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R E V I E W Open Access
Skin hyperpigmentation and its treatment
with herbs: an alternative method
Prity Rathee
1
, Sunil Kumar
1,2*
, Dinesh Kumar
1
, Beena Kumari
2
and Savita S. Yadav
3
Abstract
Background: With an increasing number of patients, those who are facing a lot of skin-related complaints, often
referred to as skin of pigmentation patients, are on the rise. Among all the most common complaints in patients
with skin of color is hyperpigmentation. So, there is need of herbal formulation for treatment of hyperpigmentation.
Main body: This review article addresses the different types of hyperpigmentation, causes, and its treatment with
herbs for the management of the skin hyperpigmentation. As uneven pigmentation of skin or hyperpigmentation is
a common skin condition, which occurs when the skin produces more melanin. This can make spots or patches of
skin appear darker than surrounding areas. Some forms of hyperpigmentation with post-inflammatory, melasma,
and sun spots are more likely to affect areas of face, arms, and legs due to sun exposure and injury. Although the
availability of multiple treatments for the condition which leads to some adverse effects, hyperpigmentation
continues to present skin care management challenges for dermatologists.
Conclusion: Some plants and phytoconstituents, e.g., Azadirachta indica,Glycyrrhiza glabra,Panax ginseng and
genistein, ellagic acids, quercetin, are very useful in herbal cosmetic as anti-hyperpigmentry agents in cosmetic
industries. Some of flavonoids and triterpenoids present in plants also show their effect as antioxidant and skin
whitening agents. It is expected that this review will compile and improve the existing knowledge on the potential
utilization of herbs for the treatment of skin hyperpigmentation.
Keywords: Melanin, Hyperpigmentation, Tyrosinase, Age spot, Melasma
Background
Skin hyperpigmentation is a disorder in which patches
of skin become darker in color than the normal sur-
rounding skin. This occurs when melanin is overpro-
duced in certain spots on the skin. Melanin is an
important pigment in skin hyperpigmentation which
is produced by the process called melanogenesis. In-
creased melanin pigment in epithelial cell is called
melanosis. Epidermal melanosis is when melanocytes
are in normal number but melanin is increased in
hyper pigmented skin and dermal melanosis occur
when melanin is present within the dermis between
bundles of collagen [1]. Melanocyte cells (one mel-
anocyte is surrounded by approximately 36 keratino-
cytes) produce two type of melanin pigment,
eumelanin (Black or brown) and pheomelanin (yellow
reddish) which are responsible for skin, hair, and eyes
color in human. There is mainly three type of skin 3
hyper-pigmentation which are melsama [2,3], post-
inflammatory hyper pigmentation, and age spot or
liver spot [4]. Skin hyper-pigmentation is caused by
sun exposure, Addison’s disease [5], hormonal imbal-
ance, and vitamin B
12
[6]. In skin cell, UV radiation
produces reactive oxygen species (ROS) which activate
the intracellular signaling pathways including
mutagen-activated protein kinase. As human keratino-
cyte exposed to UV-B radiation shows higher p38
mitogen-activated protein kinase (MPAK) activity,
which produce pro-inflammatory cytokines such as
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* Correspondence: sunilmadhuban@igu.ac.in
1
Institute of Pharmaceutical Science, Kurukshetra University, Kurukshetra
136119, India
2
Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur,
Rewari 122502, India
Full list of author information is available at the end of the article
Future Journal of
Pharmaceutical Sciences
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132
https://doi.org/10.1186/s43094-021-00284-6
1L-1, cyclooxygenase (cox-2), and TNF-αexpression
[7]. There are two enzymes responsible for melanin
production; one is tyrosinase and the other is dopa-
chrome tatuomerase. Tyrsosinase is a main enzyme in
melanin growth and over activity of tyrosinase en-
zyme causes hyper-pigmentation [8]. Tyrosinase in-
volves amino acid tyrosine which on hydroxylation
convert into L-3,4-DOPA that form DOPA-quinine by
oxidation which is further oxidized by a free radical-
coupling pathway to form melanin [9,10]. The other
enzyme dopachrome tatuomerase catalyze the trans-
formation of dopachrome into 5,6-dihydroxyindole-2-
carboxylic acid (DHICA) [11]. There are many herbs
or chemical compound found which has tyrosinase in-
hibitory properties. Tyrosinase inhibitors demands are
increasing on the industrial and clinical scale, so in-
vitro assay and screening technique are also devel-
oped for tyrosinase inhibitor and other skin whitening
agent [12]. Herbs like Glycyrrhiza glabra,Panax gin-
seng,Embica officinalis,Azadiracta indica,Curcuma
longa [13], etc. have been used for treatment of skin
hyperpigmentation as shown in Table 1. Also, phyto-
constituents like ellagic acids, quercetin, and some
whitening agent like kojic acid [72], arbutin [73], etc.
are used for treatment as skin hyperpigmentation.
Main text
Type of skin hyperpigmentation
Post-inflammatory hyperpigmentation
It is the acquired hypermelanosis after the skin inflam-
mation or injury that can occur in all skin types. It may
occur due to infections such as dermatophytosis, allergic
reactions such as mosquito bites, psoriasis, hypersensi-
tive reactions due to medications, or injury from irritant
(Fig. 1a), or cosmetic procedures. However, acne vulgaris
(Fig. 1b), atopical dermatitis, and impetigo are very
common causes of it. Indeed, post-inflammatory hyper-
pigmentation (PIH) is mainly common after acne in
dark-skinned patients. PIH results from the overproduc-
tion of melanin or an irregular dispersion of pigment
after inflammation. There may be rise in melanocyte ac-
tivity which may be stimulated by inflammatory media-
tors as well as reactive oxygen species. Light to dark
brown coloration in epidermal post inflammatory hyper-
pigmentation, whereas dermal PIH tends to be grey to
black coloration [74].
