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RESEARCH ARTICLE
Treatment of Postinflammatory Hyperpigmentation: Challenge of
using botanical extracts instead of hydroquinone.
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Napatchar Techataratip MD1, Jitlada Meephansan MD PhD1,
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Phubodin Vongtaranavuth MD2, Assoc. Prof. Pichit Suvanprakorn MD PhD2
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Keywords: Postinflammatory hyperpigmentation, botanical extracts, treatment of
postinflammatory hyperpigmentation, depigmenting agents.
Division of dermatology, Chulabhorn international college of medicine, Thammasat
University, Pathum Thani, 12120, Thailand.
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Pan Rajdhevee Suphannahong Foundation, Bangkok, 10330, Thailand.
Abstract
Any of cutaneous inflammation or trauma to the skin can all result in
postinflammatory hyperpigmentation (PIH), which is not life-threatening condition
but it may affect patient’s life as a chronic disease. PIH lesions may take months to
years for resolution by itself, especially dermal or mixed type PIH which may take
several years to fade. Actually the treatment of PIH is still challenging, because the
results from topical treatment and laser treatment or even chemical peeling are not
only unpredictable, but also relapse are frequent. Mostly the topical treatments are
depigmenting agents i.e. hydroquinone, azeleic acid, and retinoids etc. The most
effective topical treatment is hydroquinone but it can also cause a lot of side effects
such as irritation and the permanent ochronosis. In the other hand, the botanical
extracts are not melanotoxicity agents and safe for long-term use. Moreover, some
of them are more potent inhibitors of melanin production than conventional topical
agents. The ideal bleaching agents must be selective on hyperactive melanocytes
without long-term side effect or any hypopigmentation. Therefore the botanical
extracts are a good alternative choice for PIH lesion because of their efficacy and
less side effects when compared to other bleaching agents especially hydroquinone.
In addition there are many botanical extracts that could be a challenging medication
for treating PIH for example flavonoids, mulberry, ginseng, pycnogenol, soy, and
etc. These all are so inspirable to learn about their mechanisms, efficacy, and also
the side effect which will lead us to the era of natural compounds.
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Address correspondence and reprint request to: Jitlada Meephansan, Chulabhorn
international college of medicine, Thammasat University, Pathum Thani, Thailand.
E-mail address: kae_mdcu@yahoo.com.
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Methodology
This article reviews the brief pathogenesis of postinflammatory
hyperpigmentation and melanogenesis, and focuses on the botanical extracts which
can inhibit melanogenesis through many mechanisms.
This review was based on a literature search of the Pubmed database using
terms:
‘postinflammatory
hyperpigmentation’,
‘hyperpigmentation’,
‘melanogenesis’, ‘melanin’, ‘botanical extracts’, ‘plants’, ‘depigmentaing agents’,
and ‘skin lightening’. Other sources of data included dermatological textbooks.
We only included studies reporting in adult populations (>18 years old),
full-text, and published in English. We read the abstracts of all identified studies to
exclude those that were clearly not relevant. We also excluded others
hyperpigmented diseases i.e. melasma, lentigines. The full texts of the remaining
articles were read to determine if they met the study inclusion criteria. Some
journals were added after manual review of the papers references.
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Introduction
Melanogenesis
Melanogenesis is a complex process of producing melanin pigment. It takes
place in melanosome(specialized intracellular vesicle) within melanocyte.1,2 Then
melanosomes are transferred to keratinocytes via the dendrites of melanocytes.1
They stay as the cap of keratinocyte’s nucleus protecting it from UV radiation.
There are many enzymes that involve in this process but the most important
enzyme in melanogenesis is tyrosinase.2,3 Tyrosinase controls two rate-limiting
steps in melanogenesis.4,5 A lot of depigmenting agents target tyrosinase aiming to
inhibit melanin production. Epidermal melanin unit consists melanocytes and
keratinocytes. Melanocytes are stimulated by direct exogenous factors such as UV
