Received: 17 November 2020 Revised: 1 February 2021 Accepted: 24 February 2021

DOI: 10.1002/ptr.7076

REVIEW

A comprehensive review of the therapeutic potential of

α-arbutin

Majid Saeedi1,2 | Khadijeh Khezri3 | Abbas Seyed Zakaryaei4 |

Hassan Mohammadamini5

1
Pharmaceutical Sciences Research Center,
Hemoglobinopathy Institute, Mazandaran Cosmetic dermatology preparations such as bleaching agents are ingredients with
University of Medical Sciences, Sari, Iran
skin-related biological activities for increasing and improving skin beauty. The possi-
2
Department of Pharmaceutics, Faculty of
Pharmacy, Mazandaran University of Medical bility of controlling skin hyperpigmentation disorders is one of the most important
Sciences, Sari, Iran research goals in cosmetic preparations. Recently, cosmetics containing herbal and
3
Deputy of Food and Drug Administration,
botanical ingredients have attracted many interests for consumers of cosmetic prod-
Urmia University of Medical Sciences,
Urmia, Iran ucts because these preparations are found safer than other preparations with syn-
4
Urmia University of Medical Sciences, thetic components. However, high-quality trial studies in larger samples are needed
Urmia, Iran
5
to confirm safety and clinical efficacy of phytotherapeutic agents with high therapeu-
Khoy University of Medical Sciences,
Khoy, Iran tic index. Arbutin (p-hydroxyphenyl-β-D-glucopyranoside) is a bioactive hydrophilic
polyphenol with two isomers including alpha-arbutin (4-hydroxyphenyl-α-glu-
Correspondence
Khadijeh Khezri, Deputy of Food and Drug copyranoside) and β-arbutin (4-hydroxyphenyl-β-glucopyranoside). It is used as a
Administration, Urmia University of Medical medicinal plant in phytopharmacy. Studies have shown that alpha-arbutin is 10 times
Sciences, Urmia, Iran.
Email: khezripnuchemphd@gmail.com more effective than natural arbutin. A comparison of IC50 values showed that
α-arbutin (with concentration 2.0 mM) has a more potent inhibitory activity on
human tyrosinase against natural arbutin (with higher concentration than 30 mM). A
review of recent studies showed that arbutin could be beneficial in treatment of vari-
ous diseases such as hyperpigmentation disorders, types of cancers, central nervous
system disorders, osteoporosis, diabetes, etc. This study was designed to describe
the therapeutic efficiencies of arbutin.

KEYWORDS
arbutin, hyperpigmentation disorders, nanoparticles, skin whitening agents, therapeutic
mechanisms

1 | I N T RO DU CT I O N hyperpigmentation disorders through increase in skin-bleaching (Li,

Yin, Zhai, Lu, & Mi, 2019). The possibility of controlling skin hyper-
Due to the growing interest in topically applied cosmetics, research pigmentation disorders (especially in the face and neck) is a most cos-
on different types of skin depigmenting and lightening agents has also metically important research aim (Napolitano & Ito, 2018). Melasma is
increased (Khezri, Saeedi, Morteza-Semnani, Akbari, & the most common form of facial hyperpigmentation (Passeron &
Hedayatizadeh-Omran, 2021; Khezri, Saeedi, Morteza-Semnani, Picardo, 2018). Other types of hyperpigmentation disorders have
Akbari, & Rostamkalaei, 2020; Lee et al., 2018). Cosmetic dermatology been reported in studies including erythromelanosis follicularis of the
preparations such as bleaching agents (Khezri, Saeedi, & Dizaj, 2018) face and neck, Riehl's melanosis, linea fusca, poikiloderma of Civatte,
are ingredients with skin-related biological activities for increasing and cosmetic hyperpigmentations, and erythrose peribuccale pigmentaire
improving skin beauty (Kusumawati & Indrayanto, 2013). The main of Brocq (Perez-Bernal, Munoz-Perez, & Camacho, 2000). Recently,
function of skin whitening preparations is the treatment of skin cosmetics with herbal and botanical ingredients have attracted many

Phytotherapy Research. 2021;1–19. wileyonlinelibrary.com/journal/ptr © 2021 John Wiley & Sons Ltd. 1
2 SAEEDI ET AL.

interests for consumers of cosmetic products because these prepara- before using any herbal medicines: standardization of the extracts, the
tions are found safer than preparations containing synthetic and ani- accurate identification of plant species, adulteration of herbal medi-
mal components (Aburjai & Natsheh, 2003). cines, adverse effects associated with plant food supplements and
Nevertheless, a review of various studies including meta-analyses, botanical preparations, extraction methods, and the type of solvent
systematic reviews, double-blind randomized clinical trial (RCTs), pro- used in the extraction process (Andrew & Izzo, 2017).
spective cohort studies, case–control studies (retrospective), case Arbutin (p-hydroxyphenyl-β-D-glucopyranoside) is a bioactive
reports and case series, unsystematic observations, and expert opin- hydrophilic polyphenol with two isomers including alpha-arbutin
ions showed that some of several medicinal plants have serious side (4-hydroxyphenyl-α-glucopyranoside) and β-arbutin (4-hydroxyphenyl-
effects for consumers. In this regard, researchers designed main β-glucopyranoside) (Couteau & Coiffard, 2016). It has been used as a
guidelines associated with clinical trials to obtain high levels of effi- medicinal plant in phytotherapy and phytocosmetics (Migas & Krauze-
cacy and safety of herbal medicine, including evaluation of herbs and Baranowska, 2015). It is obtained from various types of natural and
herb–drug interactions, precautions for the use of herbal compounds synthetic sources including various species of plants, enzymatic pro-
in pregnancy and breastfeeding women, the pediatric, adolescent, and cesses, and metabolic engineering of microorganisms (Figure 1 and
geriatric population (Izzo, Hoon-Kim, Radhakrishnan, & Table 1). The formation of these isomers depends on how the hydro-
Williamson, 2016). Also, it is necessary to check the following items quinone binds to the anomeric carbon atom in the glucose molecule

FIGURE 1 Types of natural and synthetic sources of arbutin [Colour figure can be viewed at wileyonlinelibrary.com]
SAEEDI ET AL. 3

T A B L E 1 A list of natural and synthetic sources of arbutin derived from various species of plants, enzymatic processes, and metabolic
engineering of microbes