Melasma
Melasma is an acquired hypermelanosis characterized by
asymmetric, brown-colored, irregular, reticulated mac-
ules on sun exposed areas of the skin, especially the face
(Fig. 1c, d). However, chronic ultraviolet (UV) exposure,
female hormone stimulation, and predisposed genetic
background have all been proposed to play a role in the
development of melasma [74]. It is also noticed that a
release of histamine from mast cells in response to UV
irradiation has been demonstrated to stimulate melano-
genesis, which is mediated by H2 receptors via protein
kinase A activation. Sebocytes have been hypothesized
to contribute to the development of melasma. Further
studies are needed on the role of sebocytes in the patho-
genesis of melasma [75].
Effect of hormone on melasma Hormones play a role
in the pathogenesis of melasma, estrogen, and progester-
one have an impact in melasma development, because
melasma is common in pregnancy, hormonal contracep-
tive use, estrogen therapy in prostate cancer patients,
and conjugate estrogen use in women after menopause.
In females, melasma is more frequent than in males.
Melasma is an undesirable cutaneous effect of oral con-
traceptives. Melasma is commonly regarded as a physio-
logical change in skin caused by hormone changes.
Estrogens play a major role in both physiological and
pathological conditions of the skin, including pigmenta-
tion. Estrogen and progesterone biological effects are
regulated by their different receptors [75,76].
Therapeutic implications The main method of treating
melasma is still topical depigmentants. The most com-
mon anti-melanogic agent is hydroquinone, which in-
hibits the conversion of 1-3,4-dihydroxyphenylalanine to
melanin via competitive tyrosinase inhibition, has also
raised safety concerns such as exogenous ochronosis,
permanent depigmentation, and potential cancer hazards
[2]. The following are considered as alternatives to top-
ical agents identified for having depigmenting properties
with no adverse effects: resveratrol, azelaic acid, 4–n-
butyl resorcinol, niacinamide, kojic acid, and ascorbic
acid [75].
Age spot
Thebrownspotsoftheskinareagedmarks(Fig.1e).
Skin regions, including the face and the back of the
hands, grow primarily on that part of skin, which is
often exposed to sunlight [9].Agespotsarebrownbe-
cause of lipofuscin bodies of the basal cells. Lipofuscin
is the lysosome lipid and protein mixture in which
lipids bind by malondialdehyde to protein fragmenta-
tions. Age spots vary in form, scale, color, and degree
of protrusion in part of the skin. The skin’sagespots
are made up of the basal cells that bind to the basement
membrane in epidermis. The basal cells are the stem
cells responsible for the regeneration and repair of epi-
dermis in new epithelial cells. Basal cells and chemical
substances can be damaged by ultraviolet radiation and
some injured cells can survive and grow old by
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132 Page 2 of 14
Table 1 Herbs used for treatment of skin hyperpigmentation
S.No Herbs Part used Mechanism of action Phytoconstituents Reference
1Glycyrrhiza glabra
[Fabaceae]
Root UVB protection
Moisturing agent
Glycyrrhizic acid, Glycyrrhizin, Glabridin [14,15]
2Vitex negundo
[Verbenaceae]
Root Tyrosinase inhibitory Negundin A, [+]-lyoniresinol-3a-O-b-D-
glucoside
[16]
3Aloe-barbadensis
[Asphodelaceae]
Leaf Mosituring agent
Tyrosinase inhibitory
Aloesin, 2"-Feruloylaloesin [17,18]
4Morus alba
[Moraceae]
Fruit Tyr. 7 inhibitor
ROS scavenger
Apigenin, umbelliferone, astragalin,
Moranoline, 1-deoxynojirinmycin, resveratrol
[15,19]
5Panax ginseng
[Araliaceae]
Root Antioxidant, and skin whitening
Agent
Ginsenoside, p-Coumaric acid [20,21]
6Gingko
[Ginkgoaceae]
Flower Tyrosinasse inhibitor Ginkgolide A, bilobalide [13,22]
7Azadirachta indica
[Meliaceae]
Leaf, Bark Antioxidant
Antibactrical
Oleic Acid, Azadirachtin, isomeldenin, nimbin,
nimbinene, 6-desacetyl lnimbinene,
nimbandiol
[17]
8Santalum album
[Santalaece]
Wood Antioxidant, zskin whitening property Alpha- and beta-santalol [23,24]
9Muntingia calabura
[Muntigaceae]
Flower,
Leaf, Fruit
Antityrosinase and antioxidant activity Stigmasterol, triglyceride, α-linolenic acid [25,26]