radiation and indirect by cytokines and growth factors of keratinocytes, fibroblasts,
or other cells.6 Keratinocytes can produce some signalings which are paracrine
and/or autocrine manners which known as keratinocyte-derived factors for example
alpha-melanocyte stimulating hormone (-MSH), ACTH, basic fibroblast growth
factor (bFGF), endothelins, granulocyte-macrophage colony-stimulating factor
(GM-CSF), steel factor, and etc.7 These growth factors influence melanocyte’s
proliferation and differentiation.7 They have their own receptor and counteract
signaling such as -MSH which has been found to be able to up regulate
melanocortin-1 receptor (MC1R) within melanocytes while agouti protein has a
contrast activity.8-10
Within melanosomes, they contain a lot of melanin producing enzymes
such as tyrosinase, tyrosinase related protein 1 (TRP-1), tyrosinase related protein 2
(TRP-2), and dopachrome tautomerase (Dct).11,12 As mentioned earlier, Tyrosinase
can catalyze tyrosine (amino acid substrate) by two reactions: hydroxylation and
oxidation.13,14 Tyrosinase is a copper-dependent enzyme.14 It converts tyrosine
(substrate) to L-3,4-dihydroxyphenylalanine (L-DOPA) and then oxidize L-DOPA
to DOPAquinone.4,15 (Figure 2.) Microphthalmia-associated transcriptional factor
(MITF) is a key regulator of tyrosinase, tyrosinase-related protein 1 (TRP-1),
tyrosinase-related protein 2 (TRP-2) gene transcription in melanocyte.11,16 MITF
has a crucial role in binding to tyrosinase promoter and then turning “ON” melanin
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production process.17 P38 is one of the signal that regulates MITF and stimulate
tyrosinase transcription in response to UV radiation.17 MITF regulates melanogenic
enzymes, proliferation and differentiation of melanocytes but MITF is induced by
cAMP.18 Cyclic-AMP is a secondary messenger which regulate protein kinase A
(PKA).9 CAMP involves not only in cAMP-dependent protein kinase A (PKA) but
also cAMP-responsive element binding protein (CREB).12,18 (Figure 3.)
Melanosomes transportations occur along microtubules in dendrites of
melanocytes by protein kinesin and dynein, motor proteins.19
T. Napatchar, 2015
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Figure 2. Pathway of melanogenesis within melanosomes.
(TYR=Tyrosinase, TRP=Tyrosinase-related protein)20
cAMP-dependent signaling pathway
POM
Wnt signaling pathway
aMSH
ACTH
SCF
ERK signaling pathway
c-Kit
MC1R
Wnt
ERK1/
Raf
AC
Frizzle
DKK
Melanocyte
Ras
MEK
MITF degradation
cAMP
PKA
G0/Gq
MITF
CRE
TYR
TRP-1
TRP-2
Dvl
TCF/LEF
GSK-3b
b-catenin
Melanogenesis
T. Napatchar, 2015
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Figure 3. Pathway regulate melanogenesis including (1) cAMP-dependent
signaling pathway, (2) Wnt signaling pathway, and (3) ERK signaling pathway.17,20
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Postinflammatory hyperpigmentation
Any of cutaneous inflammation or trauma to the skin can all result in
postinflammatory hyperpigmentation (PIH), which is not life-threatening condition
but it may affect patient’s life as a chronic disease. Postinflammatory
hyperpigmentation (PIH) is one of the most common problems in cosmetic
dermatology, especially in patients with darker skin tone (Fitzpatrick skin type IVVI: Figure 1) as they tend to have higher amount of epidermal melanin than
others.21-24 PIH occurs in patients at any age and both gender equally.25
Postinflammatory hyperpigmentation characterized by a light brown to
black or grey macule resulted from the accumulation of melanin pigments. The
color of PIH lesion depends on layers that melanin increase.26 If the melanin
deposit in epidermis, the lesion will be brown and well-defined edge. In the other
hand, if the majority of melanin pigments are in dermis, the PIH lesion will be
greyish and ill-defined border. The hyperpigmentation can be from increase
production of melanin or abnormal distribution of melanin.26
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Stages of PIH
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PIH is like other disease, we can divide PIH in three stages: erythema stage,
erythema and pigment stage, and pigment stage. All of PIH stages are different in
clinical features, involving cytokines, and also treatment methods.
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1. Erythema stage: erythema represents PIH in inflammatory stage, which
can be blanchable or shows positive diascopy test result (the lesion totally
