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Skin-lightening Challenges

By: Zoe Diana Draelos, MD
Posted: January 7, 2009, from the January 2009 issue of Skin Inc. magazine.
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Topical treatments for facial pigmentation are problematic. A successful treatment must remove existing pigment from the skin, shut down the manufacture of additional melanin pigment and prevent the transfer of existing melanin pigment to the melanosomes. No currently available topical product is able to accomplish all three of these functions. This article examines the various actives contained in topical skin-lightening products.

Hydroquinone. The gold standard for topical skin lightening in the United States remains hydroquinone. This substance is controversial and has been removed from the OTC markets in Europe and Asia. Concern arose from reports that oral hydroquinone caused cancer in mice fed large amounts of the substance. Although oral consumption probably is not related to topical application, hydroquinone remains controversial because it actually is toxic to melanocytes. Hydroquinone, a phenolic compound chemically known as 1,4 dihydroxybenzene, functions by inhibiting tyrosine, a key substance in melanin pigment production. Specifically, it covalently binds to histidine or interacts with copper at the active site of tyrosinase. It also inhibits ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) synthesis and may alter melanosome formation, selectively damaging melanocytes. These activities suppress the melanocyte, causing a gradual decrease of melanin pigment production.1

Hydroquinone is available in both the OTC and prescription U.S. markets. Although concern has arisen because of its availability, no restrictions on hydroquinone use have been issued by the U.S. Food and Drug Administration (FDA) as of this writing. Hydroquinone is a medication that received grandfather status from the FDA because it was in common use when the FDA was founded. Therefore, some hydroquinone formulations have never undergone the testing required for today’s drug approval. Many prescription products have made submissions to the FDA and completed the required safety and efficacy testing, but OTC formulations and some generic formulations were never tested. It is these untested formulations that have created concern. The maximum concentration in OTC products is 2% and most prescription formulations are 4%. In general, 4% hydroquinone is more effective than 2% hydroquinone, but neither concentration will lighten pigment that is deep in the skin because it can’t penetrate that deeply. Current hydroquinone preparations are unable to reach the middle-to-deep dermis where post-inflammatory acne pigmentation may lie; therefore, its pigment-lightening abilities are limited. Deep penetration of hydroquinone also raises unresolved safety issues. In all formulations, hydroquinone is highly unstable and turns brown on contact with air, which oxidizes the hyroquinone molecule. Once the hydroquinone has oxidized, it is no longer active and should be discarded. It would be advisable to label OTC products with a warning that brown, discolored cream is unsuitable for use.

Mequinol. With the regulatory issues related to hydroquinone, a new pigment-lightener known as mequinol has been introduced. At present, mequinol is only available by prescription, but has been approved for use in the United States and Europe. It is chemically known as 4-hydroxyanisole and is chemically synthesized. Other names include methoxyphenol, hydroquinone monomethyl ether and p-hydroxyanisole. Mequinol is available in the United States in a 2% concentration and is commercially marketed as a prescription skin-lightener in combination with 0.01% tretinoin as a penetration enhancer; 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. It is unknown exactly how mequinol lightens skin, but it is a competitive inhibitor in the formation of melanin precursors. It does not damage the melanocyte like hydroquinone.

Retinoids. Many dermatologists combine hydroquinone with prescription vitamin A formulations, such as tretinoin, to improve skin-lightening results. Tretinoin has an effect on skin pigmentation as seen by a decrease in freckling.2 Freckling is created by the irregular grouping of melanocytes,3 which can be normalized with retinoids through alterations in pigment transfer.4 Although this effect is more dramatic with topical prescription tretinoin, topical OTC retinol has been thought to provide similar effects.