10 Blumea balsamifera
[Asteraceae]
Leaves Antityrosinase, lipid peroxidation inhibitory
activities, liver-protective
3-O-7W-Biluteolin, [25,27]
11 Magnolia officinalis
[Magnoliaceae]
Bark Melanogenesis inhibition Magnoloside I
a
, crassifolioside, magnoloside
V
a
[28,29]
12 Pueraria
thunbergiana
[Leguminosae]
Root Melanogenesisinhibition Schaftoside, puerarin, genistin [30,31]
13 Emblica officinalis
[Phyllanthaceae]
Fruit Antioxidant, skin whitening property Quercetin, Kaempferol, Gallic acid, Methyl
gallate, Ellagic acid, Trigallayl glucose,
Phyllantine, Phyllembein
[32,33]
14 Curcuma longa
[Zingiberaceae]
Root Antioxidant, skin whitening property Curcuminoids [23]
15 Camellia sinensis
[Theaceae]
Leaves Antioxidant Epigallocatechin gallate, epicatechin,
gallocatechin
[23,34]
16 Nelumbo nucifera
Gaertn
[Nelumbonaceae]
Flower Antioxidant, tyrosinaseinhibotry activity Pronuciferine, Armepavin, Kaempferol-3-o-glu-
coside, Luteolinglucoside
[35,36]
17 Crocus sativus
L.[Iridaceae]
Dried
stigmas
tyrosinaseinhibotry activity Crocin, picrocrocin, β- carotene, safranal. [37,38]
18 Hemidesmus
indicus
[Asclepiadaceae]
Root Antioxidant, tyrosinaseinhibotry activity Hemidesminine, Lupeal, vanillin [39,40]
19 Vitis vinifera
[Vitaceae]
Seed and
leaf
Tyrosinaseinhibotry activity Gallic, protocatechuic, vanillic, syringic and
ellagic acids
[17,41]
20 Euphorbia supina
[Euphorbiaceae]
Leave,
flowers
and tubers
Antioxidant, skin lighting agent Protocatechuic acid, nodakenin, 3-O-glucoside [42]
21 Brillantaisia
cicatricose Lindau
[Acanthaceae]
Leaves Hyperpigmentation, leprosy, vermifuge, emetic,
eczema, snakebite, lactogenic
Alkaloids, glycosides, terpenoids, steroids,
flavonoids, tannins and saponins
[43,44]
22 Chenopodium
uganda
[Chenopodiaceae]
Stem,
leaves and
flower
Tyrosinase inhibitory Phenolics, flavonoids, saponins, and
triterpenoids
[44]
23 Sesamum
angolense Welw.
[Pedaliaceae]
Leaves hyperpigmentation, dysentery Terpenoids and steroids [43]
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132 Page 3 of 14
Table 1 Herbs used for treatment of skin hyperpigmentation (Continued)
S.No Herbs Part used Mechanism of action Phytoconstituents Reference
24 Proteamadiensis
Oliv.[Proteaceae]
Root, bark Skin disease, hyperpigmentation Terpenoids and steroids [43]
25 Carica papaya L.
[Caricaceae]
Leaves Moisturing agent, antioxidant, Papain, chymopapain A and B [45]
26 Acacia catechu
[Mimosaceae]
Bark Antioxidant activity, Skin whitening property Catechin, catechutannic acid. [46]
27 Arnica Montana
[Asteraceae]
Flower Inhibitor in B16 melanoma cells Triterpene, essential oils, fatty acids, thymol,
pseudoguaianolidesesquiterpene lactones
[47]
28 Artemisia
dracunculus
[Asteraceae]
Leaves inhibit melanocyte-stimulating hormone Isobutyl and piperidiyl [48]
29 Glycine max
[Fabaceae]
Seed Antioxidant, tyrosinase inhibitory activity Kunitz-type trypsin inhibitor and Bowman-Birk
protease inhibitor
[49]
30 Thymelaea hirsuta
[Thymelaeaceae]
Leaves,
Stem and
flower
Antioxidant property, antimelanogenesis effect Genkwadaphnin, gnidicin [50]
31 Betula pendula
[Betulaceae]
Bark, leaves tyrosinase inhibitory activity Phenolics, flavonoids, tannins, saponins,
glycosides, sterols and terpene derivatives
[51]
32 Caesalpinia sappan
[Fabaceae]
Wood Inhibit melanogenesis and cellular tyrosinase
activity
Homoisoflavanone, sappanone A [52]
33 Callicarpa
longissima
[Lamiaceae]
Leaves Inhibits melanin production [53]
34 Carthamus
tinctorius L.
[Asteraceae]
Seeds Melanogenesis inhibitory activity Essential oils contains palmitic acid,
palmitoleic acid, margaric acid, margaroleic
acid
[54,55]
35 Coccoloba uvifera
[Polygonaceae]
Antioxidant and anti-tyrosinase activities, inhib-
ited the production of IL-1a, TNF-a and a-MSH
in melanocytes
Titratable acid
Ascorbic acid
[56,57]
36 Colocasia
antiquorum
[Araceae]
Root and
bark
Inhibits the melanogenesis Colocasinol A [58]
37 Crataegus azarolus
L. [Rosaceae]
Leaves Effect on B16F10 melanoma cells vitexin-200-O-rhamnoside [59]
38 Juniperus chinensis
L. [Cupressaceae]
Fruit Inhibition of tyrosinase and melanogenesis Amentoflavone-7-O-D-glucoside [60]
39 Glechoma
hederacea L.