Sources Plant families/bacterial species References

Japanese pear trees Pyrus pyrifolia cv. Kousui Sasaki, Ichitani, Kunimoto, Asada, and
Nakamura (2014)
Bearberry Arctostaphylos uva-ursi Parejo, Viladomat, Bastida, and
Codina (2001)
Majoram Origanum majorana Lukas, Schmiderer, Mitteregger, and
Novak (2010)
Fruit peel P. pyrifolia Nakai Cho et al. (2011)
Fruit peel P. pyrifolia Niitaka Lee and Eun (2012)
Leaves P. biossieriana Buhse Shahaboddin et al. (2011)
Oriental pear P. Bretschnrideri Cui, Nakamura, Ma, Li, and Kayahara (2005)
Oriental pear P. pyrifolia Cui et al. (2005)
Oriental pear P. ussuriensis Cui et al. (2005)
Oriental pear P. sinkiangensis Cui et al. (2005)
Occidental pear The flowers, buds, and young fruits of Cui et al. (2005)
Pholiota communis
Leaves Bergenia crassifolia (L.) Fritsch Carmen, Vlase, and Tamas (2009)
Leaves A number of Lamiaceae species Rychlinska and Nowak (2012)
Leaves A number of Ericaceae species Rychlinska and Nowak (2012)
Leaves A number of Saxifragaceae species Rychlinska and Nowak (2012)
Leaves A number of Rosaceae species Rychlinska and Nowak (2012)
Pear P. serotina Rehder Lee, Choi, et al. (2018)
Pear Achillea millefolium Lee, Choi, et al. (2018)
Strawberry tree leaves Arbutus unedo L. Jurica et al. (2017)
Leaves Asteraceae Thogchai and Liawruangrath (2013)
Leaves Betulaceae Thogchai and Liawruangrath (2013)
Leaves Lamiaceae Migas and Krauze-Baranowska (2015)
Leaves Apiaceae Migas and Krauze-Baranowska (2015)
Bacteria Bacillus subtilis and Leuconostoc Migas and Krauze-Baranowska (2015)
mesenteroides
Metabolic engineering of microbes Pseudomonas chlororaphis P3 Wang et al. (2018)
(engineering shikimate pathway)
Fed-batch fermentation Escherichia coli Wu, Nair, Chu, and Wu (2008)
Shoot culture Origanum majorana L. (Lamiaceae)
, Gołdyn,
Skrzypczak-Pietraszek, Kwiecien
and Pietraszek (2017)
Metabolic engineering of microbes Yarrowia lipolytica Shang et al. (2020)
(engineering shikimate pathway)
Blueberry — Program (2006)
Cranberry — Program (2006)
Cowberry Vaccinium vitis-idaea L., Ericaceae Program (2006)
Juvenile foliage of the New Zealand tree Halocarpus biformis, Salvia mexicana L. var. Program (2006)
minor Benth, Rhodiola sacra S H Fu,
Onobrychis viciifolia (Sainfoin), and
Origanum majorana
By the incubation of HQ with — Program (2006)
enzyme extracts from bean or wheat
plants
The germination of seeds Viguna mungo seeds Program (2006)
Plant tissues in the presence of HQ — Program (2006)
Biotransformation of HQ Catharanthus roseus cells Misawa (1994)

(Continues)
4 SAEEDI ET AL.

TABLE 1 (Continued)

Sources Plant families/bacterial species References

It can be synthesized from — Program (2006)
acetobromglucose and HQ or from the
reaction of β-D-glucose pentaacetate
and HQ monobenzyl ether in the
presence of phosphorus oxychloride
Sucrose phosphorylase + hydroquinone L. Mesenteroides Kitao and Sekine (1994)
Sucrose isomerase + hydroquinone E. rhapontici Zhou et al. (2011)
Dextransucrase + hydroquinone L. Mesenteroides Seo et al. (2009)
α-Glucosidase + hydroquinone S. cerevisiae Prodanovi
c et al. (2005); Prodanovi
c,
Milosavi
c, Sladi
c, Veličkovi
c, and
Vujči
c (2005)
CGTase + hydroquinone Thermoanaerobacter sp. Mathew and Adlercreutz (2013)
Amylosucrase + hydroquinone D. Geothermalis Seo et al. (2012)
Amylosucrase + hydroquinone C. Carboniz Yu et al. (2018)
α-Amylase + hydroquinone B. subtilis X-23 Nishimura, Kometani, Takii, Terada, and
Okada (1994)
α-Glucosidase + hydroquinone X. campestris WU-9701 Kurosu et al. (2002)

erci, 2021). It has been shown that

(Hazman, Sarıova, Bozkurt, & Cig searches were carried out with no restrictions on publication date and
alpha-arbutin is 10 times more effective than natural arbutin. A com- language.
parison of IC50 values showed that α-arbutin (with concentration
2.0 mM) has a more potent inhibitory activity on human tyrosinase in
comparison with natural arbutin (with higher concentration than 2 | CHEMICAL CHARACTERIZATIONS AND
30 mM) (Zhu et al., 2018). In a study, tyrosinase inhibitory capacity of T H E R A P E U T I C EF F E C T S OF A R B U T I N I N
α-arbutin has been evaluated using cultured human melanoma cells and COSMETIC AND PHARMACEUTICAL
a human skin model. It revealed that α-arbutin can potentially inhibit PREPARATIONS
melanin formation without the induction of cytotoxicity (Sugimoto,
Nishimura, & Kuriki, 2007; Sugimoto, Nishimura, Nomura, Sugimoto, & In recent years, herbal and medicinal plant extracts such as arbutin
Kuriki, 2004). Therefore, α-arbutin synthesis is very much valuable and have attracted special attention due to multiple biological and phar-
useful for cosmetic and pharmaceutical industrials (Zhu et al., 2018). macological properties and their unique therapeutic benefits (Shang,
Recent studies show that seven microbial enzymes are able to Wei, Zhang, & Ye, 2020; Zhu et al., 2018). Kawalier discovered arbutin
synthesize alpha-arbutin, including sucrose isomerase, cyclodextrin (in the leaves of Uva ursi) in 1851. It is identified as a glucoside and
glycosyltransferase, alpha amylase, amylosucrase sucrose phosphory- can convert into sugar, hydroquinone (C6H6O2) (arctuvin of kawalier)
lase, dextransucrase, and α-glucosidase (Hazman et al., 2021). Arbutin (Maisch, 1874).
as a hydroquinone glycoside has various biological functions in cos- Arbutin is a white powder (pure synthetic) with crystal structure
metics and pharmaceutical preparations (Lee & Kim, 2012). It is widely and it is classified in polyphenolic compounds. Its IUPAC name is
used in cosmetic products as a skin bleaching agent and antiaging (2R,3S,4S,5R,6S)-2-hydroxymethyl-6-(4-hydroxyphenoxy) oxane-3,-
agent (Zhou et al., 2017). Furthermore, a review of recent studies 4,5-triol. It is also called hydroquinone β-D-glucopyranoside. It is used
showed that arbutin could be beneficial in the treatment of various as a skin whitening agent (in skin care and cosmetic preparations) for
diseases (Table 2). the inhibition of melanin synthesis in patients with hyperactive mela-
In accordance with the presented practical guidelines by Izzo nocyte and hyperpigmentation disorders (Araujo-Andrade, Lopes, Fau-
et al. and to provide new perspectives in research studies of herbal sto, & Gómez-Zavaglia, 2010). In vitro studies on dermal penetration
medicine (Izzo et al., 2020), this review aims to update and describe showed that the hydrolysis of alpha-arbutin to hydroquinone is done
applications and the therapeutic benefits of arbutin in the treatment in two ways including human skin microbe interactions and enzymatic
of various diseases. Also, a search method of study was performed by activity (Bang, Han, & Kim, 2008; Degen, 2016). Trade brand of
searching the electronic databases, including Scopus, Google Scholar, arbutin is Aqua lotion (Amarte) (Couteau & Coiffard, 2016). Absor-
PubMed, Science Direct, Web of Science, using search keywords such bance measurements of arbutin by UV–Vis spectrophotometer
as arbutin, hyperpigmentation disorders, and therapeutic mechanisms, showed that it has two main absorbance peaks at approximately
skin whitening agents, arbutin nanoparticles. In this study, literature 230–280 nm (Yang et al., 2013). Because arbutin does not have
SAEEDI ET AL. 5