fade after apply the pressure on that exact area.)27 They mostly contain
hemosiderin pigment which is secondary to hemorrhage.28 The melanin
pigment is not formed. Thus, anti-inflammatory agents are the first choice
of this stage.
2. Erythema and melanin stage: in this stage PIH has already been deposited
by some melanin pigment but some hemosiderin pigment (represent by
erythema) still presents.28 Therefore the lesion will partially fade when
diascopy test is applied. The lesions in this stage are in borderline between
inflammatory phase and melanin producing phase, so anti-inflammatory
agents are still useful. Moreover the depigmenting agents that block early
stages of melanogenesis play an important role to decrease melanin
production for instance tyrosinase transcription inhibitors and tyrosinase
inhibitors.
3. Melanin stage: In melanin stage or late phase of PIH lesion is fully filled
with melanin pigment. All the vascular components absent, so the diascopy
test is negative (non-blanchable).27 Thus in this stage treating by inhibition
of melanosomes transferring agents, increasing epidermal turnover, and
dispersing melanin compound could be useful.
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Pathogenesis of Postinflammatory hyperpigmentation.
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The definite mechanism of PIH is still not known.29 It can be caused by
either an excessive increase in melanin production (hypermelanogenesis) or an
abnormal distribution of melanin pigment deposited in the epidermis and/or
dermis.30,31
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Normally, when the patients have a cutaneous trauma or any inflammation,
melanocytes can react normally by increasing or decreasing formation of
melanin.30 Keratinocytes, Langerhans cells, Lymphocytes, and Neutrophils all
involve in the inflammatory response.31 These cells generate specific biochemical
signals such as inflammatory cytokines or chemokines which affect the function of
the pigment cells, making PIH a part of normal response of skin to the
inflammatory stimuli.31 However some of the studies believed that PIH is related to
the consequence of inflammation due to the pigmentation is greater in chronic and
recurrent inflammatory processes.29
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Moreover there are various inflammatory mediators involving in PIH
process including arachidonic acid metabolites, prostaglandins (PGE2),
leukotrienes (LTC4, LTD4), thromboxane (TXB2), interleukines (IL-1, IL-6),
epidermal growth factor and reactive oxygen species (nitric oxide).23,32 All of these
cytokines have a role in stimulating melanocyte by enhance tyrosinase enzyme
activity then increasing in melanin production (Figure1, 2) as well as triggering
dendrite of the melanocyte proliferation.23,29,32 In addition to the inflammatory
process, LTC4 significantly increases tyrosinase enzyme activity in cultured
melanocyte, mitotic activity of melanocyte, and also transforming growth factoralpha to stimulates the migration of melanocytes and transfer pigment to the
surrounding keratinocytes.21,30 Some in vitro studies have shown that all of these
inflammatory cytokines stimulate human melanocyte enlargement and dendritic
proliferation.21,29,30 Fisk WA et al.13 stated that elevating level of inflammatory
cytokines such as interleukine-6, leukotriene C4, leukotriene D4, prostaglandin E2
all stimulate the dendrite proliferation, melanin pigment production, and
melanocyte cell growth.
Botanical extracts for postinflammatory hyperpigmentation treatment.
Nowadays, botanical extracts are another emerging trend in cosmeceutical
and pharmaceutical segment because people have more concern more in using
chemical or conventional treatment. Gold standard of PIH treatment is
Hydroquinone which can cause a lot of side effects from erythema, irritation, or
halo hypopigmentation to the most serious one: “exogenous ochronosis”.31,33 This
is the reason we try to find a novel active compound that has less side effects and
efficacy is equal to or higher than hydroquinone. Plant extracts are good alternative
to hydroquinone in treatment of PIH. All of natural extracts do not have
melanotoxicity activity, so they will not cause permanent ochronosis.34
In this review, we collect the study about plant or botanical extracts, herbal
preparations, and also isolated plant-derived compound.
Arbutin
Arbutin, from the dried leaves of bearberry (Arctostaphylos uva-ursi), blueberry,
cranberry, and pear trees, are natural -D-glucopyranoside and derivative of