[Lamiaceae]
Stem Reduced the cellular melanin content and
tyrosinase activity
Germacrene D
Ursolicacid, oleanic acid
[61,62]
40 Garcinia livingstonei
T[Clusiaceae]
Bark Inhibit melanin production Amentoflavone
3βhydroxyeupha-5 ,22-diene
O-methylfukugetin
Morelloflavone
Volkensiflavone
[63,64]
41 Viola odorata
[Violaceae]
Leaves Anti-melanogenic activity Vitamin C, methyl salicyte [65,66]
42 Passiflora edulis
[Passifloraceae]
Seed Inhibits melanogenesis Piceatannol [67]
43 Stewartia
pseudocamellia
[Theaceae]
Bark and
fruit
anti-melanogenic activity deoxystewartianol-40 -O-arabinoglucoside
stewartianol-3-O-glucoside
[68]
44 Cyperus rotundus
[Cyperaceae]
Rhizomes TRPV1 Channel Inhibition and ORAI1Channel
Inhibition.
Valencene camphene [69]
45 Cudrania
tricuspidata
[Moraceae]
Fruit Inhibition of L-DOPA Auto-Oxidation Flaniostatin [70,71]
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132 Page 4 of 14
misrepairs [77]. Age spot are treated by some skin
lighting agents like kojic acid [78].
An aged cell has two effects on a tissue, i.e., reduced
neighborhood cell productivity in resolving environmen-
tal changes and enhanced damage fragility; and de-
creased local tissue repair performance. The adjacent
cells in an old cell are thus at increased risk of injury
and misrepairs. Through this process, an aged cell
causes neighboring cells to age [77].
Causes of hyperpigmentation
Hyper pigmentation is caused by many factors. These
may be exogenous and endogenous factor like endocri-
nologic factor: Addison’s disease, Cushing’s syndrome,
Nelson syndrome, Pheochromocytoma, Carcinoid, Acro-
megaly, Hyperthyroidism, Acanthosis nigricans, Dia-
betes. Nutritional factor: Kwashiorkor, Vitamin B
12
deficiency [5,79], Folic acid deficiency, Niacin defi-
ciency, Tryptophan deficiency, Vitamin A deficiency.
Melasma is an undesirable skin effect on contraceptive
use hormonal [76].
Treatment skin hyperpigmentation by herbs
In addition to photosafety, there are several medica-
tions and treatments to treat hyperpigmentation of
the skin of darker skin patients safely and efficiently
with some adverse reactions. So, herbs and phytocon-
stituents are better choice for treatment for skin
hyperpigmentation. Some herbs with their mechanism
of action for treatment of skin hyperpigmentation are
given in Table 1. Hydroquinone, azelaic acid, kojic
acid, liquoric extract, retinoids, etc., and treatments
like chemexfoliation and laser therapy may be effect-
ive on their own properties, or in combination with
other drugs [78,80].
The possible mechanisms of actions by which herbs
are used for the treatment of skin hyper pigmentation
are namely tyrosinase inhibitory, antioxidant, and skin
whitening effects.
Tyrosinase inhibitory effect
Tyrosinase is a copper-containing enzyme which per-
forms various functions, glycosylated, and found exclu-
sively in melanocytes [81]. It catalyzes conversion of L-
tyrosine into L-DOPA which further converted into
dopaquinone then dopachrom e[82]. Dopachrome poly-
merizes to form melanin. Inhibition of tyrosinase en-
zyme inhibit the melanin production which help to
remove the skin hyperpigmentation. Extract of herbal
drugs like licorice, Aloe vera,Vitex negundo,Morus alba,
and many other drugs are used for inhibition of tyrosin-
ase activity.
Tyrosinase inhibitory effects were calculated by the
formula:
Percentage inhibitory effect
¼hControl−Control blankðÞ−Test−Test blankðÞ
100=Control−Control blankðÞ
i
Antioxidant
Antioxidants are substances that used to neutralize re-
active oxygen species to prevent (for preventing) cells
and tissues from oxidative damage. The cutaneous anti-
oxidant system includes enzymatic and non-enzymatic
substances. Some enzymatic antioxidants like vitamin E,
vitamin C, resveratrol, and lipoic acids. These molecules
perform removal of free radicals; neutralization of singlet
oxygen in the cell membrane; prevent lipid peroxidation,
oxidative and mutagenic action to DNA inhibition; and
repair of endogenous antioxidant systems [83]. IC
50
for
resveratrol was 57.05 μg/mL, which demonstrated a
great tyrosinase inhibitory potency. But analog of kojic
acid shows the most powerful tyrosinase inhibitor [IC
50
= 28.66 μg/mL], two times more active than resveratrol
[84]. Some herbs also show antioxidant effect which are
used for the treatment of skin hyperpigmentation are
Asphodelus microcarpus [42], Euphorbia supine [85],
and Panax ginseng [42].
Fig. 1 Symptoms of skin hyperpigmentation. aPost-inflammatory hyperpigmentation. bAcne produced PIH. cMelsama on face. dMelsama spot.
eAge spots on face
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132 Page 5 of 14
Skin whitening drugs
Potency of skin whitening agents is due to phenolic
component present in the herbs. Arbutin is a natural
occurring tyrosinase inhibitor which has skin whiten-
ing property with IC
50
value of 3.0 mM in HEMn
cells [81]. The most commonly used chemical agents
are hydroquinone [HQ], arbutin, kojic acid, liquid ni-
trogen, laser treatment, chemical skinning, and super
natural dermabrasion [28]. Also, ascorbic acid and its
products and there are many of herbs or herbal ex-
tract used as skin whitening agents are Syzygium aro-
maticum,Magnolia officinalis,andHolarrhena
antidysentrica.
