Commentary

Lignin Peroxidase


 

Lignin peroxidase, a novel skin-lightening active agent that is derived from a fungus, is being studied with some interest and is being developed as an ingredient in products to treat pigmentation disorders.

Melanin, the dark pigment in the skin, is produced in the basal layer of the epidermis by melanocytes. Melanocytes make melanin, which is packaged into melanosomes and then transferred to the epidermal cells (keratinocytes). Accumulation of melanin in the epidermis is the main cause of pigmentation disorders, which are observed in all demographic groups but most commonly in people with darker skin types.

Excessive sun exposure in dark and light skin types can lead to unwanted accumulation of pigment (known as solar lentigo) in the skin. Pigmentation disorders are notoriously difficult to treat. Melanin is a very durable compound, and researchers have been largely unsuccessful in finding ways to break down melanin to reduce unwanted skin pigment. The existing topical treatments for skin lightening focus on the prevention of melanin formation by blocking tyrosinase and inhibiting its biosynthesis; by preventing the stimulation of melanocytes by UVA: or by blocking the transfer of melanosomes to keratinocytes via the PAR-2 receptor.

Alternative to Hydroquinone

Historically, the most effective treatments for skin lightening have contained hydroquinone. However, hydroquinone has become controversial, and related safety concerns have prompted research into alternative agents to treat skin pigmentation disorders. In addition, the skin develops tachyphylaxis to hydroquinone requiring 1-month "holidays" in order to maintain effectiveness, and a subset of people may develop contact allergy to hydroquinone. Many other compounds have been studied for the treatment of pigmentation disorders, including retinoids, mequinol, azelaic acid, arbutin, kojic acid, aloesin, licorice extract, ascorbic acid, soy proteins, N-acetyl glucosamine, and most recently, lignin peroxidase.

The enzyme lignin peroxidase (LIP) was first identified in 1984 (Arch. Biochem. Biophys. 1984;234:353-62), and has been researched for many years as a potential agent to break down lignin to whiten wood pulp in paper production. It was later found to break down eumelanin, which has a chemical structure similar to lignin. The development of lignin peroxidase as a skin-lightening agent resulted from these discoveries (U.S. Patent and Trademark Office Patent Application 20060051305). This novel skin-lightening active ingredient is produced extracellularly during submerged fermentation of the fungus Phanerochaete chrysosporium 3 (Biotechnol. Bioproc. E. 2004;9:153-68) and then purified from the fermented liquid medium (Lonza of Switzerland).The LIP enzyme (trademarked as Melanozyme) identifies eumelanin in the epidermis and specifically breaks down the pigment without affecting melanin biosynthesis or blocking tyrosinase. Although there are other types of lignin peroxidase enzymes, at this point, Melanozyme is the only one that has been developed and proved to be effective for skin lightening. Melanozyme is a glycoprotein active at pH 2-4.5 and inactive above that pH level. (The normal pH of skin is around 5.5, with slight variations between 5.0 and 6.5.)

Product Based on Lignin Peroxidase

Melanozyme is currently proprietary and is available only in a new skin-lightening product known on the market as Elure The Elure products are presented in a two-sided dispenser with one side containing the Melanozyme component and the other side an activator. Melanozyme alone has little ability to lighten skin, and first needs to be oxidized by hydrogen peroxide (0.012% in the activator) to enter an "activated state." The activator, which contains a small amount of hydrogen peroxide, is applied to the surface of the skin after the Melanozyme.

When applied to skin, the products that contain the Melanozyme and the activator have to be slightly acidic and buffered in order for the enzyme to perform. In addition, the enzyme is required to be first oxidized by H2O2, and then reduced by a substrate molecule (for example, veratryl alcohol) before the melanin is oxidized. After application of Elure lotion or cream, the skin pH is temporarily reduced to 3.5 but subsequently increases to its normal level of around 5.5. As the skin surface returns to the normal pH level, the enzyme is inactivated. It becomes a simple glycoprotein and is hydrolyzed in the skin by the naturally present proteases and other glycosidases into amino acids.

The safety of lignin peroxidase as a skin-lightening active ingredient has been demonstrated in preclinical studies (data on file at Rakuto Bio Technologies Ltd., 5 Carmel Street, P.O. Box 528, New Industrial Park, Yokneam 20692 Israel) with doses that are 17,000 times the recommended dose without prompting any side effects. LIP is nonmutagenic and nonirritating to eyes. The potential for skin irritation is very low, and in studies of 50 subjects each, there were no reports of skin irritation during acute sensitivity or cumulative sensitivity, or when used in sensitized skin.

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