Acta Dermato-Venereologica 98-10CompleteContent | Page 6
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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.
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Journal Compilation © 2018 Acta Dermato-Venereologica.