent currently known is hydroquinone; however, this ingredient has become somewhat controversial. It has been banned in Europe and the Orient, and a ban is under consideration in the United States. This has encouraged research into alternative agents to inhibit skin pigmentation such as retinoids, mequinol, azelaic acid, arbutin, kojic acid, aleosin, licorice extract, ascorbic acid, soy proteins, and N-acetyl glucosamine. This article examines the efcacy and safety of each of these ingredients as possible topical alternatives to hydroquinone

Hydroquinone
The gold standard for hyperpigmentation therapy in the United States remains hydroquinone. This substance predated formation of the Food and Drug Administration (FDA), and many formulations currently on the market have never been studied for safety and efcacy. These formulations include those that contain 2% hydroquinone, the maximum concentration allowed in OTC drugs, and some of the generic 4% hydroquinone formulations, only available by prescription. Other proprietary hydroquinone-containing drugs that have undergone FDA scrutiny through the investigational new drug pathway have well-established safety and efcacy validated through carefully controlled large-scale vehicle-controlled clinical trials. Many new hydroquinone formulations have appeared in the last 2 years in physician-dispensed lines, but these products have not undergone clinical study. It is this plethora of hydroquinonecontaining creams for sale in many different markets that has caused health concerns. There are several important health issues that need to be considered before determining the safety of hydroquinone. For many years, it has been known that hydroquinone can cause ochronosis (3). Whether this is a result of the effect of hydroquinone alone or other substances present in the formulation or higher concentrations of hydroquinone is unknown. Additional concern arose when oral hydroquinone was reported to cause cancer in rodents fed with large amounts of the substance, yet human carcinogenicity has not been established (4). Although oral consumption probably is not related to topical application, hydroquinone remains controversial because it may be toxic to melanocytes.

Hydroquinone, a phenolic compound chemically known as 1,4 dihydroxybenzene, functions by inhibiting the enzymatic oxidation of tyrosine and phenol oxidases. It covalently binds to histidine or interacts with copper at the active site of tyrosinase. It also inhibits RNA and DNA synthesis and may alter melanosome formation, thus selectively damaging melanocytes. These activities suppress the melanocyte metabolic processes inducing gradual decrease of melanin pigment production (5). Issues regarding the topical toxicity of hydroquinone arise because it is a strong oxidant rapidly converted to the melanocyte toxic products, pbenzoquinone and hydroxybenzoquinone. These byproducts may cause depigmentation. Hydroquinone is very difcult to formulate in a stable preparation. It is a highly reactive oxidant that rapidly combines with oxygen. Typically, hydroquinone skin-lightening creams are a creamy color that changes to a darker yellow or brown as oxidation occurs. As the discoloration progresses, the activity of the hydroquinone decreases. Products with any off-color change should be immediately discarded. Prescription hydroquinone formulations have tried to increase the skin-lightening potency of formulations by adding penetration enhancers such as glycolic acid or tretinoin as a supplemental pigment-lightening agent. Other prescription formulations have added microsponges to create time delivery of hydroquinone to the skin, whereas others have placed the hydroquinone in a special one-way airtight dispenser. Some formulations have added sunscreen ingredients to the hydroquinone to prevent UV-induced pigment darkening. The future of hydroquinone in the United States is still uncertain as of this writing. Apparently, some of the controversy arose when the FDA asked the industry to perform some collaborative selffunded studies on the safety of hydroquinone and submit a written report detailing the ndings. The report was not submitted as requested, and the FDA acted by stating that it would withdraw all OTC 2% hydroquinone preparations and prescription formulations that were not studied as investigational new drugs once currently manufactured supplies are depleted. Whether this ruling will be enforced and how it will be enforced is unknown. More details regarding the future of hydroquinone in the United States should be forthcoming shortly. The potential withdrawal of hydroquinone from some of the US markets and its removal from European and Japanese markets has spurred interest in developing pigment-lightening

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alternatives. The remainder of this discussion will focus on other pigment-lightening ingredients and their relative efcacy and safety as compared to hydroquinone.

