Acta Dermato-Venereologica 98-10CompleteContent | Page 6

924 REVIEW ARTICLE Melanogenesis Inhibitors Sulekha KUMARI 1 , Steven Tien Guan THNG 2 , Navin Kumar VERMA 3 and Hemant K. GAUTAM 1 Institute of Genomics and Integrative Biology, Council for Scientific and Industrial Research, New Delhi, India, 2 National Skin Centre, and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore 1 3 Abnormally high production of melanin or melanoge- nesis in skin melanocytes results in hyperpigmenta- tion disorders, such as melasma, senile lentigines or freckles. These hyperpigmentary skin disorders can significantly impact an individual’s appearance, and may cause emotional and psychological distress and reduced quality of life. A large number of melanoge- nesis inhibitors have been developed, but most have unwanted side-effects. Further research is needed to better understand the mechanisms of hyperpigmen- tary skin disorders and to develop potent and safe inhibitors of melanogenesis. This review summarizes the current understanding of melanogenesis regulato- ry pathways, the potential involvement of the immune system, various drugs in current use, and emerging treatment strategies to suppress melanogenesis. Key words: skin pigmentation; melasma; melanin; tyrosinase. Accepted Jul 3, 2018; Epub ahead of print Jul 4, 2018 Acta Derm Venereol 2018; 98: 924–931. Corr: Navin Kumar Verma, Lee Kong Chian School of Medicine, Derma- tology and Skin Biology, Nanyang Technological University Singapore, 59 Nanyang Drive, Experimental Medicine Building, Singapore 636921. E-mail: [email protected]; Hemant K. Gautam, Institute of Genom- ics and Integrative Biology, Council for Scientific and Industrial Research (CSIR-IGIB), Sukhdev Vihar, Mathura Road, New Delhi 110 025, India. E-mail: [email protected] M elanogenesis is a multistep physiological process that results in the synthesis of a complex darkly- pigmented biopolymer called “melanin”. Melanin is syn- thesized by melanosome, a lysosome-related organelle in melanocytes, and helps protect the skin from the harmful effects of sunlight, toxic drugs and chemicals (1, 2). There are 2 types of melanin; eumelanin and pheome- lanin. In the melanogenesis pathway, 3 main enzymes are involved; tyrosinase, tyrosinase-related protein 1 (Tyrp1, also known as gp75 glycoprotein or gp75) and tyrosinase-related protein 2 (Tyrp2, also known as dopa­ chrome tautomerase or Dct). The melanogenesis process is initiated either by the hydroxylation of phenylalanine into L-tyrosine or directly by L-tyrosine, which is then hydroxylated to L-dihydroxyphenylalanine (L-DOPA). L-DOPA is further oxidized into L-DOPAquinone (DQ). Both of these reactions are catalysed by tyrosinase, which is therefore a key rate-limiting enzyme in melanogenesis. The downstream pathway of melanogenesis invol- ves intramolecular addition of an amino group to DQ, generating DOPAchrome. After the formation of DQ, the downstream melanogenesis pathway is divided into doi: 10.2340/00015555-3002 Acta Derm Venereol 2018; 98: 924–931 SIGNIFICANCE Skin hyperpigentation disorders, including melasma, solar lentigines and freckles, are common dermatological con- cerns. These disorders are caused by excessive accumula- tion of melanin in the skin through a process called mela- nogenesis. While there are a diverse range of therapeutic modalities available to manage skin hyperpigmentation, there is an ongoing quest to develop more potent and safe inhibitors of melanogenesis. Here we provide an overview of the current understanding of melanogenesis pathways and review various inhibitors that are currently being app- lied or investigated to target melanogenesis. 2 parts, leading to the synthesis of “black-brownish eumelanin” and “red-yellow pheomelanin”. In the eumelanogenesis pathway, the DOPAchrome is either spontaneously converted to 5,6-dihydroxyindole or enzy- matically converted to 5,6-dihydroxyindole-2-carboxylic acid by Tyrp2. Finally, polymerization of indole and qui- nones results in the formation of eumelanin. Pheomelanin synthesis is dependent on the presence of cysteine, which reacts with DQ to form cysteinyl-DOPA, and is further converted into quinoline, then, finally, polymerizes to pheomelanin (Fig. 1). While melanin plays a key role in protecting the skin from harmful ultraviolet (UV) radiation, abnormally high production and accumulation of melanin in the skin can lead to hyperpigmentation disorders. HYPERPIGMENTATION SKIN DISORDERS While hyperpigmentation of the skin is usually harmless, increased pigmentation, especially on the face, such as melasma, solar lentigines and freckles, presents a sig- nificant cosmetic nuisance and can cause distress to the affected individual. Melasma presents with dark patches distributed symmetrically on the face and neck and hy- perpigmented macules over the skin (Fig. 2A). Freckles are flat, small tan, predominantly present on the face, although other sun-exposed areas of the skin are at high risk (Fig. 2B). Lentigines are marked by the presence of a small brown patch, a benign lesion that mostly occurs on sun-exposed areas (Fig. 2C). Lentigines and freckles differ in terms of the number of melanocytes. In freckles, the number of melanocytes remains the same, but there is an increased amount of melanin; whereas, lentigines result from an increased number of melanocytes. This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2018 Acta Dermato-Venereologica.