hydroquinone.31,34-36 The mechanism of suppressing melanin production is to
competitively inhibit tyrosinase enzyme at binding site and DHICA (5,6dihydroxyindole-2-caboxylic acid) and also inhibit melanosome maturation.34,35,37
Arbutin can cause paradoxical hyperpigmentation when being used at high
concentration.21,38
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Deoxyarbutin has shown a promising skin lightening qualification.37 Alphaarbutin are widely used and 20-fold more potent form of arbutin.34,37
Aloesin
Aloesin is a natural compound isolated from aloe plant.34,39 It is a competitive
inhibitor at binding site of tyrosinase and DOPA (3,4-dihydroxyphenylalanine)
oxidase.34,35 Aloesin inhibits melanogenesis enzymes in dose-dependent manner.39
Some study showed that Aloesin has an additive effect when use with arbutin.40
Aloesin has an excellent safety profile in cosmetic use.41
Ellagic acid
Ellagic acid is polyphenol compound found in many plants such as strawberry,
grapes, cherries, walnuts, Emblica officinalis and also green tea.13 Ellagic acid is a
derivative of gallic acid which derived from Emblica officinalis.42 It is tyrosinase
inhibitor via copper chelation.43 The study by A. Dahl et al.44 compared 0.5%
ellagic acid and 0.1% salicylic acid with 4% hydroquinone in hyperpigmentation
and dark spots. They have shown that no adverse effect or reaction from ellagic
acid group and there were no statistically significant between the 2 groups.44
Emblica Extract
Emblica extract obtained from Indian gooseberry, gooseberry, amla, amalaki, or
aonla: Emblica officinalis.45 These plants can be found in many subtropical
countries such as China, India, Thailand, Pakistan, Sri Lanka, Uzbekistan and
Indonesia.42,46 The active ingredients from Emblica extracts have high levels of
phenolic compounds including tannins (e.g. gallic acid, ellagic acid and its
derivatives) and flavonoid (e.g. quercetin) which inhibit melanogenesis and have
antioxidant properties.45-47
Flavonoids
Flavonoid are polyphenolic substances which can be found in green tea leaves,
gallic acid, barley, ellagic acid, red wine, cranberry juice and etc.34 Flavonoids are
secondary metabolites synthesized via the phenylpropanoid pathway.48 There are
six majors sub-type of flavonoids: chalcones, flavones, flavonols, isoflavones,
anthocyanins and flavonones.34,48 The mechanism of action may be antioxidant,
inhibit melanocyte proliferation, and inhibit tyrosinase enzyme.34
Ginseng
Panax ginseng or ginseng has been used for thousand years especially in Asia.49 It
has an effect on several systems in body. There are a lot of active compounds in
ginseng including ginsenosides, polysaccharides, peptides, polyacetylenic alcohols,
and fatty acids, ginsenosides contain most of pharmacological effect of ginseng.11
In the study by Seung Jae Lee et al. about Rg3 (active ingredient found in Ginseng)
have shown that Rg3 downregulates MITF expression, tyrosinase and TRP-1.11 In
some studies, they isolated three ginsenosides (ginsenoside Rh6, vina-ginsenoside
R4, and ginsenoside R13) from the leaves of hydroponic P. ginseng which all have
in inhibitory effect on tyrosinase.50 Moreover, Yeonmi Lee et al.51 extracted
compound from ginseng seeds which also have tyrosinase inhibitory effect on
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melanogenesis. In addition, Dae Young Lee et al. get ginsenosides Rb2 (Gin-Rb2)
from P.ginseng berry that decrease MITF protein expression and tyrosinase
enzyme.52 Whereas ginsenosides Rb1 is isolated from ginseng roots that inhibit melanocyte-stimulating hormone (-MSH) in dose dependent.53
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Niacinamide (Available concentration: 2-5%)
Niacinamide, a biologically active amide form of niacin or vitamin B3, found
extensively in many root vegetables and yeasts.34 It involved in inhibiting transfer
of melanosomes from melanocytes to the surrounding keratinocytes by modulating
PAR-2.23,34,35,59 It also improve epidermal barrier function by increasing ceramides
and other lipids synthesis in stratum corneum.59 Moreover, niacinamide shows antiinflammatory activity by decreasing mononuclear cells and phagocytic cells
infiltrate, and free radical scavenging properties.23,60 Niacinamide has high
stability, so the efficacy is not effected by heat, light, moisture, acids, alkalis, or
oxidizers.21,61 Furthermore, niacinamide does not cause “niacin flush”.61 In vitro