Glycyrrhiza glabra
Glycyrrhiza glabra extracts play a large role on the skin
mainly as a result of its antioxidant activity, especially its
strong antioxidant glycyrrhizin, triterpene saponins, and
flavonoids. The main attributes are skin whitening, skin
depigmentation, lightening of skin, anti-aging, anti-
erythemic, emollient, anti-acne, and photoprotective ef-
fects [86]. Gabridin is present in the hydrophobic part of
the root extract of Glycyrrhiza and it can reduce tyrosin-
ase activity in culture on melanocytes and inhibit UVB
induction [86].
The extract of licorice inhibits the tyrosinase activity
by inhibiting oxidation of L-DOPA to an IC
50
value of
53 μg/mL. Glabridin content has highest inhibition ac-
tivity on tyrosinase. The highest inhibitory activity was
reported on the first oxidation of tyrosine with IC
50
value of 0.9 μg/mL [87].
Vitex negundo
A poultice of this plant is used for the diagnosis of
hyperpigmentation as melasma or ephelides by local
cosmetic practitioners. Negundin contains lactone
functionally at C-2 position with potent IC
50
value of
10.06 mM against tyrosinase enzyme [16]. Vitex
negundo is used as skin whitening agent, tyrosinase
inhibitor, and inhibit the synthesis of post inflamma-
tory pigmentation [88]. Vitex negundo contains a
number of chemical constituents, one of them is
negundin A.
Aloe
The leaf gel is used as a cure for minor burns and sun-
burns [7] and Aloe vera gel mainly has antifungal, anti-
inflammatory, and hepatoprotective potential [89]. The
isolates of Aloe vera are barbaloin, aloesin, aglycone of
aloenin, 2′′-O-feruloyl aloesin, isoaloeresin D, and aloe
resin E shows potent tyrosinase inhibitory properties.
Lyophilized gel shows IC50 = 10.53 and 6.08 mg mL
−1
is
for methanolic extract. Aloesin shows highest inhibition
value than other molecules extracted form aloe [90].
Morus alba
Flavonoids present in Morus alba extract shows antioxi-
dant and tyrosinase-inhibiting properties. Tyrosinase-
inhibiting activity of mulberry extract is comparable with
HQ and kojic acid [29]. Oxyresveratrol and
Mulberroside-A derived from M.alba root which
strongly inhibit the monophenolase production and in-
hibit mushroom tyrosinase activity in melanin synthesis
[44]. They have properties of fever reduction, liver pro-
tection, and blood pressure lowering. The polyphenols
in the leaves have properties for depigmentation [86].
Mulberroside F have 51.6% inhibition at 1 μg/mL con-
centration on 0.29 μg/mL IC
50
value [91].
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132 Page 6 of 14
Panax ginseng
Panax ginseng is a herb containing various therapeut-
ically active ginsenosides. P-Coumaric acid isolated
from Panax ginseng fresh leaves was used to inhibit
L-tyrosine oxidation catalyzed by mushroom tyrosin-
ase. The Panax ginseng berry isolates are Floralginse-
noside [FGA], Ginsenoside [GRd], and Ginsenoside
Re [GRe].
Of these 3, floralginsenoside [FGA] has been ob-
served to have a powerful inhibitory effect on mela-
nogenesis by means of reduced expression of the
microphthalmic-associated factor [3]. Ginseng’sim-
portance lies in its many pharmacological roles, such
as anticancer activity, as well as shows activity like
antioxidant, aging, antistress, and anti-fatigue. Due to
the free radical activity of DPPH, the potent antioxi-
dant activity of PgAuNPs has been observed. Panax
ginseng leaves also have skin whitening, skin-
protective and moisture retention properties [13,21,
22]. Extract of panax ginseng shows 3.65mM IC
50
value [92].
Gingko biloba
Ginkgo biloba is a member of the Ginkgoaceae family.
The G.biloba extract EGb 761, which contains, most
of it, quercetin and Kaempferol derivatives, and ter-
pens [6%] from tree leaves, containing flavone glyco-
sides [33%] which has shown capacity to minimize
sunburn cells in mice from ultraviolet B (UVB) [93].
Gingko shows anti-inflammatory, anti-vasculature,
antioxidant, and tyrosinase properties [8]. Gingko is
used to treat various medical problems such as poor
circulation of the blood, hypertension, poor memory,
and depression [93]. The water extract of Gingko
biloba inhibit 50% of tyrosinase activity at 2.25 mg/
mL IC
50
. Also, ethanol and ethanol-ether mixture ex-
tract shows 50% inhibitory activity at IC
50
value 75
and 0.32 mg/Ml respectively [94].
Azadirachta indica
Azadirachta indica shows activity against tyrosinase en-
zyme and also shows antioxidant and antibacterial prop-
erties [95]. It contains isomeldenin, nimbin, nimbinene,
6-desacetyllnimbinene, nimbandiol, and Azadirachtin.
Santalum album
Sandalwood has many medicinal properties like anti-
inflammatory, antiphlogistic, antiseptic, antispasmodic,
carminative, diuretic, emollient, hypotensive, memory
booster, sedative, etc. [96]. Sandalwood oil has protect-
ing, smoothening, moisturizing, hydrating, and skin anti-
wrinkling properties. The oil inhibits the oxidative en-
zyme 5-lipoxygenase and has DPPH radical scavenging
activity [24]. Alpha-santalol is the major ingredient of
sandalwood oil. In comparison to kojic acid and arbutin,
it is a potent inhibitor of tyrosinase [IC
50
= 171 μg/mL].