TABLE 2 A list of biological activities of alpha-arbutin

Functions Results Model References

Wound healing This study represents wound healing effects of In silico and Polouliakh et al. (2020)
arbutin on human dermal fibroblast cell in vitro
cultures with the downregulated ROS
expression, inhibition of the forkhead box
protein O1 and sirtuin 1 genes, upregulating
type I procollagen, the matrix
metallopeptidase 3, epidermal growth factor
receptor genes, and insulin/IGF-1 signaling
pathway.
Cytotoxicity and hypopigmentation The results of this study revealed that arbutin In vitro Chang et al. (2017)
effects from UVB-irradiated has effective toxic and brightening effects on
arbutin Detroit 551 human fibroblast cells B16-F10
mouse melanoma cells. It can decrease the
melanin synthesis in melanoma cells by
activating caspase-3 pathway.
Arbutin effects on bone cells and the Arbutin showed protective role on osteoblast- In situ and in Bonifacio et al. (2020)
development of antioxidant like cells (Saos-2) and periosteum-derived vitro
titanium implants progenitor cells (PDPCs) with the high
biocompatibility and upregulation of the
expression of PDPC differentiation markers
and it can use as a promising strategy for the
development of antioxidant titanium
implants.
Cytoprotective effects Arbutin demonstrated the good antioxidative In vitro Seyfizadeh et al. (2012)
and cytoprotective activities with high cell
viability.
Decrease of potentially toxins Arbutin exhibited anti-inflammatory activity In vitro Pečivová, Nosáľ, Sviteková, and
produced in human blood through downregulation of the expression of Mačičková (2014)
neutrophils phospholipase D, myeloperoxidase, elastase
activity, suppression of the synthesis of
superoxide, and reactive oxygen species.
Estrogen-like effects Arbutin identifies as a phytoestrogen ingredient In vitro and in Zeng et al. (2018)
with estrogen-like effects. vivo
Pro-apoptotic effects Arbutin and its derivatives indicated potential In vitro Jiang et al. (2018)
skin brightening and anti-malignant
melanoma activities.
Stability of membranes Arbutin acts as stabilizing cellular membranes In vitro Hincha, Oliver, and Crowe (1999)
and increases plant stress tolerance via
presence of different lipid composition such
as the non-bilayer-forming chloroplast lipid
monogalactosyldiacylglycerol.
Inhibitory effects on melanin Arbutin inhibits melanin formation through Ex vivo and in Lim et al. (2009)
biosynthesis downregulation of the expression of vitro
α-melanocyte-stimulating hormone.
Anti-inflammatory effects Arbutin revealed anti-inflammatory activity In vitro Lee and Kim (2012)
through inhibition of BV2 microglial cells
activation in response to LPS stimulation.
Effects on immuno-inflammation It can be concluded that arbutin was effective In vivo Matsuda et al. (1990)
in inhibiting activity of dexamethasone and
prednisolone on picryl chloride and sheep red
cell delayed type hypersensitivity.
Effects on radiation-induced Experiments showed that arbutin has anti- In vivo Nadi, Msc, Mozdarani, Mahmodzade,
micronuclei clastogenic and radioprotective activities and Pouramir (2016)
against gamma radiation.
Hepatoprotective effects Hepatoprotective effects confirmed by In vivo Mirshahvalad et al. (2016)
antioxidant and free radical scavenger
activities of arbutin.
Cardiac hypertrophy Arbutin exhibited an anti-hypertrophic effect In vivo Nalban et al. (2020)
by decreasing TLR-4/NF-κb pathway.

(Continues)
6 SAEEDI ET AL.

TABLE 2 (Continued)

Functions Results Model References

Anti-ulcerogenic activities Arbutin acts as an anti-ulcer through anti- In vitro and in Taha et al. (2012)
oxidant and lipid peroxidation inhibitory, vivo
immuno modulatory and lipid peroxidation
inhibitory mechanisms.
Epilepsy Arbutin showed anti-epilepsy effect via In vitro and in Ahmadian et al. (2019)
inhibiting glial activity, downregulate in the vivo
expression of memory impairment markers,
and suppressing inflammatory cytokine
release.
Hypoglycemic activity Results confirmed the potential anti-diabetic In vitro Yousefi, Mahjoub, Pouramir, and
effects of arbutin through inhibitory activities Khadir (2013)
on α-amylase and α-glucosidase.
Diuretic The availability in urine is about 65% of the Clinical trial Schindler et al. (2002)
administered dose of arbutin.
Enhanced antimicrobial activities Findings of this research confirm that phenolic In vitro Kajiwara et al. (2019)
groups of polymers increased the
antimicrobial activity of polymeric arbutin
than monomeric arbutin.
Parkinson's disease (PD) These results suggested that arbutin can act as In vitro and in Dadgar et al. (2018), Ding et al. (2020)
a neuroprotective agent and can considerably vivo
decrease behavioral deficits, oxidative and
nitrosative stress in PD animal models both
in vitro and in vivo.
Antitussive activities Finding of this study showed that arbutin In vivo Strapkova, Jahodar, and
formulations in doses of 50 and 100 mg/kg Nosal'ova (1991)
b.w.p.o. and i.p. can effectively reduce
intensity of cough attack and cough
frequency in cats.
Increase of longevity and stress Arbutin considerably increases lifespan and In vitro and in Zhou et al. (2017)
resistance improves stress resistance of nematodes. vivo
Decrease of intracellular ROS Arbutin as an antioxidant and anti-inflammatory In vitro Safari et al. (2020)
agent can inhibit the activity of the
intracellular ROS, the expression level of IL-
1β and TNF-α gene.
Alzheimer's disease These results suggested that arbutin has In vitro and in Dastan et al. (2019)
neuroprotective activities against memory vivo
impairment and oxidative damage in the
brain.
Chronic bacterial prostatitis This study reveals that arbutin is effective Clinical trial Busetto et al. (2014)
strategy in treatment of chronic bacterial
prostatitis.
Positively regulate DAF-16 Arbutin regulates nuclear localization of DAF- In vitro and in Zhou et al. (2017)
expression in nuclear 16 by activating antioxidant signaling vivo
pathways.
Radioprotective effect Arbutin at dose of 50 mg/kg revealed potent In vitro and in Nadi et al. (2019)
radioprotective properties. vivo
Enhance recovery and osteogenic Arbutin- loaded dehydrated human In vitro Jamil et al. (2005)
differentiation in dried and mesenchymal stem cells increases the
rehydrated human mesenchymal stabilizing activities of trehalose through
stem cells activation mechanisms of endogenous heat
shock proteins.
Anti-myocardial infarction effects Arbutin at dose 50 mg/kg bw showed effective In vivo Sivasangari, Asaikumar, and
anti-myocardial infarction effects in animal Vennila (2020)
model against mitochondrial, hyperlipidemia,
and DNA and lysosomal membrane damages.
Sperm cryoprotective agent Arbutin increased sperm longevity by increasing In vitro Aboagla and Maeda (2011)
the membrane fluidity.
SAEEDI ET AL. 7

TABLE 2 (Continued)

