Skin Lightening Agents

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Chapter 15 Skin Lightening Agents

Marta I. Rendon, Jorge I. Gaviria

INTRODUCTION

Hyperpigmentation is a common skin problem that is particularly prevalent in middle-aged and elderly individuals. It is cosmetically important and can greatly detract from both appearance and quality of life, particularly in cultures where smooth skin is valued as a sign of health or in cultures that are beauty conscious. Hyperpigmented skin lesions may be postinflammatory as a sequel to acne, trauma, chemical peels, or laser therapy. Exogenous causes, particularly ultraviolet (UV) light exposure, are a common factor in pigmentary abnormalities such as melasma, solar lentigines, and ephelides (Fig. 15.1). Exposure to certain drugs and chemicals as well as the existence of certain disease states can result in hyperpigmentation (Box 15.1).

Fig. 15.1 The typical appearance of melasma with reticulated hyperpigmented plaques. (A) Before cosmeceutical treatment. (B) Eight weeks after cosmeceutical treatment

The treatment of acquired hyperpigmentation has traditionally been challenging and frequently discouraging. Many of the agents that have been used cause skin irritation, require many months of regular use before results are apparent, or are only partly effective. Patient compliance with therapy must be strict. Sun avoidance and the religious use of a high sun protection factor (SPF) sunblock are mandatory for successful treatment.

SKIN LIGHTENING COSMECEUTICALS

Multiple depigmenting cosmeceuticals are currently available, although published clinical evidence to support their effectiveness is lacking. These skin lightening compounds work by removing undesired pigment by acting at one or more steps in the pigmentation process (Box 15.2). Since tyrosinase is the rate-limiting enzyme for melanin biosynthesis, many of the cosmeceuticals for skin lightening exert their effect on this enzyme.

Box 15.2 Depigmenting agents and reported effect on the melanin synthetic pathway

BEFORE MELANIN SYNTHESIS

Tyrosinase transcription:

Tretinoin

Modified from Briganti S, Camera E, Picardo M 2003 Chemical and instrumental approaches to treat hyperpigmentation. Pigment Cell Research 16:1–11.

• Hydroquinone

For many years, the phenolic compound hydroquinone has been the most widely and successfully used skin lightening agent for the treatment of melasma, postinflammatory hyperpigmentation, and other disorders of hyperpigmentation (Fig. 15.2). Hydroquinone occurs naturally in many plants as well as in coffee, tea, beer, and wine. Hydroquinone depigments skin by inhibiting the conversion of tyrosine to melanin. It has been shown to decrease tyrosinase activity by 90%. It may also inhibit DNA and RNA synthesis, as well as degrade melanosomes.

Fig. 15.2 (A) The appearance of facial melasma before treatment. (B) Improvement in hyperpigmentation following hydroquinone therapy (8 weeks after treatment)

In the US, hydroquinone is available over the counter (OTC) in strengths up to 2%. Most prescription strength hydroquinone formulations contain 3–4%, but concentrations as high as 10% may be available through compounding pharmacies.

Also, several new combination agents are now available in the US. A prescription drug containing 4% hydroquinone, tretinoin, and a low-potency fluorinated steroid, fluocinolone acetonide, is effective and safe in the treatment of melasma. Other combination products contain glycolic acid, vitamin C, and/or retinol to function as penetration enhancers for the hydroquinone active.

Hydroquinone is generally considered safe. Common side effects are skin irritation or contact dermatitis, which can be treated with topical steroids. A rare but serious side effect of hydroquinone is the development of exogenous ochronosis, a sooty hyperpigmentation in the treatment area, which may be difficult to reverse. Exogenous ochronosis appears to be prevalent among darker complected individuals when hydroquinone is used at high concentrations or for prolonged periods even at low concentrations.

For this reason, hydroquinone is restricted in several African countries and highly regulated in many Asian countries. Because of potential mutagenic properties, hydroquinone is also banned as an OTC depigmenting agent in the European Union and Japan. As a result of the restrictions, alternative depigmenting agents are increasingly being used either as monotherapy or in combination with hydroquinone or other skin lightening agents. Alternating the use of hydroquinone with one of these alternative agents in 4-month cycles will help prevent side effects such as irritation as well as decreasing the risk of exogenous ochronosis.

• Natural cosmeceuticals for dyspigmentation

Increasing interest in the use of natural actives, as well as the need to find an alternative to hydroquinone, has led to research on a variety of dyspigmentation treatment cosmeceuticals derived from natural ingredients (Box 15.3).

Box 15.3 Natural depigmenting agents

KOJIC ACID

Kojic acid is a tyrosinase inhibitor derived from various fungal species such as Aspergillus and Penicillium. It is used in food processing to prevent browning and to promote the reddening of unripe strawberries. It is used in Asia both topically as a skin lightening agent and also in the diet.

Kojic acid is used in concentrations between 1 and 4% and is often more effective in combination with other ingredients (Box 15.4). Kojic acid has been reported to have a high sensitizing potential and may cause irritant contact dermatitis. However, it is useful in patients who cannot tolerate hydroquinone and studies show it may be combined with a topical corticosteroid to reduce irritation. Skin lightening products that contain kojic acid are typically used twice per day for 1 or 2 months or until the desired effect is achieved.

VITAMIN C

Topical vitamin C products can be derived from such natural sources as fruits and vegetables, as discussed in Chapter 8, which is solely devoted to vitamin C. Vitamin C interferes with pigment production at various oxidative steps of melanin synthesis by interacting with copper ions at the tyrosinase active site and reducing dopaquinone. A stable derivative, magnesium L-ascorbic acid-2-phosphate (MAP), has been shown to lighten dyspigmentation.

MELATONIN

Melatonin is a hormone that is secreted by the pineal gland in response to sunlight. In addition to its effects on diurnal rhythms in mammals, it has been shown in vitro to inhibit melanogenesis in a dose-related manner. It does affect tyrosinase activity, suggesting that its effect occurs more proximally in the melanogenesis pathway. It has been shown to inhibit cyclic AMP-driven processes in pigment cells. The concentration needed for effective cosmeceutical skin lightening in human skin has not yet been established. It has been shown to have anti-inflammatory activity at a dosage of 0.6 mg/cm².

GLYCOLIC ACID

Glycolic acid, an alpha-hydroxy acid derived from sugarcane, is an important cosmeceutical (discussed in detail in Chapter 16) that has skin lightening effects. At low concentrations, glycolic acid has an epidermal discohesive effect, which results in more rapid desquamation of pigmented keratinocytes. Like retinoids, glycolic acid shortens the cell cycle so that pigment is lost more rapidly. At higher concentrations, glycolic acid results in epidermolysis. Several studies have shown that the removal of superficial layers of epidermis with glycolic acid peels at concentrations of 30–70% can enhance the penetration of other topical skin lighteners such as hydroquinone.

When glycolic acid is used in the treatment of postinflammatory hyperpigmentation or melasma, it has been suggested that it should be initiated at low concentrations to avoid skin irritation or induce postinflammatory hyperpigmentation, especially in dark-skinned individuals. The use of hydroquinone both prior to and after the peel can lessen the risk of such pigmentary changes. Also, the addition of glycolic acid to hydroquinone formulations seems to increase efficacy due to enhanced penetration.