Muntingia calabura
Muntingia calabura extracts are prepared in different
solvents such as ethanol, aqueous, hydro-ethanol, petrol-
eum ether using decoction methods with various parts
of plant including leaves, flora, and fruits. This results in
optimum anti-thyrosinase and antioxidant activity in the
leaf extract of Muntingia calabura in hydroethanol [25].
Plant extracts have an inhibitory effect on melanogene-
sis. The human body’s reactive oxygen species increases
the damage done to DNA, the melanin biosynthesis, and
the melanocyte proliferation. M.calabura leaf hydro-
ethanol shows 94.00 ± 1.97% inhibition of tyrosinase
enzyme
Blumea balsamifera
Blumea balsamifera is a medicinal plant that belongs to
the Asteraceae family. The leaves are used for certain
conditions such as rheumatism and high blood pressure.
As part of the plant with different physiological activ-
ities, its leaves have attracted attention, including plas-
mine inhibitory, antifungal, and hepatroproof,
antidiabetic, wound cure, angiogenic. In addition, anti-
bacterium, free radical scavenging, inhibitory activity of
lipid peroximization, xanthine ojidase inhibition, super-
oxide scavenging activities, and antityrosinase activity
were identified in the methanol extracts of the leaves of
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132 Page 7 of 14
the plant [97]. Nine flavonoids are isolated from Blumea
balsamifera from ethyl acetate extract [25].
Magnolia officinalis
Magnolia officinalis [Magnoliaceae] has antispas-
modic, anticancer, antioxidative, and antidiabetic ac-
tivities. The extract of plant Magnolia officinalis
inhibits melanogenesis by a pre-translational regula-
tion on tyrosinase gene expression. It also exhibits
depigmenting activity. The fermented methanol bark
extract shows antityrosinase activity and at a conc.
of 200 μg/mL, it reduces 99.8% of melanin forma-
tion [98,99].
Pueraria thunbergiana
P.thunbergiana root and flower have various medi-
cinal properties. EtOAc-soluble extract fractions
were more effective than kojic acid, a whitening
agent used for positive control for a MSH-induced
melanin synthesis. Tyrosinase specifically affected by
the aerial portion of P.thunbergiana [30]. Extrac-
tion of root have % inhibition of tyrosinase at 1
mg/mL, 2 mg/mL, and 4 mg/mL are 10.36%, 0.78%,
13.22%, and 3.13% respectively [100].
Emblica officinalis
E.officinalis is recognized for its nutritional content. A
wide range of chemicals are present, including flavonol-
glycosides, carbohydrates, mucic acids, amino acids, ses-
quiterpenoids, alkaloids, flavone glycosidses, phenolic
glycosides, phenolic acids, and tannins. E.officinalis fruit
juice contains the highest amount of vitamin C and vita-
min E as compared to other fruit juice. The extract
could inhibit tyrosinase, by inhibiting microphthalmia-
associated transcription factor (MITF) and Trp-1 gene
expression, but under low concentration of the extract
treatment would induce Trp-2 gene expression. EPE has
higher IC
50
than the MPE; emblica fruit shows IC
50
4346.95 ± 166.23 μg/mL. Ethanolic extract has higher
antioxidant and anti-melnogenesis effect [101,102].
Curcuma longa
Curcuma longa contains some active ingredient which
have tyrosinase inhibitory or depigmentry activity like
curcumin, demethylcurcumin, and bisdemethyl curcu-
min. Among these, curcumin has the highest percentage
of tyrosinase inhibition [23].
Natural curcuminoides show potent inhibitory activ-
ity as compared to synthetic curcumin analog. Curcu-
min analog has higher tyrosinase activity with
compound o-diphenols and m-diphenols than other
compound. Tyrosinase activity is inhibited by curcu-
minoids by inhibiting L-dopa oxidation [103]. Partially
purified curcuma longa [PPC] inhibits the level of
tyrosinase protein like MITF, TRP1, and also suppress
the α-MSH stimulated cells. Activation of ERK or
PI3k/Akt in signaling pathway by suppressive mech-
anism of PPC on melanogenesis [104].
Camellia sinensis
It is commonly known as green tea. It belongs to the
Theaceae family. Green tea is made of steamed, dried,
rolling leaves to inactivate endogenous polyphenol oxi-
dase [PPO]. The activities of Camellia sinensis, melanin
synthesis, and expression of melanogenic enzyme at the
protein and mRNA levels in melan-A cells were evalu-
ated by researchers [105]. Green tea contains active in-
gredients like -[-]-epigallocatechin-3-gallate[EGCG],
[-]-epigallocatechin[EGC], [-]-catechin[C], [-]-gallocate-
chingallate [GCG], and [-]-epicatechingallate [ECG].
EGCG inhibit melanin production in mouse melanoma
cells. All active ingredients do not show potent inhibi-
tory activity but EGCG and gallic acid show higher tyro-
sinase inhibitory activity by cell proliferation. EGCG and
GA also inhibit cell proliferation in cell line of K562 [hu-
man leukemia cell] and 293T [human embryonic kidney]
[106]. Further, 6.2% of IC50 of methanol extract of seed
[644.93 ± 1.44 μg/mL]. Methanol extract of pericarp
shows 12 time stronger IC
50
value than the methanol ex-
tract of seed which is IC50 = 57.77 ± 0.34 μg/mL [107].