Functions Results Model References

Multiple sclerosis (MS) Arbutin showed high therapeutic capacity for In vivo Ebrahim-Tabar et al. (2020)
demyelinating disorders such as multiple
sclerosis by reducing expression of
inflammation markers, astrocyte activation,
and oxidative stress.
Optic nerve injury Arbutin has a protective role in retinal ganglion In vivo Zhao et al. (2019)
cells injured due to oxidative stress through
up-regulation of miR-29a and suppressing
p38MAPK and MEK/ERK signaling pathways.
Antioxidant activity The present findings suggested that arbutin has In vitro Takebayashi et al. (2010)
a potent antioxidant activity in the skin.
Prostate cancer Arbutin showed a prostate anticancer effect by In vitro Safari et al. (2020)
increasing apoptosis and reducing expression
of pro-inflammatory markers and ROS.
Breast cancer Results indicate that arbutin has a breast Clinical trial Cacchio, Prencipe, et al. (2019)
anticancer activity.
Human bladder cancer Arbutin plays an antiproliferation role on In vitro Li, Jeong, Kim, Kim, and Kim (2011)
TCCSUP human bladder carcinoma cells by
suppressing ERK signaling pathway and p21
up-regulation.
Antidiabetic and anti-glycation Arbutin showed antidiabetic and anti-glycation In vitro Lv et al. (2019)
activities activities via JNK and mTOR-signalling
pathways and up-regulating miR-27a.
Osteoporosis treatment Arbutin has effective role in osteoporosis In vitro Man et al. (2019)
treatment by Wnt/β-catenin signaling
pathway and increasing osteoblastic
proliferation and differentiation of
MC3T3-E1 cells.
Acute lung injury Finding of this study reveals that arbutin is a In vitro and in Ye et al. (2019)
promising therapeutic strategy in vivo
inflammation-related lung injury via
regulating the Nrf-2/HO-1/NF-κB signaling
pathway.
Post-trauma/surgery persistent hand Arbutin was an effective method in the Clinical trial Cacchio, Di Carlo, Vincenza, and
edema management of patients with post-trauma/ Elisabetta (2019)
surgery persistent hand edema.
Antiapoptotic role and radio- Arbutin showed an anti-apoptotic effect via In vitro Wu et al. (2014)
protector downregulation of the expression of
intracellular hydroxyl radical formation,
activation of the JNK/p38 MAPK pathway
and suppression of Bax-mitochondria
pathway.

chromophores that are absorbed at wavelengths above 290 nm functional group and a phenolic group (as a melanin inhibitor) (Zhou
(Lyman, Reehl, & Rosenblatt, 1990), it is found that maximum absor- et al., 2017). Chemical structure and multiple biological activities of
bance peak of arbutin is in 267 nm. Arbutin shows the most stability arbutin (C12H16O7) are shown in Figure 2.
at pH 5–7 (Couteau & Coiffard, 2000). It has very high solubility in In various studies, it is revealed that arbutin formulations can be
water with logP value −1.49 and this causes insufficient absorption useful for the treatment of various diseases due to its multi-target
from the skin layers (Wen, Choi, & Kim, 2006). Its physical state is biological effects such as treatment of hyperpigmentation disorders
needle-shaped crystals and it can be transformed into a white or gray (Ayumi, Sahudin, Hussain, Hussain, & Samah, 2019; Park et al., 2019),
powder. It has high solubility in methyl alcohol, ethyl alcohol, acetoni- anti-diabetic (Lv et al., 2019), wound healing (Polouliakh et al., 2020),
trile, and tetrahydrofuran, but it does not dissolve in some solvents anti-osteoporosis (Bonifacio et al., 2020), treatment of acute lung
such as DMSO, chloroform, petroleum, diethyl ether, and cyclohex- injury (Ye et al., 2019), management of cardiac hypertrophy (Nalban
ane. It is unstable in acidic medium and is easily hydrolyzed. The et al., 2020), anticancer (Jiang et al., 2018; Safari et al., 2020; Wang,
chemical structure of arbutin contains a hydrophilic anhydroglucose Wang, Li, Zhang, & Wang, 2020), antioxidant activity (Bonifacio
8 SAEEDI ET AL.

F I G U R E 2 Chemical structure and

multiple biological activities of arbutin
[Colour figure can be viewed at
wileyonlinelibrary.com]

et al., 2020), treatment of optic nerve injury (Ebrahim-Tabar, Nazari, According to the studies reported in Table 2, arbutin seems to be a
Pouramir, Ashrafpour, & Pourabdolhossein, 2020; Zhao, Wang, Qin, & promising therapeutic agent in management of various diseases.
Wang, 2019), treatment of central nervous system disorders
(Ahmadian, Ghasemi-Kasman, Pouramir, & Sadeghi, 2019; Dastan
et al., 2019; Ding et al., 2020), hepatoprotective activity 3 | HY PE R P IG ME NT ATI ON DI SOR D E RS
(Mirshahvalad et al., 2016), effect on human mesenchymal stem cells A N D SI G N A L I N G P A T H W A Y S A S S O C I A T E D
(Bonifacio et al., 2020; Jamil, Crowe, Tablin, & Oliver, 2005), radiopro- W I T H M E L A N I N P RO D U C T I O N
tective effect (Nadi, Elahi, Moradi, & Banaei, 2019), antimicrobial
(Nadi et al., 2019), antiaging (Zhou et al., 2017), antitussive (Koul, Hyperpigmentation is one of the most common skin disorders
Kumar, Yadav, & Jin, 2020), diuretic (Myagchilov, Mineev, Sokolova, (Khezri et al., 2020, 2021) in dermatology clinics that results from
Gerdasova, & Gorovoi, 2020), anti-inflammatory (Lee & Kim, 2012; excessive synthesis of melanin or melanin deposition on various
Zhou, Zhao, Li, & Reetz, 2019), inhibitory effects on melanin forma- skin layers (Kaur, Aggarwal, & Nagpal, 2019). Excessive synthesis of
tion (Li, Du, & Du, 2018), estrogen-like effects (Zeng et al., 2018), and melanin and its accumulation can cause disorders such as
cytoprotective effects (Seyfizadeh et al., 2012) etc. acanthosis melasma, skin cancer risk, periorbital hyperpigmentation,
In the study by Takii et al., it showed that arbutin was able to cervical poikiloderma, lentigines, neurodegeneration associated
delay hyperglycemia after postprandial. The results of this investiga- with Parkinson's disease, and nigricans (Zolghadri et al., 2019). Vari-
tion suggested that arbutin could be used as an effective supplement ous agents such as UV radiation, inflammatory mediators, hormones
to control blood sugar in diabetes (Takii, Matsumoto, Kometani, disorders, and radicals caused upregulated expression of melano-
Okada, & Fushiki, 1997). genesis process and hyperpigmentation (Kanlayavattanakul &
It has been shown that the alpha form has photostable property Lourith, 2018a). Currently, melanin pigmentary disorders are a cos-
with the highest inhibitory activity against mammalian tyrosinase. But metic problem that causes mental and psychological damage to
it is unstable to heat and decomposes, and must be formulated at low patients (Sarkar, Arora, & Garg, 2013).
temperatures (Couteau & Coiffard, 2000; Sugimoto et al., 2005). Poor A literature review showed that changes in the serum levels of
stability of arbutin has limited its application. Glycosylation process is female sex hormones (estrogen and progesterone) during the men-
a very common and key structural modification for enhancement of strual cycle play main role in catamenial hyperpigmentation of the skin
light and oxidation stability. This process improves hydrophilicity, (Mobasher et al., 2020). Hyperpigmentation disorders can be classified
pharmacokinetic, and physicochemical properties of bioactive pheno- as acquired, congenital, or inherited (Jimbow & Minamitsuji, 2001).
lic substances (Nakano et al., 2002). In a study, Li et al. designed a Recent advances in cellular and molecular sciences such as trans-
complex of arbutin and hydroxypropyl-β-cyclodextrin. They showed criptome analysis, sequencing technologies, and genome sequencing
that this complex can considerably improve the heat stability of and epigenetic analysis to evaluation of various skin diseases have
arbutin and has capacity for developing arbutin applications in phar- upgraded our understanding of melanogenesis. Discovering more
maceuticals, chemicals, food products, and cosmetics (Li et al., 2016). details of the different cell signaling pathways associated with melanin
SAEEDI ET AL. 9