Mequinol
The primary prescription lightening alternative to hydroquinone is mequinol, approved for use in the United States and Europe. Mequinol is chemically known as 4-hydroxyanisole. Other names include methoxyphenol, hydroquinone monomethyl ether, and p-hydroxyanisole. Mequinol is available in the United States in 2% concentration and is commercially marketed as a prescription skin lightener in combination with 0.01% tretinoin, functioning as a penetration enhancer, and vitamin C, in the form of ascorbic acid and ascorbyl palmitate, to enhance skin lightening. These active agents are dissolved in an ethyl alcohol vehicle. The exact mechanism of action accounting for the skin-lightening properties of mequinol is unknown; however, it is a substrate for tyrosinase thereby acting as a competitive inhibitor in the formation of melanin precursors. It does not damage the melanocyte like hydroquinone, but is not generally felt to be as effective. Mequinol has been observed to cause long-standing depigmentation in some Caucasian patients, but repigmentation generally occurs with time. Tretinoin in combination with mequinol may cause postinammatory hyperpigmentation in some African American patients; but again the skin darkening lightens with time when the product is discontinued.

tretinoin, but without the irritation of retinoic acid (11). Retinol has been shown to convert to retinoic acid in a two-step oxidation process in the skin. Although retinol has a lower potency than retinoic acid and requires 10-fold higher concentrations to produce similar epidermal effects, it can be effective in improving the appearance of photodamage (12). The main challenge to retinol formulations has been the successful development of high concentration stabilized formulas. Retinol is not nearly as effective as tretinoin or tazarotene in pigment lightening. Retinoids are sometimes used to indirectly lighten dyspigmentation. In this case, the retinoids are used as penetration enhancers. A side effect of retinoids is an irritant dermatitis characterized by erythema, dryness, and scaling (8,13). These cutaneous changes damage the skin barrier, allowing increased access of other pigment-lightening agents, such as hydroquinone and mequinol, to the melanocytes. Some preparations that combine tretinoin and hydroquinone must also incorporate a potent topical corticosteroid to prevent excess irritation resulting in decrease patient compliance and/or postinammatory hyperpigmentation.

Azelaic acid
The irritation proles of hydroquinone and retinoids have led to the search for other pigmentlightening ingredients in the prescription realm. One such ingredient is azelaic acid. Azelaic acid is available currently as a 15% gel approved in the United States for the treatment of rosacea. It is a 9-carbon dicarboxylic acid obtained from cultures of Pityrosporum ovale. Although its lightening effects are mild, several large studies carried out with a diverse ethnic background population have compared its efcacy to that of hydroquinone (14,15). It too interferes with tyrosinase activity, but may also interfere with DNA synthesis. It appears to have a specicity for abnormal melanocytes, and for this reason has been used to suppress the progression of lentigo maligna to lentigo maligna melanoma. Azelaic acid has an excellent safety prole, but may cause short-lived stinging when topically applied in some individuals. It can be safely combined with retinoids to yield an additive benet, but it is not as effective as hydroquinone in treating dyschromias. Thus, hydroquinone, mequinol, and azelaic acid are the only three prescription active ingredients used for pigment lightening, which is remarkable, given the size of the dyschromia

Retinoids
Retinoids have been used both directly and indirectly as pigment-lightening agents. The prescription retinoids used for direct improvement in skin pigmentation are tretinoin and tazarotene (6,7). These retinoids have an effect on skin pigmentation as demonstrated by a decrease in cutaneous freckling and lentigenes (8). It is the irregular grouping and activation of melanocytes that accounts for the dyspigmentation associated with photoaging (9), which is normalized by retinoids (10). Although this effect is more dramatic with prescription topical tretinoin and tazarotene, topical OTC retinol has been thought to provide similar effects as a cosmeceutical. Retinol, the dietary form of vitamin A, induces changes in the skin similar to those produced by

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market. All of the other ingredients used for pigment lightening are found in the OTC realm, the next topic of discussion.

Arbutin
The most effective OTC pigment-lightening ingredients are botanicals that contain a structure similar to hydroquinone. Arbutin is one of these ingredients obtained from the leaves of the bearberry plant, but also found in lesser quantities in cranberry and blueberry leaves. It is a naturally occurring gluconopyranoside that causes decreased tyrosinase activity without affecting messenger RNA expression (16). It also inhibits melanosome maturation. Arbutin is not toxic to melanocytes and is used in a variety of pigment-lightening preparations in Japan at concentrations of 3%. Higher concentrations are more efcacious than lower concentrations, but a paradoxical pigment darkening may occur as a result of postinammatory hyperpigmentation. At present, a synthetic form, known as deoxyarbutin, is available with greater inhibition of tyrosinase than the botanically derived chemical (17). Deoxyarbutin is probably the most effective pigment lightening agent in the OTC realm.

from the aloe vera plant. It is a natural hydroxymethylchromone functioning to inhibit tyrosinase by competitive inhibition at the dihydroxyphenylalanine oxidation site (20,21). In contrast to hydroquinone, it shows no cell cytotoxicity; however, it has a limited ability to penetrate the skin because of its hydrophilic nature. It is commonly used in combination with arbutin or deoxyarbutin to decrease tyrosinase activity through several different mechanisms.