study, Bora Kim et al. synthesized N-nicotinoyl dopamine, a newly niacinamide
derivative, which significantly reduce skin pigmentation.62
Ginkgo
Ginkgo (Ginkgo biloba) is extracted to flavone glycosides and biflavones, mostly
quercetin and kaempferol derivatives.54,55 It shows tyrosinase inhibiting properties
by chelating copper in this enzyme and free radical scavenging effect.54
Green tea
Green tea extracts are polyphenolic compounds which the major active ingredient
is epigallocatechin-3-gallate (ECGC).36,56 They also have antioxidant and antiinflammatory properties.36 Green tea phenolic components inhibit tyrosinase to
promote depigmenting effect.36,57 Moreover, Camellia sinensis L. water extracts in
green tea inhibit tyrosinase activity more efficiently than arbutin in Young Chul
Kim et al. study.56
Hesperidin
Hesperidin (3′, 5, 7-trihydroxy-4′-methoxyflavanone) found in the peel of many
citrus fruits.34,58 It is one kind of bioflanonoid. Hesperidin inhibits melanogenesis
by being a reversibly competitive binding of tyrosinase.58 In addition, it suppressed
UVA-induced oxidative damage.13
Licorice extracts (Available concentration of glabridin: 0.5%)
Licorice extracts are derived from Glycyrrhiza Glabra Linnera and Glycyrrhiza
uralensis.21,35 Licorice extracts properties are like two-face of coin, there are many
active compounds that may inhibit or stimulate melanogenesis. Glabridin, a
polyphenolic isoflavonoid, is the main ingredient in licorice extract which is
tyrosinase inhibitor.34 Moreover, it has an antioxidant activity and antiinflammatory effect which inhibit both cyclooxygenase and lipoxygenase products
(PGE-2, TXB-2, and LTB-4).36 In addition, it has a role in dispersing the melanin
by liquiritin and decrease free radical formation.21,31,35
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Mulberry
Mulberroside F and mulberroside A, as the active compound, are derived from
dried mulberry root bark (Morus alba L).34,35,63 It can inhibit tyrosinase activity and
scavenge superoxide in melanogenesis process.34,35 In the compared study,
inhibitory effect of mulberroside F is stronger than kojic acid.64 Moreover, Purified
mulberroside A was biotransformed to oxyresveratrol and oxyresveratrol-3-Oglucoside which could inhibit tyrosinase more potent than mulberroside A.63
Pycnogenol
Pycnogenol is derived from Pinus pinaster bark the French maritime pine bark.65 It
contains bioflavonoids, catechins, procyanidins, and phenolic acids.65 It plays role
in anti-oxidative stress, anti-inflammatory, and free radicals scavenger.35
Furthermore, in melanogenesis pycnogenol inhibits tyrosinase and result in
decrease melanin production.66
Soy
Phospholipids and essential fatty oils are the main components of soy.35 There are
many active components including isoflavones, vitamin E, serine protease
inhibitors, and soybean trypsin inhibitor (STI), and Bowman-Birk protease
inhibitor (BBI).35 The role of soy extract in melanogenesis is to inhibit serine
protease enzyme. Serine protease inhibitor is heat labile enzyme, thus soybean
extracts have to be preserved to maintain their effect.36 Soybean extract inhibits
protease activated-receptor-2 (PAR-2) (a G-protein couple receptor) of keratinocyte
leading to reducing melanosomes transfer and inhibiting phagocytosis
melanosomes by keratinocytes.13,21,31,35 Skin will also be smoothed and softened by
large soy proteins.45 Furthermore, isoflavones play role in antioxidants activity.36
Table 1 demonstrate the efficacy of natural compounds or extracts.
Compounds/
Extracts
Arbutin
Mechanisms
 Competitive tyrosinase
inhibitor.
 Inhibit melanosome
maturation.
Efficacy
 In human clinical trial, topical
deoxyarbutin for 12 weeks resulted in a
significant or a slight reduction in overall
skin lightness.67
 In vitro study, deoxyarbutin demonstrated
the effective inhibition by using lower
concentration that HQ, and arbutin.67
 In human study, suppressed pigmentation
by 43.5%68
Aloesin
 Competitive tyrosinase
inhibitor in dosedependent manner.
 In human study, suppressed pigmentation
by 34%68
 In human study, co-treatment with arbutin
suppressed pigmentation by 63.3%68
9
 Inhibited mushroom tyrosinase more potent
than arbutin.69
Ellagic acid
 Tyrosinase inhibitor via
copper chelation.
 Suppressed pigmentation more than kojic
acid or arbutin at the same dose on B16/F0
mouse melanoma cells.70
 12-week, single-center, double-blinded
clinical study, topical 0.5% ellagic acid and
0.1% salicylic acid was more effective in
reduce pigmentation in early intervals