synthesis can be useful in the control of melanogenesis process regard, new treatment strategies have been designed to inhibit mela-
(D'Mello, Finlay, Baguley, & Askarian-Amiri, 2016). nogenesis and melanocyte dysfunction (Pillaiyar, Manickam, &
Excitation of keratinocytes by ultraviolet radiation causes the syn- Jung, 2015). Hyperpigmentation disorders have therapeutically been
thesis of proopiomelanocortin-derived α-melanocyte stimulating hor- challenging and discouraging (Khezri et al., 2020). In this regard, vari-
mone (α-MSH) peptide. The surface receptor of melanocyte cells ous therapeutic approaches have been developed to improve the
attaches to α-MSH. By doing this reaction, the melanogenesis process treatment of hyperpigmentation disorders including topical therapies,
expresses multiple signaling pathways including protein kinase A combination therapy, emerging topical agents, chemical peels, micro-
(PKA), microphthalmia-associated transcription factor (MITF) activity, dermabrasion, microneedling, lasers, oral agents, botanical agents,
and cAMP (cAMP response element-binding protein [CREB]) emerging oral treatments, and intravenous agents (Cheng &
(Kanlayavattanakul & Lourith, 2018b). MITF as a main transcriptional Vashi, 2017). These studies offered that developing new treatment
regulator plays a key role in the replication of multiple melanogenic approaches for inhibiting skin hyperpigmentation could lead to modu-
enzymes (tyrosinase-related protein-1 (TRP-1), and tyrosinase-related late these disorders and provide new perspectives on the manage-
protein-2 (TRP-2)) (Shin et al., 2020). There are three main subgroups ment of melanogenesis and melanocyte dysfunction.
of mitogen-activated protein kinases (MAPKs) including p38, stress-
activated protein kinases (SAPKs) also known as c-Jun NH2-terminal
kinases (JNK), and extracellular signal-regulated kinases (ERKs) 6 | A B R I E F O V ER V I E W O F T Y R O S I N A S E
(Johnson & Lapadat, 2002). Pro-inflammatory cytokines and factors AND ITS APPLICATIONS
such as heat, UV radiation, and hydrogen peroxide stimulate P38 and
SAPKs kinases and eventually damage DNA (Kanlayavattanakul & Tyrosinase as a bifunctional metalloenzyme is a protein complex with
Lourith, 2018b). Activation of the ERK signaling pathway suppresses two copper atoms in its active site (Cabanes, Chazarra, & GARCIA-
melanogenesis process in the melanocytes by downregulating MITF CARMONA, 1994). The first research of tyrosinase was performed on
expression (Kim et al., 2003). Therefore, sufficient knowledge about the mushroom Russula nigricans in 1895. Because this mushroom
these signaling pathways can lead to better understand the factors turned red after being cut and then changed its color to black
influencing melanogenesis process. (Bourquelot & Bertrand, 1895), an attempt was made to find the rea-
son for this color change (Van Gelder, Flurkey, & Wichers, 1997). In
agricultural products such as raisins, tea, and cocoa, the tyrosinase
4 | CLINICAL FEATURES AND activity is used for the production of distinct organoleptic properties.
P A T H O P H Y S I O L O G Y OF It is also reported that tyrosinase has applications in food and animal
H Y P E R P I G M E N T A T I O N D I S O RD E R S feed, monitoring environmental pollution and dye production
(Nunes & Vogel, 2018). Tyrosinase has a key role in melanin biosyn-
Histological studies have shown that pigment disorders can occur in thesis in mammalian (Ma et al., 2019). Skin melanin is a biological pig-
the dermis and epidermis layers or both layers. These disorders can ment that is synthesized through melanogenesis in the melanocytes
occur with an increase in the number of melanocytes (Khezri et al., 2020). It removes ROS (Kim & Uyama, 2005) and acts as
(i.e., melanocytosis), an upregulation of melanin synthesis without any a photoprotective agent against harmful rays of the sun and skin
changes in the number of melanocytes (i.e., melanosis), and/or exis- photocarcinogenesis (Brenner & Hearing, 2008). It is also applied as
tence of non-melanin pigments (e.g., tattoo pigment) (Jimbow & natural antibacterial substance for the treatment of wounds (Nunes &
Minamitsuji, 2001). In the management of hyperpigmentation disor- Vogel, 2018). Tyrosinase has capacity in various biotechnological
ders, it is important to identify the type of dermal and epidermal pig- applications such as formation of L-DOPA, synthesis of novel mixed
mentation disorder by clinical tests such as using a wood's lamp. melanins, biocatalysis, protein crosslinking, phenol and dye removal,
Using wood lamp, disorders of epidermal pigmentation are usually and phenolic biosensors (Fairhead & Thöny-Meyer, 2012). Extracted
seen prominently, which shows dark brown or black fluorescence. tyrosinase of Streptomyces glausescens, the fungi Neurospora crassa
But, disorders of dermal pigmentation using wood lamps usually and Agaricus bisporus have the best properties (Parvez, Kang, Chung, &
appeared less prominent, which emits often a slate gray or blue fluo- Bae, 2007). Increasing and decreasing melanin synthesis (hyper-
rescence (Lawrence & Al Aboud, 2020). These findings can be used as pigmentation and hypopigmentation, respectively) can cause serious
a powerful tool to better clinical management of hyperpigmentation problems in human's quality of life and skin beauty (Khezri
disorders. et al., 2020). Also, it is showed that tyrosinase has the main role in
physiologically vital processes of invertebrates such as defense reac-
tions (immunity), producing pigmentation, wound healing and cuticular
5 | T R E A T M E NT ST R A T E G I E S F O R S K I N solidify (sclerotization), and structural proteins formed in the process of
HYPERPIGMENTATION hard cuticle formation (Zaidi, Ali, Ali, & Naaz, 2014). In the fungal stud-
ies, it has been shown that melanin acts as a virulence factor in patho-
In recent years, studies have significantly increased on the biological genic fungi and is associated with the formation of sexual organs and
function of melanocytes and melanin synthesis processes. In this spores and the protection of tissue after damage (Molloy et al., 2013).
10 SAEEDI ET AL.