Licorice extract
The safest pigment-lightening agents with the fewest side effects are the licorice extracts. It is for this reason that licorice extract is the most commonly used agent in cosmetics for brightening skin. Licorice extract can be incorporated into facial foundations or moisturizers. In addition, the licorice extract has topical antiinammatory properties theoretically helpful in decreasing skin redness and postinammatory hyperpigmentation. The active agents are known as liquiritin and isoliquertin, which are glycosides containing avonoids (22). Liquiritin induces skin lightening by dispersing melanin. It is typically applied to the skin in a dose of 1 g per day for 4 weeks to see a clinical result; however, the extract is quite expensive, and the concentration used in most cosmetics is modest.

Kojic acid
The second most effect OTC skin-lightening agent is kojic acid, chemically known as 5-hydroxymethyl4H-pyrane-4-one. It is a hydrophilic fungal derivative obtained from Aspergillus and Penicillium species. It is the most popular agent employed in the Orient for the treatment of melasma (18); however, it is somewhat controversial as it has been disallowed and then reinstated as an acceptable pigment-lightening agent. It is a known sensitizer and has been shown to be mutagenic in cell culture studies. The activity of kojic acid is attributed to its ability to prevent tyrosinase activity by binding to copper (19).

Ascorbic acid
Many times licorice extract is combined with ascorbic acid, also known as vitamin C. Ascorbic acid interrupts the production of melanogenesis by interacting with copper ions to reduce dopaquinone and by blocking dihydrochinindol2-carboxyl acid oxidation (23). However, ascorbic acid is rapidly oxidized and is of limited stability, making biologically active formulations challenging. It is a poor skin-lightening agent when used alone and is usually combined with licorice extracts and soy, the next topic of discussion, to create a minimally effective skin lightening product sold as a cosmeceutical as these ingredients have excellent safety proles.

Aleosin
After deoxyarbutin and kojic acid, the available skin-lightening ingredients decrease in efcacy. For this reason, many manufacturers combine multiple ingredients in one formulation hoping to inhibit pigment production by interrupting melanogenesis at multiple steps along the pathway. Aleosin is a low-molecular-weight glycoprotein obtained

Soy proteins
The most commonly used skin-lightening agent in cosmeceutical moisturizers is a soy extract known

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as soybean trypsin inhibitor (STI). STI inhibits the activation of a pathway necessary for keratinocyte phagocytosis of melanosomes and melanosome transfer (24). This pathway, known as the proteaseactivated receptor-2 pathway (PAR-2), can be inhibited after 3 weeks of raw soy milk application. The inhibition of melanosome transfer is reversible, thus side effects are minimal, and the safety prole excellent (25). However, the pigmentlightening effect is not as pronounced as with hydroquinone as only melanosome transfer is inhibited and not melanin production.

hydroquinone. In the present authors opinion, hydroquinone preparations should be removed from the OTC market, but maintained in the prescription market where clinical testing should be required prior to approval as a safe and effective drug. Formulations should be carefully tested for stability, as it is some of the oxidative byproducts of hydroquinone that are most toxic to melanocytes. This is achieved through proper manufacturing, low oxygen exposure packaging design, expiration dating of products, and a formulation with robust antioxidants. Hydroquinone can be used in a safe manner under the direction of a dermatologist.

N-acetyl glucosamine
The newest cosmeceutical pigment lightening agent to be introduced this past year was N-acetyl glucosamine, an amino-monosaccharide produced by the body through the addition of an amino group to glucose (26). It has many roles within the body, including functioning as a substrate for the production of hyaluronic acid, heparan sulfate, and proteoglycans. These substances are important in maintaining the water content of the dermis by serving as humectants. N-acetyl glucosamine also inhibits the glycosylation of tyrosinase, an important enzyme in melanin production, accounting for its pigment-lightening abilities (27). A randomized double-blind clinical study utilizing topical 2% N-acetyl glucosamine applied twice daily for 8 weeks in a cosmeceutical moisturizer showed modest pigment lightening (28).