compared to 4% HQ. But after 8-12 weeks,
4% HQ was better.44
Emblica extract
 Antioxidant.
 Inhibit melanogenesis.
 In facial dyschromia, similar effectiveness
between product containing kojic acid,
emblica extract, and glycolic acid,
compared to 4% HQ.71
Flavonoids
 Antioxidant.
 Inhibit melanocyte
proliferation.
 Tyrosinase inhibitor.
 Suppressed UVAinduced oxidative
damage.
 Competitive and
reversible tyrosinase
inhibitor.
 Antioxidant.
 Anti-inflammatory.
 Inhibit melanosome
transfer.
 Garcinia gardneriana inhibited
melanogenesis by 35.2% while kojic acid
inhibited by 87%.72
 Antioxidant.
 Anti-inflammatory.
 Tyrosinase inhibitor.
 The concentration for inhibiting mushroom
tyrosinase of licorice extracts are lower
than kojic acid.76
 In clinical trial study, topical liquiritin
therapeutically effective in melasma, with
complete disappearance in 18 (90%) out of
20 at week 4.77
 No statistic differences between emblica,
licorice and belides group in the
Hesperidin
Niacinamide
Licorice extracts
 Hesperetin bound more tightly to
tyrosinase than kojic acid.58
 No effect on the activity of mushroom
tyrosinase in cultured melanocytes.73
 In vitro study, inhibited melanosome
transfer by 35–68%. 73
 Topical 0.05% and 0.1% N-nicotinoyl
dopamine emulsions decreased melanin
production by 31.1% and 28.5%.74
 The niacinamide + tranexamic acid
formulation was significantly more
effective than the vehicle control in
reducing the pigmentation. 75
10
Mulberry
 Antioxidant.
 Tyrosinase inhibitor.
Soy
 Antioxidant.
 Reduce melanosome
transfer.
 Inhibit phagocytosis
melanosomes by
keratinocytes.
improvement of melasma compared to
2%HQ with less skin adverse events.78
 There is no human clinical study of licorice
extracts in PIH.
 Mulberroside F was used at higher
concentration than kojic acid to suppress
mammalian tyrosinase activity for 50%.79
 A 16-week, double-blinded, clinical study
of Fitzpatrick skin types III to V and acneinduced PIH, there was a significant
improvement in PIH with the soy
formulation compared to placebo.21
 Significant improvement in mottled
hyperpigmentation, using soy-containing
moisturizer.80
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Currently, There are a lot of new
emerging natural compounds or plant extracts Table 2: Anti-inflammatory agents
 Alpinia zerumbet (alpinia).81
from all around the world. They act as an
 Betulinic acid from Vitis amurensis
effective depigmenting or whitening agents with
root.82
less or no side effect. Their inhibiting
 Calamondin.3
mechanisms involve most steps of melanogenesis
 Corn silk (Zea mays L.).83
including before melanin production, during
 Doenjang: fermented soybean
melanin production, and even after melanin
paste.84
production as the table 2 shown.
 Ephedra sinica, (common names Ma
Many compounds can decrease melanin
Huang or Ephedra) (ephedrannins A
and B).85
production at the start point which inhibit the
 Eupafolin, from Phyla nodiflora.86
signals stimulating melanogenesis. As mentioned
 Hesperetin.58
earlier, inflammatory mediators, reactive oxygen
 Oil content of Idesia polycarpa
species, or even UV radiation could aggravate the
fruit.87
severity of PIH. Therefore, antioxidant, antiinflammatory, and the absorbing UV agents could
be the potential agents in reduce melanin synthesis. Some of the natural compounds
are antioxidants for instance Corn silk (Zea mays L.)83, Doenjang84, Garcinia
garderiana72, Hesperetin58 which are not shown in the table.
There are many enzymes play a role in melanogenesis and one of the most
important enzymes is tyrosinase. They have been controlled by the transcription
factors such as MITF. Tyrosinase is the most popular target in inhibiting
melanogenesis because it is the rate limiting step enzyme. Table 3 shows a lot of
compounds that inhibit tyrosinase, increase tyrosinase degradation, or even
suppress or degraded MITF transcription factors.
At present, the last step that can reduce melanin accumulation is inhibiting
melanosome transfer from melanocytes to keratinocytes. There is not much natural
extracts involving in this step.
11
351
352
353
354
355
356
357
358
Several mechanisms of the natural compounds or plant extracts in the table
3 have the same goal which reduce melanin synthesis or decrease melanin
accumulation in the keratinocytes.
Table 3 shows the recent active botanical ingredients/compounds,
mechanisms of action, and study.
Table 3. Botanical or plants extract from Journals and their mechanism of actions
both in Vitro and in Vivo studies.
Mechanism
Compounds/extracts

