Topical skin depigmentation agents: current products and discovery of novel inhibitors of melanogenesis

Novel topical dermatologic or cosmeceutical agents are needed to treat cutaneous hyperpigmentation, since most currently available products typically contain hydroquinone (HQ), which has significant disadvantages. Although most studies have found HQ therapies to be efficacious, this compound is highly toxic and mutagenic to mammalian cells. Skin pigmentation results from the enzymatic conversion of tyrosine into melanin within the melanosomes of melanocytes, followed by transfer of the melanosomes into the keratinocytes of the epidermis. In order to identify novel inhibitors of skin pigmentation based on inhibition of tyrosinase, the key enzyme responsible for initiating melanogenesis, agent screening methods have been developed using both melanocyte cell cultures and cell-free enzymatic assays. An example of an HQ analog that demonstrates the desired activity in these assays is methyl gentisate (MG), which was discovered as an inhibitor of de novo melanogenesis in cultured melanocytes, with significantly reduced cytotoxicity and lack of mutagenic potential compared to HQ. A strategy is summarized for discovering new compounds capable of inhibiting melanogenesis, such as MG, and developing them into dermatologic or cosmeceutical products. In addition, consideration is given to the major differences in product registration requirements in various global markets for topical skin-lightening agents.