Nelumbo nucifera Gaertn
Family of Nelumbo nucifera Gaertn is Nelumbonaceae.
Commonly, it is known as Indian lotus. Its seed and
leaves extract contain alkaloids, saponine, and phenols
which shows antioxidative activity against tissue oxida-
tion. Lotus seed and leaves show protective effects on
skin against UVB irradiation, anti-wrinkle effect, and
skin whitening effect [35,108].
Crocus sativus L
It is commonly known as saffron belonging to family Iri-
daceae. The antioxidant activity of extract was 81% using
70% ethanol. Crocus sativus decreases the melanin pig-
ment from the skin. Emulsion is use in the cosmetic or
medicine preparation to treat skin hyperpigmentation
and used as skin whitening agent [40]. Isorhamnetin-3,
49-diglucoside has 55.7% at 2666.7 μm/mL concentra-
tion with 1.84 mm IC
50
[109].
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132 Page 8 of 14
Hemidesmus indicus
It belongs to family Asclepiadaceae and commonly
known as Anantmul. H.indicus decreases the monophe-
nols and diphenols activity of tyrosinase by inhibiting L-
dopa to dopachrome synthesis in melanin production.
Monophenolase activity inhibition by 2-hydroxy-4-meth-
oxybenzaldehyde MBALD was studied with a substra-
tum l-tyrosin e[39]. Hemidesminine, Lupeal, and vanillin
are the active constituents which shows antioxidant ef-
fect [40].
Vitis vinifera
The main active ingredients of which are red vine leaf
extract (RVLE), contains many flavonoids. Deionized
water was the solvent used in RVLE preparation. The so-
lution RVLE showed the possibility of inhibiting dopa-
chrome formation that can be observed at wavelength of
475 nm with a spectrophotometer. The bioactive com-
ponents of RVLE included gallic acid, chlorogenic acid,
epicatechin, rutin, and resveratrol. RVLE solution is also
used in cosmetic formulations as natural whitening
agent [52]. Extract of VVC is more potent then arbutin
to inhibit tyrosinase activity and its has30 휇gmL
−1
IC
50
value [110].
Euphorbia supina
The ES extract has a non-cytotoxic effect on the prolif-
eration of B16F10 cells. Clear cytotoxicity is observed in
B16F10 cells at a concentration of 1000 μg/mL. The ES
extract showed an occurrence of 93.05 ± 0.6% at 200 μg/
mL almost equivalent to ascorbic acid. ES extracts had a
relatively high ABTS+ radical scavenge activities of 8
and 40 μg/mL [14]; protocatechuic acid, nodakenin, and
3-O-glucoside are the chemical constituent present in
the Euphorbia supina [111].
Acacia catechu
The extract has recorded high tyrosinase inhibition ac-
tivity at a concentration of 120 μg/ml, with an inhibition
percentage of 61.58 compared to a positive kojic acid
regulation [98.73% inhibition] at a concentration equiva-
lent to 120 μg/ml. Without preservative, A.catechu
whitening cream has maintained strong stability for 3
months [46].
Carica papaya
It contains papain, chymopapain A and B which shows
antioxidant activity. It also contains calcium, sugar, fiber,
vitamin C, thiamine, riboflavin, niacin, amino acid, caro-
tene, and malic acids. It also includes proteins and fats
[45]. It has been found that carica fruit extract is having
87% of antioxidant activity. The phenolic compounds in
papaya fruit contained two major groups. The most im-
portant natural antioxidant groups are these phenolic
compounds [111].
Arnica montana
3β,16β-Dihydroxy-21a-hydroperoxy-20[30]-tariaxasten is
a compound present in Arnica montana that is found to
be 50 times stronger than 4-methoxyphenol, a com-
monly used depigmenting agent; it inhibited in the mel-
anin biosynthesis, without affecting cells production and
much stronger than arbutin as well. At 0.125 mg/mL,
Arnica flowers inhibit melanin synthesis in 80% ethanol
extract [47].
Artemisia dracunculus
Undeca-2E,4E-dien-8,10-dynoic acid isobutylamide and
piperidylamide are two active compounds found in Arte-
misia dracunculus. These compounds inhibit mediated
melanin production in B16 cells of mouse melanoma po-
tently by inhabitation of melanocyte-stimulating hor-
mone [-MSH]. Consequently, the cytotoxicity was not
related to the inhibitor activity of compounds 1 and 2
against melanin biosynthesis [48].
Thymelaea hirsuta
T.hirsuta extract shows a time-dependent decrease in
cytoplasmic accumulation of melanin and do not
show any cytotoxicity effect. Genkwadaphnin and gni-
dicin are the active constituents in the extract of T.
hirsuta which shows effect against melanin synthesis.
By ERK1/2 phosphorylation, melanogenesis effect on
B16 cells are decreases. Inhibition of melanin produc-
tion by downregulation of tyrosinase by Thymelaea
hirsuta [112].
Betula pendula
In addition to metal chelating, Betula pendula is a sig-
nificant source of strong depigmentants with an effect
on tyrosinase to decrease and scavenge properties.