Alpinia zerumbet
(alpinia) from the
Zingiberacea.81

Calamondin.3

pods.88
Antioxidant

Cocoa
Pomegranates.89
Before
melanogenesis
Antiinflammatory
Absorb UV
Study
 Strongly inhibited the ROS
production.
 Antioxidant activity of immature
calamondin peel (56.9–64.3%)
higher than mature (35.0–48.9%).
 Good antioxidant activity,
compared to ascorbic acid and
standardized pine bark extract.
 Concentrations 1 mg/mL or higher
exhibited scavenging activity
similar to the vitamin C and vitamin
E.
In table 2


Cocoa pods.88
Alpinia zerumbet
(alpinia).81
Melanogenesis Inhibit/ downregulate MITF
 Higher sun-protecting action in
cocoa pods extract (luteolin) at
UVA wavelength (330 nm), which
were absent in pine bark extract.
 Moderate absorbance of UVA (315400 nm), significantly better than
pine bark extract.
 The presence of methyl salicylate
enhanced the absorbance.
 Significant better absorbance than
Avobenzone at 308 nm.
 Inhibited tyrosinase activity by 7083% in murine B16F10 melanoma
cells.
 Reduced the melanin content by 6379%.
 Inhibited tyrosinase, TRP-1, and

Betulinic acid from
Vitis amurensis root.82
TRP-2 expression through the
modulation MITF and CREB in
B16F10 cells.
12



Inhibit/ downregulate MITF

Melanogenesis
Doenjang: fermented
soybean paste.84
Eupafolin, from Phyla
nodiflora.86
Kadsuralignan F. from
Kadsura coccinea.91

Phyla nodiflora Greene
(Verbenaceae).92

Sweroside from
Lonicera japonica.93


Inhibit
transcription of
melanogenic
enzyme
Citrus unshiu.90


Arthrophytum
scoparium.12
Betulinic acid from Vitis
amurensis root.82
Citrus unshiu.90
Corn silk (Zea mays
L.).83
 Significant decreased melanin
content in a dose-dependent manner
compared to the control group in
B16F10 cells.
 Inhibited melanin production in
mushroom tyrosinase + B16
melanoma cells.
 Reduced pigmentation in human
skin equivalents compare to kojic
acid.
 Western blot assay, the protein
levels of p-CREB and MITF
decreased in Eupafolin treatment
group when compared to the control
group in B16F10 cells.
 At the highest concentration of
Kadsuralignan F, MITF was
decreased to 72% levels of the
untreated control.
 Reduced synthesis of tyrosinase,
TRP-1, TRP-2, and melanin
content.
 Inhibited cellular tyrosinase activity
in B16F10 cells.
 Significantly reduced MITF in
melan-a cells, using PTU as a
positive control.
 Significantly decreased the
expression of tyrosinase.
 Significantly down-regulated
tyrosinase, TRP-1, MITF and Mc1R
mRNA expressions.
 Suppressed tyrosinase, TRP-1, and
TRP-2 via inactivation of
transcription factors, CREB and
MITF in B16F10 cells.
 Inhibited α-MSH, TRP-1, and TRP2 expression of B16/F10 melanoma
cells in a dose-dependent manner.
 Corn silk extract decreased melanin
production by 37.2%, more than
arbutin at the same concentration in
melan-A cells from C57Bl/6 mice.
13
Inhibit
transcription of
melanogenic
enzyme

Hordenine from
germinated barley.
(Hordeum vulgare L.).94

Kadsuralignan F. from
Kadsura coccinea.91

Pomegranates.90

Sweroside from
Lonicera japonica.93

Withaferin A from
Withania somnifera,
commonly known as
Ashwagandha or Indian
winter cherry.95
Melanogenesis
Inhibit tyrosinase

Calamondin.3

Cocoa pods.88
 Ephedra sinica, (common
names Ma Huang or
Ephedra)(ephedrannins A
and B)85