Thus, these studies highlight key and main considerations in polyphenols (arbutin and quercetin), aldehydes (transcinnamaldehyde
developing and designing future preclinical and clinical investigations and cumic acid), fungi derived materials (azelaic acid and kojic acid),
associated with biological activities of tyrosinase. and other derivatives. Tyrosinase inhibitors are used in cosmetic, agri-
culture, and food industries (Parvez et al., 2007). In this regard, effort
to find potential tyrosinase inhibitors from natural and herbal sources
7 | T Y R O S I N A S E I NH I B I T I O N is very important. Because, as mentioned above, these natural com-
pounds can cause serious side effects for consumers, it is necessary to
Tyrosinase plays a key and main role in the melanogenesis process. In check their safety before consumption.
this regard, many studies have been done to find effective inhibitors The studies indicated that depigmentation agents can inhibit the
from natural (fungi, bacteria, plants) and synthetic sources (Muñoz- melanin synthesis through various mechanisms including free-radical
Muñoz et al., 2010). To evaluate the potency of tyrosinase inhibitors, trapping agents (glycyrrhetinic acid, topical steroids), inhibition of
they are assayed by a monophenolic substrate (such as tyrosine) or a tyrosinase transcription (N-acetyl glucosamine, glucosamine, tretinoin,
diphenolic substrate (such as L-dopa) and ultimately their activity evalu- retinaldehyde, retinol), epidermal turnover accelerant (liquiritin, reti-
ates based on the rate of dopachrome formation (Khezri et al., 2020, noids, vitamin C, lactic acid, thioctic acid, vitamin E, glycolic acid, sali-
2021). Therefore, inhibition of tyrosinase activity and preventing over- cylic acid), tyrosinase inhibition (arbutin, hydroquinone, kojic acid,
synthesis and accumulation of melanin in skin are the most important resveratrol, ellagic acid, mequinol, oxyresvaretrol, azelaic acid), anti-
cosmetic goals in clinical treatment of hyperpigmentation disorders. inflammatory (soy milk, niacinamide), and inhibition of melanosome
transfer (linoleic acid) (Couteau & Coiffard, 2016). Figure 3 presents
the mechanism of melanogenesis inhibition of α-Arbutin.
8 | M E L A N O G E N E S I S P RO C E S S A N D In summary, identifying and understanding cellular mechanisms
I N H I B I TI O N M E C H A NI S M S O F regulating human melanogenesis can help the management and inhibi-
DEPIGMENTATION AGENTS tion of melanogenesis process and the development of potential
bleaching agents.
Melanogenesis is known as a biosynthetic pathway. It has a key role
in skin melanin synthesis. Regulation of melanogenesis expression
occurs through intracellular signaling pathways related with the 9 | U S E OF ZE B R A F I S H M O D E L (I N V I V O )
enzymes tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1), and FO R S C R E E NI NG OF A L P H A - A R B U T I N A N D
tyrosinase-related protein-2 (Chang, 2012). Tyrosinase initiates the O T H E R SK I N L I G H T E N I N G A G E N T S I N
melanogenesis process by performing three basic reactions including COS M ET IC
the tyrosine hydroxylation to L-DOPA, L-DOPA oxidation, and finally
its conversion to dopaquinone. After this step, dopaquinone forms Recently, a zebrafish model (in vivo model) is proposed as a preclinical
melanin through a series of complex reactions involving cyclization and animal model to study antimelanogenic efficacy of skin lightening
and oxidative polymerizations (Olivares, Jiménez-Cervantes, Lozano, agents. Using this model, special tests have been designed for this
Solano, & García-Borrón, 2001; Raper, 1928). A review of patents purpose including melanin content, gene expression, phenotype
since 2009 shows that melanogenesis inhibitors are effective for the based test, tyrosinase test, and protein expression (Lajis, 2018). Sev-
treatment of cutaneous hyperpigmentation disorders by two mecha- eral studies have been performed using zebrafish embryo model for
nisms including direct inhibition of catalytic activity or reduction of screening of skin lightening agents in cosmetic preparations (Lajis,
tyrosinase production. Studies on oligopeptides and siRNA have Hamid, Ahmad, & Ariff, 2017; Lajis, Hamid, & Ariff, 2012). This ani-
shown that these compounds are effective candidates for tyrosinase mal model is used for bioactive and depigmenting agents such as
inhibition (Pillaiyar et al., 2015). A review of the literature shows that arbutin and kojic acid too. Depigmenting assay by in vitro
herbal inhibitors can be extracted from plant sources containing (i.e., melanocytes) and in vivo (i.e., mice) models along with zebrafish

F I G U R E 3 Mechanism of
melanogenesis inhibition of α-arbutin
[Colour figure can be viewed at
wileyonlinelibrary.com]
SAEEDI ET AL. 11

model can lead to a better understanding of the effectiveness of common diseases among women. Therefore, it is necessary to make
antimelanogenic agents and better and safe development of these sure that cosmetics ingredients such as arbutin are safe and their ben-
lightening agents (Lajis et al., 2012; Lee et al., 2018; Park eficial/harmful effects on breast cancer should be carefully studied
et al., 2019). Findings from these investigations highlighted the and monitored (“disorders.eyes.arizona.edu,”). It is reported that
importance of zebrafish used as an alternative model in the anti- arbutin is widely used in a variety of cosmetic products in Japan,
melanogenic evaluations of cosmetics ingredients because of similar Korea, and United States (Davis & Callender, 2010). An evaluation of
gene sequences to humans. recent studies showed that arbutin is identified as a safe and effective
strategy for treating breast cancer (Berdowska et al., 2013; Cacchio
et al., 2019; Hazman et al., 2021).
10 | SYNERGISTIC/ANTAGONISTIC Experimental studies using animal models have demonstrated
E F F E C T S WI T H C O M B I N A T I O N T H E R A P Y OF that arbutin metabolites such as hydroquinone have a high potential
ARBUTIN for carcinogenic, nephrotoxic, hepatotoxic, and mutagenic (Nowak,
Shilkin, & Jeffrey, 1995; Peters, Jones, Monks, & Lau, 1997). There-
In an investigation, Kubo et al. designed a combination therapy con- fore, the use of the glycosylation process for arbutin stability can lead
taining arbutin and prednisolone/dexamethasone. Effects of this co- to the formation of new compounds with unknown properties, which
therapy evaluated in a mice model induced by picryl chloride and require tests to determine their safety before use in food and medi-
sheep red blood cell delayed type hypersensitivity. The results of this cine (Liu et al., 2012). It is reported that arbutin is widely absorbed
study showed that this formulation is able to increase the inhibitory from the gastrointestinal tract and is available as hydroquinone in liver
potency against swelling of contact dermatitis induced in mice com- (Deisinger, 1996). In various studies, evaluation of oral administration
pared to either of the two chemicals alone (Kubo, Ito, Nakata, & of arbutin showed that arbutin and other arbutin-rich herbal prepara-
Matsuda, 1990). In this regard, Matsuda et al. developed co-delivery tions can metabolize into hydroquinone and glucose in the liver by the
systems using arbutin plus indomethacin (on carrageenin-induced process of β-glucosidase. It then forms conjugations with glucuronic
edema and adjuvant-induced arthritis) and arbutin plus dexametha- and sulfuric acids that are rapidly eliminated through urine and it is
sone ointment (on picryl chloride and carrageenin-induced paw not a significant threat (Jurica, Benkovi
c, Sikiri
c, Kopjar, & Brči
c
edema). The findings of these studies demonstrated stronger inhibi- Karačonji, 2020; Migas & Krauze-Baranowska, 2015; Schindler
tory effect of these co-delivery systems than arbutin, indomethacin, et al., 2002).
and dexamethasone alone in these models (Matsuda, Nakata, Several investigations demonstrate that arbutin is less toxic than
Tanaka, & Kubo, 1990; Matsuda, Tanaka, & Kubo, 1991). In another hydroquinone. It is reported that arbutin is a suitable alternative to
study, it showed that co-delivery of arbutin with nonsteroidal anti- hydroquinone in treating hyperpigmentation disorders (Draelos,
inflammatory drugs such as ibuprofen and indomethacin can increase Deliencourt-Godefroy, & Lopes, 2020; Nordlund, Grimes, &
the anti-inflammatory effects (Program, 2006). In an in vivo study on Ortonne, 2006). A review of the studied cases with different concen-
UV-induced pigmentation in human skin, Choi et al. have investigated trations of arbutin (3, 5, and 7%) in the patch tests showed that
anti-tyrosinase activity of aloesin (an anti-inflammatory) alone and treated patients with these formulations developed various symptoms
combined with arbutin. They showed that combined therapy could be of contact dermatitis including edematous pruritic erythema, infil-
considerably effective (63.3% suppression of pigmentation) in treating trated small erythema, depigmented spot, pruritic erythema,
hyperpigmentation disorders by synergistic inhibition mechanism of oedematous erythema in different areas of facial skin such as cheek,
tyrosinase compared to therapy of aloesin (34%) and arbutin (43.5%) eyelid, and forehead (Li et al., 2018; Numata, Tobita, Tsuboi, &
alone (Choi, Park, Lee, Kim, & Chung, 2002). Also, in another study, it Okubo, 2016). The Scientific Committee on Consumer Safety (SCCS)
is revealed that co-therapy with arbutin can suppress UV-induced has expressed that the best range of safe and effective concentrations
nuclear factor-kappa B activation in human keratinocytes (Ahn, Moon, of α-arbutin is concentrations greater than 0.5% for body lotions and
Lee, & Kim, 2003). In a mouse skin model system induced using 12-O concentrations higher than 2% in facial creams (Degen, 2015, 2016).
tetradecanoylphorbol-13-acetate, Nakamura et al. indicated that These reports confirm that formulations containing alpha-arbutin are
coadministration of arbutin can effectively prevent oxidative stress considered as a safe health care product for consumers.
(Nakamura et al., 2000). These results suggest that combination thera-
pies of arbutin can be considered with positive effects through syner-
gistic and antagonistic interactions. 12 | C L I N I C A L S T U D I E S OF A R B U T I N I N
COS M ET IC S P REP A RAT I ONS