References
1. Kligman LH, Gans EH. Re-emergence of topical retinol in dermatology. J Dermatol Treatment 2000: 11: 4752. 2. Draelos ZD. Hydroquinone: optimizing therapeutic outcomes in the clinical setting of melanin-related hyperpigmentation. J New Dev Clin Med 2001: 19: 191 201. 3. Lawrence N, Bligard CA, Reed R, et al. Exogenous ochronosis in the United States. J Am Acad Dermatol 1988: 18: 1207 1211. 4. Nordlund JJ, Grimes PE, Ortonne JP. The safety of hydroquinone. J Euro Acad Dermatol Venerol 2006: 781787. 5. Halder RM, Richards GM. Management of dischromias in ethnic skin. Dermatol Ther 2004: 17: 151157. 6. Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical tretinoin for photoaged skin. J Am Acad Dermatol 1986: 15: 836859. 7. Kligman AM. The treatment of photoaged human skin by topical tretinoin. Drugs 1989: 38: 18. 8. Weinstein GD, Nigra TP, Pochi PE, et al. Topical tretinoin for treatment of photodamaged skin. Arch Dermatol 1991: 127: 659665. 9. Gilchrest BA, Blog FB, Szabo G. Effects of aging and chronic sun exposure on melanocytes in human skin. J Invest Dermatol 1979: 73: 141143. 10. Bhawan J, Serva AG, Nehal K, et al. Effects of tretinoin on photodamaged skin a histologic study. Arch Dermatol 1991: 127: 666672. 11. Kang S, Duell EA, Voorhees JJ, et al. Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels of irritation. J Invest Dermatol 1995: 105: 549556. 12. Duell EA, Kang S, Voorhees JJ. Unoccluded retinol penetrates human skin in vivo more effectively than unoccluded retinyl palmitate or retinoic acid. J Invest Dermatol 1997: 109: 301 305. 13. Green CK, Grifths CEM, Finkel LJ, et al. Topical retinoic acid (tretinoin) for melasma in Black patients. Arch Dermatol 1994: 130: 727733. 14. Fitton A, Goa KL. Azelaic acid: a review of its pharmacological properties and therapeutic efcacy in acne and hyperpigmentary skin disorders. Drugs 1991: 5: 780798. 15. Balina LM, Graupe K. The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol 1991: 30: 893895.

Summary
Pigment lightening is an important part of dermatologic therapy and a recognized segment of the cosmeceutical and cosmetics market. This discussion has served to highlight the paucity of effective ingredients able to lighten skin. The major themes that have emerged are the melanocyte toxicity, carcinogenic potential, irritation prole, and sensitizing abilities of the existing ingredients. Most agents with excellent pigment-lightening effects also have increased side effects. No one agent has achieved the delicate balance between interrupting melanogenesis effectively without causing other cellular damage. Hydroquinone remains the most effective pigment-lightening agent discovered to date, but it does not have a clean safety prole, making it the subject of controversy. It is unclear exactly how the FDA will rule regarding the future of

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16. Hori I, Nihei K, Kubo I. Structural criteria for depigmenting mechanism of arbutin. Phytother Res 2004: 18: 475 469. 17. Oissy RE, Visscher M, DeLong MA. Deoxyarbutin: a novel reversible tyrosinase inhibitor with effective in vivo skin lightening potency. Exp Dermatol 2005: 14: 601. 18. Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg 1999: 25: 282 284. 19. Garcia A, Fulton JE Jr. The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions. Dermatol Surg 1996: 22: 443447. 20. Choi S, Lee SK, Kim JE, et al. Aloesin inhibits hyperpigmentation induced by UV radiation. Clin Exp Dermatol 2002: 27: 513 515. 21. Jones K, Hughes J, Hong M, et al. Modulation of melanogenesis by aloesin: a competitive inhibitor of tyrosinase. Pigment Cell Res 2002: 15: 335 340. 22. Amer M, Metwalli M. Topical Liquiritin improves melasma. Int J Dermatol 2000: 39: 299 301. 23. Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A double blind randomized trial of 5% ascorbic acid vs 4% hydroquinone in melasma. Int J Dermatol 2004: 43: 604 607. 24. Seiberg M, Paine C, Sharlow E, et al. Inhibition of melanosome transfer results in skin lightening. J Invest Dermatol 2000: 115: 162167. 25. Paine C, Sharlow E, Liebel F, et al. An alternative approach to depigmentation by soybean extracts via inhibition of the PAR-2 pathway. J Invest Dermatol 2001: 116: 587 595. 26. Bissett DL. Glucosamine: an ingredient with skin and other benets. J Cosmet Dermatol 2006: 5: 309315. 27. Bissett DL, McPhail SJ, Farmer TL, et al. Topical N-acetyl glucosamine affects pigmentation-relevant genes in in vitro genomics testing. Pig Cell Res 2006: 19: 373. 28. Bissett DL, Robinson L, Li J, Miyamoto K. Topical N-acetyl glucosamine reduces the appearance of hyperpigmented spots on human facial skin. J Am Acad Dermatol 2006: 54: AB54.

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