Garcinia garderiana.72
 Significantly decreased MITF
expression in a concentrationdependent manner.
 Inhibited the production of
tyrosinase, TRP-1, and TRP-2.
 Remarkably decreased the protein
expression of tyrosinase in western
blot analysis.
 Reduced the protein level of TRP-1,
tyrosinase, and MITF in treated
group compared to control in
B16F10 cells.
 Reduced in tyrosinase, TRP-1, and
TPR-2 protein expression compared
to the vehicle treatment.
 Decreased in total melanin content
and tyrosinase activity in zebrafish.
 Significantly suppressed CREB and
MITF.
 Significantly suppressed Tyrosinase
activity.
 C-glycosylated flavonoid shows the
strongest inhibitory activity against
tyrosinase among the components in
this fruit, with concentration 0.87
mg/ml for inhibiting 50%
tyrosinase.
 Inhibited mushroom tyrosinase
more than kojic acid and ascorbic
acid, but less than pine bark extract.
 Both compounds significant
inhibited mushroom tyrosinase, but
ephedrannin B was more effective
than ephedrannin A.
 A maximal inhibition of mushroom
tyrosinase activity was 35%.
 Decrease in melanin content and a
maximal inhibition of tyrosinase
was 34.13% in B16F10 murine
melanoma cells.
14




Inhibit tyrosinase

Hesperetin.58
Morus alba leaves.96
Oil content of Idesia
polycarpa fruit.87
Oxyresveratrol, Morus
alba L.97
Pouteria torta and
Eugenia dysenterica
extracts.98
Melanogenesis
Tyrosinase
degradation

Resveratrol.97

Salvia miltiorrhiza
Bunge (Lamiaceae)
Danshensu (DSU) and
salvianolic acid B
(SAB).99

Schinus terebinthifoliu
Raddi and a linoleic acid
fraction isolated from
Passiflora edulis oil.15

Kadsuralignan F. from
Kadsura coccinea.91
 Tyrosinase was almost completely
inactive at 50 mM Hesperetin.
 In vitro study, Morus alba leaves
inhibited 74.8% mushroom
tyrosinase.
 At the same concentration, oil
content of Idesia polycarpa fruit
showed qualitatively similar
inhibitory effects to HQ (𝑃 > 0.05).
 Oxyresveratrol, decreased melanin
contents to 64.63% compared to
vehicle control (100 %), using a
three-dimensionally reconstituted
TM
skin model, MelanoDerm .
 In vitro study, potent tyrosinase
inhibition compared to positive
control kojic acid.
 Extract of Eugenia dysenterica
leaves show significant tyrosinase
inhibitory activity using less
concentration than kojic acid.
 Pouteria torta aqueous extract
leaves show significant inhibitory
activity using more concentration
than kojic acid.
 Resveratrol decreased melanin
content to 41.06% compared to
vehicle control, using a threedimensionally reconstituted skin
TM
model, MelanoDerm .
 DSU inhibit dopachrome formation
74% at a concentration of 60 mM,
in a dose-dependent manner.
 SAB inhibit dopachrome formation
31% at a concentration of 17 mM,
in a dose-dependent manner.
 In vitro tyrosinase activity assay,
show a significant and dosedependent potential to inhibit
tyrosinase activity, concentration
less than HQ, and near to the gallic
acid.
 Kadsuralignan F induced tyrosinase
degradation via the proteasomal
pathway, and subsequent melanin
15
contents were reduced in melan-A
cells and human skin equivalents.
Melanogenesis
After
melanogenesis
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
Inhibit
melanosome
transfer.

Saururus chinensis Baill
(ESCB) and components,
manassantin B.100
 ESCB and manassantin B inhibit
melanosome transport in Melan-a
melanocytes by disrupting the
interaction between Mlph and
myosin Va, but not the interaction
between Mlph and Rab27a, in a
dose-dependent manner.
Conclusion
Recently, the botanical extracts are very popular in many researches and
many new botanical active compounds are discovered. This trend occurs in
accordance to patient’s behavior as they seek natural compound therapies as an
alternative to chemical and/or conventional treatment. From the plants all over the
world, there are a lot of active ingredients that could reduce melanin production in
both direct and indirect ways. This review article tries to collect the data regarding
active compounds or extracts from plants and its mechanism of actions in order to
act as a database of skin lightening products, especially for postinflammatory
hyperpigmentation. Using several active compounds, which having different
pathway to inhibit melanogenesis, is the excellent combination for the best
effective topical therapies.
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