11 | SAFETY ASSESSMENT OF ARBUTIN IN One of the successful treatments for hyperpigmentation disorders is
COSMETICS AND PHARMACEUTICAL long-term therapy using depigmenting and bleaching agents, either
PREPARATIONS alone, or in combination with other skin lightening agents at various
concentrations (Saeedi, Eslamifar, & Khezri, 2019). Several clinical
Cosmetic products, especially preparations containing skin lightening studies suggested the use of arbutin with other depigmenting agents
ingredients, are very popular. Breast cancer is one of the most in melasma therapies and other hyperpigmentation disorders
12 SAEEDI ET AL.

(Table 3). However, in some studies, side effects such as contact der- permeability, poor physicochemical stability, extensive metabolism in
matitis (with arbutin alone) (Numata et al., 2016), allergic contact der- the gut, very low biosolubility at acidic and physiological pH, short
matitis in a combination therapy (containing arbutin and dipotassium half-life in plasma, rapid fecal elimination, poor oral bioavailability,
glycyrrhizate) (Oiso, Tatebayashi, Hoshiyama, & Kawada, 2017) and a redox instability, etc. (Dewanjee, Chakraborty, Mukherjee, & De
monotherapy (with arbutin alone) (Matsuo, Ito, Masui, & Ito, 2015), Feo, 2020; Murthy, Monika, Jayaprakasha, & Patil, 2018). Actually,
erythema, burning, and irritation (the combination of arbutin 5% nano-phyto therapy has been reported as a simple, eco-friendly,
+ glycolic acid 10% + kojic acid 2%) (Fragoso-Covarrubias, Tirado- improved cellular uptake, rapid, controlled release, stable, enhanced
Sánchez, & Ponce-Olivera, 2015) have been reported due to the use dissolution rates, safe, cost-effective, excellent blood stability, and
of arbutin in combination therapy. According to Table 3, it is revealed novel treatment approach for synthesis of herbal nanoformulations
that combination of arbutin with other lightening agents can be con- (Thangadurai, Sangeetha, & Prasad, 2020; Sarli & Ghasemi, 2020). In
sidered to be better than monotherapy. this regard, the strategy using arbutin nanoformulations (as a nano-
phyto therapy agent) has been reported in various studies. In an inves-
tigation, to obtain efficient drug loading, Wen et al. designed
1 3 | N A N O - P H Y T O T H E R A P Y —A nanoliposomes containing arbutin. They found that high encapsulation
P O T E N T I A L ST R A T E G Y F O R I N C R E A S I N G of arbutin in liposomes was dependent on the amount of lipid in lipo-
BIOAVAILABILITY OF ARBUTIN somal formulations (Wen et al., 2006). In the study by Cho et al., it is
revealed that the stability of combined formulation by liposomal
As previously mentioned, high hydrophilicity and hygroscopicity prop- arbutin and phosphatidylcholine cholesterol in o/w emulsion was
erties of arbutin cause its insufficient absorption from the skin layers effectively improved by adding poly (methacrylic acid–co-stearyl
and, therefore, reduce the therapeutic effectiveness of arbutin in topi- methacrylate) (Cho, Lim, Shim, Kim, & Chang, 2007). In an in vivo
cal products (Aung et al., 2020). The review of the literature shows study, Park et al. designed arbutin–gold nanoparticle complexes. They
that attempts have been made to develop delivery systems of herbal exhibited that these nanoparticles have very stronger whitening effect
medicines (Fathi, Lotfipour, Dizaj, Hamishehkar, & Mohammadi, 2020; than arbutin and can be used as a new therapeutic strategy for the
Negahdari et al., 2020; Sharifi et al., 2020). Recently, nanotherapy- development of novel anti-pigmenting agents (Park et al., 2019).
based herbal drugs (nano-phyto therapy) have emerged as a promising In another study, the whitening capacity of chitosan-sodium
strategy to overcome the poor biopharmaceutical properties of herbal triphosphate-nanoparticles containing α- and β-arbutin were inves-
and botanical ingredients including highly soluble in water, low tigated by Ayumi et al. In this formulation, chitosan has the positive
absorption, loss of bioavailability and efficacy, poor membrane charge due to having amine functional groups and arbutin, and TPP

TABLE 3 Melasma therapies (clinical trials) using arbutin alone and in various combinations

Treatment formulation given Patients Duration Results Reference

A topical serum formulation containing a 30 4 weeks Serum combination can be considered as a Santoso et al. (2018)
combination of tranexamic acid safe and effective option to increase skin
(containing tranexamic acid 3%, brightness with no significant side effect
galactomyces ferment filtrate 4%,
niacinamide 2%, and α-arbutin 4%)
2% arbutin 54 8 weeks The arbutin mask scored better than the Han et al. (2011)
control in patient satisfaction and
investigator assessment
A novel cream formulation containing 33 60 days This formulation has proven to be an Crocco, Veasey, Boin, Lellis,
nicotinamide 4%, arbutin 3%, bisabolol effective, safe, and tolerable treatment and Alves (2015)
1%, and retinaldehyde 0.05% for option for patients with epidermal
treatment of epidermal melasma melasma
7% arbutin in conjunction with laser 35 24 weeks Combination therapy with the MedLite C6 Polnikorn (2010)
therapy and 7% α-arbutin solution is an effective
and well-tolerated treatment for
refractory melasma
1% arbutin 10 6 months Melanin level was significantly decreased Ertam et al. (2008)
Arbutin (5%) + glycolic acid (10%) + Kojic 33 3 months The triple combination was equally Fragoso-Covarrubias
acid (2%) cream effective than hydroquinone, although et al. (2015)
with more frequent occurrence of side
effects. Side effects were erythema,
burning, and irritation in both groups,
mainly in A group
SAEEDI ET AL. 13