Chlorogenic acid, Catechin, p-Coumaric acid, Isoquerci-
trin, Chrysoeriol, and Quercetin-3-O-glucuronide are
the active constituents present in the extract. The power
of chain-breaking antioxidants, phenolic compounds, in-
cluding flavonoids, which scavenge lipid peroxyl radicals,
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132 Page 9 of 14
Table 2 Phytoconstituents for the treatment of skin hyperpigmentation
S.No. Phytoconstituent Common
source
Structure Traditional use Reference
1 Resveratrol Vitis vinifera Inhibition of melanin synthesis, tyrosinase
inhibitor
[84,114]
2 Genistein Glycine max Antioxidant, inhibit melanogenesis pathway [115]
3 Ellagic acid Rubus idaeus Antioxidant, suppresses melanogenesis [116]
4 Quercetin Citrus aurantium Anti-melanogenesis effect, tyrosinase inhibitor [117]
5L-ascorbic acid Embelica
officinalis
Skin lightening effect [118]
6 Hydroquinone Agaricus
hondensis
Epidermal-type melasma inhibitor, tyrosinase
inhibitor
[119]
7 Kojic acid Aspergillus
oryzae
Tyrosinase inhibitor [120]
8 Taxifolin Cedrus deodara Inhibit melanin synthesis [121]
9 6-Hydroxydiadzein Glycine max Inhibit melanin synthesis [122]
10 Gnetol Gnetum gnemon Tyrosinase inhibitor [123]
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132 Page 10 of 14
break through chain sequences with the same mechan-
ism as radical hydroxyl scavenging. Then, 30.21 ± 0.23%
of tyrosinase inhibitory effect were observed at 80 μg/
mL concentration on 119.08 ± 2.04 μg/mL IC
50
[113].
Caesalpinia sappan
Homoisoflavanone, sappanone A are isolated from the ex-
tract of Caesalpinia sappan. The crude extract has dem-
onstrated highest melanogenesis inhibitory activity in
mouse B16 melanoma cells and crude extract of C.sappan
has been evaluated in a previous study for antiproliferating
activity in B16 melanoma cells. Homoisoflavanones are a
small class of oxygen that occur naturally. Sapanone A
shows a dose-dependent inhibition of melanogenesis [52].
Callicarpa longissima
Callicarpa longissima inhibits the development of mel-
anin by suppressing the MITF [microphthalmia-associ-
ated transcription factor] gene expression of the B16F10
mouse melanoma cells. Carnosol is present in the ex-
tract of Callicarpa longissimi which has oxidative prop-
erty and carnosol and carnosic acid are responsible for
inhibiting melanin synthesis [53].
Phytoconstituents used for the treatment of skin
hyperpigmentation are given in Table 2.
Conclusion
In this review, we discussed many of herbs and phyto-
constituent which are used as tyrosinase inhibitor and
also as skin whitening agents. Skin is the most important
part of our body. The colour of skin is determined by
the presence of melanin in the skin. Melanin is a pig-
ment present in skin which is responsible for the skin
color in plants and mammals. When the amount of mel-
anin is increased in the skin, then it causes hyper-
pigmentation on the skin. Synthesis of melanin depends
mainly on tyrosinase enzyme. It convert L-tyrosine in L-
DOPA and L-DOPA to dopaquinone by which melanin
is produced in the epidermis layer of skin and affect the
skin color. Plants like Azadiracta indica,Glycyrrhiza
glabra,Panax ginseng and genistein, ellagic acids, quer-
cetin, and many other phytoconstituents which are used
in herbal cosmetic as anti-hyperpigmentry agents in cos-
metic industries. Some of flavonoids and triterpenoids
present in these herbs show their effect as antioxidant
and skin whitening agents.
Abbreviations
MITF: Microphthalmia-associated transcription factor; ROS: Reactive oxygen
species; MPAK: Mitogen-activated protein kinase; COX: Cyclooxygenase;
DHICA: Dihydroxyindole-2-carboxylic acid; HQ: Hydroquinone; PPC: Purified
curcuma longa; RVLE: Red vine leaf extract; PPO: Polyphenol oxidase
Acknowledgement
Not applicable.
Table 2 Phytoconstituents for the treatment of skin hyperpigmentation (Continued)
S.No. Phytoconstituent Common
source
Structure Traditional use Reference
11 9-Hydroxy-4-
methoxypsoralen
Angelica
dahurica
Tyrosinase inhibitor [124]
12 Kuraridin Sophora
flavescens
Tyrosinase inhibitor [125]
13 p-Coumaric Acid Arachis
hypogaea
Antioxidant, inhibit melanin synthesis [126]
Rathee et al. Future Journal of Pharmaceutical Sciences (2021) 7:132 Page 11 of 14
Authors’contributions
We declare that this work was done by the authors named in this article: SK
conceived and designed the study. PR carried out the literature collection of
the data and writing of manuscript. SSY helped in writing of the manuscript.
DK and BK assisted in the data analysis and corrected the manuscript. All the
authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
All the information in the manuscript has been referred from the included
references and is available upon request from the corresponding author.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Institute of Pharmaceutical Science, Kurukshetra University, Kurukshetra
136119, India.
2
Department of Pharmaceutical Sciences, Indira Gandhi
University, Meerpur, Rewari 122502, India.
3
Department of Pharmaceutical
Chemistry, Bharati Vidyapeeth Deemed University, Poona College of
Pharmacy Erandwane, Pune 411038, India.
Received: 13 January 2021 Accepted: 15 June 2021
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