TABLE 4 List of arbutin patents for cosmetic applications

Patent/application Number
number Title of the patent Inventors Current assignee of claims References
US9883998B2 Methods for lightening Judy Hattendorf, Steve Obagi cosmeceuticals 15 Hattendorf and
skin using arbutin Carlson LLC Carlson (2018)
compositions
US7056742B2 High level production of Knut Meyer, Paul V. University of North 12 Meyer, Viitanen, and
arbutin in green plants Viitanen, Dennis Flint Texas Flint (2006)
US7431949B2 Topical cosmetic Arnold Neis, Robert Neis, Browne E T drug co Inc 16 Neis, Neis, and
compositions Jerry Whittemore Whittemore (2008)
containing α-arbutin
US6306376B1 Use of arbutin Michel Philippe LOreal SA 14 Philippe (2001)
monoesters as
depigmenting agents
US20090069253A1 Whitening cosmetic Teruyuki NANBU ASKA Corp co ltd 2 Nanbu (2009)
composition containing
arbutin nanoparticles
US20060188559A1 Topical cosmetic Arnold Neis, Robert Neis, Browne E T drug co Inc 4 Neis, Neis, and
compositions Jerry Whittemore Whittemore (2006)
comprising α-arbutin
US7217810B2 High level production of Meyer Knut, Dennis University of North 3 Knut, Flint, and
arbutin in green plants Flint, Paul V. Vitanen Texas Vitanen (2007)
and microbes
US20040042984A1 Skin whitening Deok Park, dong II Jang, COTDE Inc 12 Park, Jang, and
composition containing Kuk Hyun Kim Kim (2004)
arbutin and
glucosidase as active
ingredients
US3201385A Synthesis of arbutin Arthur D Jarrett Polaroid Corp 1 Jarrett (1965)
US6388103B2 Preparation method of Yeon Soo Lee, bum Tae Korea research institute 8 Lee et al. (2002)
arbutin intermediates Kim, Yong Ki Min, no of chemical technology
Kyun Park, Ki ho Kim, KRICT, Biolano co ltd
Jae Seob Lee, see Wha SK, Bioland co ltd
Jeoung, Ki Soo Kim
US20010053350A1 Cosmetic composition Veronique Chevalier, LOreal SA 27 Chevalier and
comprising N- dang-Man Pham Pham (2001)
ethyloxycarbonyl-
4-amino-phenol and
arbutin or its
derivatives and/or
ellagic acid or its
derivatives

has negative charge. These polymeric nanoparticles were prepared therapy as a modern therapeutic approach has open promising
via ionic cross-linking of chitosan and sodium triphosphate. The pharmaceutical perspectives in better and safer health care. Also, a
findings of this study showed that the positively charged list of arbutin patents for cosmetic applications is provided in
nanoparticles are able to improve the delivery of arbutin through Table 4.
skin compared to the negatively charged nanoparticles because the
skin has a negative charge in neutral pH (Ayumi et al., 2019). In
another study, Huang et al. designed a co-delivery system using 14 | C O N CL U S I O N
hydrocolloid gelatin networks of arbutin (as hydrophilic ingredient)
and coumaric acid (as hydrophobic ingredient). They indicated that Recently, cosmetics with natural and bioactive ingredients have
this multiphase nanoemulsion (w/o/w) can be used to improve sta- attracted many interests for consumers of cosmetic products because
bility and bioaccessibility of important phenolic compounds such as these preparations are found safer than preparations containing syn-
arbutin and coumaric acid (Huang, Belwal, Liu, Duan, & Luo, 2019). thetic components. However, high-quality trial studies in larger sam-
According to these results, it can be concluded that nano-phyto ples are needed to confirm safety, and clinical efficacy of
14 SAEEDI ET AL.

phytotherapeutic agents with high therapeutic index. The studies indi- multivariate analysis. Journal of Molecular Structure, 975(1–3),
cated that depigmentation agents can inhibit the melanin synthesis 100–109.
Aung, N. N., Ngawhirunpat, T., Rojanarata, T., Patrojanasophon, P.,
through various mechanisms including free radical trapping agents,
Pamornpathomkul, B., & Opanasopit, P. (2020). Fabrication, characteri-
inhibition of tyrosinase transcription, epidermal turnover accelerant, zation and comparison of α-arbutin loaded dissolving and hydrogel for-
tyrosinase inhibition, anti-inflammatory, etc. The present review ming microneedles. International Journal of Pharmaceutics, 586,
focuses on therapeutic potentials of arbutin in broad spectrum of vari- 119508.
Ayumi, N. S., Sahudin, S., Hussain, Z., Hussain, M., & Samah, N. H. A.
ous diseases such as hyperpigmentation disorders.
(2019). Polymeric nanoparticles for topical delivery of alpha and beta
The Scientific Committee on Consumer Safety has expressed that arbutin: Preparation and characterization. Drug Delivery and Transla-
the best range of safe and effective concentrations of α-arbutin is tional Research, 9(2), 482–496.
concentrations greater than 0.5% for body lotions and concentrations Bang, S. H., Han, S. J., & Kim, D. H. (2008). Hydrolysis of arbutin to hydro-
quinone by human skin bacteria and its effect on antioxidant activity.
higher than 2% in facial creams. It has been shown that the alpha form
Journal of Cosmetic Dermatology, 7(3), 189–193.
has photostable property with the highest inhibitory activity against
ski, B., Fecka, I., Kulbacka, J., Saczko, J., & Gamian, A.
Berdowska, I., Zielin
mammalian tyrosinase. But it is unstable to heat and decomposes and (2013). Cytotoxic impact of phenolics from Lamiaceae species on
must be formulated at low temperatures. Several investigations dem- human breast cancer cells. Food Chemistry, 141(2), 1313–1321.
Bonifacio, M. A., Cerqueni, G., Cometa, S., Licini, C., Sabbatini, L., Mattioli-
onstrate that arbutin is less toxic than hydroquinone. High hydrophi-
Belmonte, M., & De Giglio, E. (2020). Insights into Arbutin effects on
licity and hygroscopicity properties of arbutin cause arbutin
bone cells: Towards the development of antioxidant titanium implants.
insufficient absorption from the skin layers and, therefore, reduce the Antioxidants, 9(7), 579.
therapeutic effectiveness of arbutin in topical products. The review of Bourquelot, E., & Bertrand, A. (1895). A re-examination of the Raper's
the literature shows that attempts have been made to develop deliv- scheme: Cyclodopa as a biological precursor of eumelanin. CR Society
Biology, 47, 582–584.
ery systems of arbutin. In this regard, expert opinions on arbutin
Brenner, M., & Hearing, V. J. (2008). The protective role of melanin against
nanoformulations have effectively increased its bioavailability and UV damage in human skin. Photochemistry and Photobiology, 84(3),
therapeutic efficacy. These studies exhibited that arbutin 539–549.
nanoparticles have very stronger whitening effect than arbutin and it Busetto, G. M., Giovannone, R., Ferro, M., Tricarico, S., Del Giudice, F.,
Matei, D. V., … De Berardinis, E. (2014). Chronic bacterial prostatitis:
can be used as a new therapeutic strategy for the development of
Efficacy of short-lasting antibiotic therapy with prulifloxacin
novel anti-pigmenting agents. Nevertheless, it appears that more (Unidrox®) in association with saw palmetto extract, lactobacillus spo-
detailed studies are required for clinical and industrial applications. rogens and arbutin (Lactorepens®). BMC Urology, 14(1), 53.
Cabanes, J., Chazarra, S., & GARCIA-CARMONA, F. (1994). Kojic acid, a
cosmetic skin whitening agent, is a slow-binding inhibitor of
CONF LICT OF IN TE RE ST
catecholase activity of tyrosinase. Journal of Pharmacy and Pharmacol-
Authors declare that there is no conflict of interests in this study. ogy, 46(12), 982–985.
Cacchio, A., Di Carlo, G., Vincenza, C., & Elisabetta, D. B. (2019). Effective-
DATA AVAI LAB ILITY S TATEMENT ness and safety of a mixture of diosmin, coumarin and arbutin
(Linfadren®) in addition to conventional treatment in the management
The data for this study can be requested from the corresponding
of patients with post-trauma/surgery persistent hand edema: A ran-
author via email. domized controlled trial. Clinical Rehabilitation, 33(5), 904–912.
Cacchio, A., Prencipe, R., Bertone, M., De Benedictis, L., Taglieri, L.,
ORCID D'Elia, E., … Di Carlo, G. (2019). Effectiveness and safety of a product
containing diosmin, coumarin, and arbutin (Linfadren®) in addition to
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