Biomedicine & Pharmacotherapy 110 (2019) 582–593

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Kojic acid applications in cosmetic and pharmaceutical preparations T

a b,⁎ c,⁎
Majid Saeedi , Masoumeh Eslamifar , Khadijeh Khezri
a
Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
b
Department of Environmental Health Engineering, Faculty of Health, Mazandaran University of Medical Sciences, Sari, Iran
c
Student Research Committee, Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: Skin color disorders can be caused by various factors, such as excessive exposure to sunlight, aging and hormonal
Melanin imbalance during pregnancy, or taking some medications. Kojic acid (KA) is a natural metabolite produced by
Hyperpigmentation fungi that has the ability to inhibit tyrosinase activity in synthesis of melanin. The major applications of KA and
Cosmetic its derivatives in medicine are based on their biocompatibility, antimicrobial and antiviral, antitumor, anti-
Health brightening products
diabetic, anticancer, anti-speck, anti-parasitic, and pesticidal and insecticidal properties. In addition, KA and its
Kojic acid
derivatives are used as anti-oxidant, anti-proliferative, anti-inflammatory, radio protective and skin-lightening
agent in skin creams, lotions, soaps, and dental care products. KA has the ability to act as a UV protector,
suppressor of hyperpigmentation in human and restrainer of melanin formation, due to its tyrosinase inhibitory
activity. Also, KA could be developed as a chemo sensitizer to enhance efficacy of commercial antifungal drugs
or fungicides. In general, KA and its derivatives have wide applications in cosmetics and pharmaceutical in-
dustries.

1. Introduction
Skin is one of the most important organs of the body which consists
of several layers including the stratum corneum (SC), viable epidermis,
and dermis. The SC is selectively permeable to specific material such as
drugs [1,2]. The major obstacle for transdermal absorption in percu-
taneous Drug Delivery System (PDDS) is predominance of the SC bar-
rier. Several systems have been developed to enhance drug permeation
through the skin. Chemical transdermal enhancers and prodrugs are the
main paths for conquest of the SC barrier. A new intracellular screening
method in delivery of biologically active ingredients is using a protein
transduction system with a topical delivery enhancer. The combination
of naturally derived melanogenesis inhibition peptide and protein
transdermal delivery system is very useful for whitening peptides that
could be applied in cosmetics and pharmaceutical industry [3,4].
Over the past few decades, the skin has been considered as an im-
portant route in drug delivery. However, it is identified as a significant
and effective barrier [5] and is associated with some transdermal pro-
blems in drug delivery. A major advance to solving this problem, is the
novel drug delivery methods which is designed for topical, local, and
systemic treatments. Nevertheless, few number of drugs have been re-
cognized and they need to pass effectively through the layer of stratum
corneum to achieve effective blood concentration levels. Different
methods have been developed to enhance the transdermal absorption of
drugs, including drug derivatives, drug saturation systems, and che-
mical and physical enhancers. All these facilitate the penetration of
drugs through the stratum corneum layer [6,7]. Drug resistance is a big
problem in systemic chemotherapy in cancer. Therefore, delivery of
chemotherapeutic agents and anti-apoptotic genes possess advantages
to overcome this problem. The nano-carrier system prepared from kojic
acid shows effective deliveries of anti-cancer drugs, significantly in-
hibits cell proliferation and also reduces tumor growth [8,9].
Skin brighteners are a kind of therapy methods that can be used for
the treatment of skin disorders caused by hyperpigmentation. They may
inhibit the synthesis of melanin [10]. Melanin is a pigment that is
produced inside the melanocytes. They synthesize from thyrosine in a
complex process in the presence of thyrosinase and after packaging in
melanosomes immigrate to keratinocytes, the main epidermal cells
[11]. When these pigment productions are more than usual situation or
their distribution are not normal, development of skin hy-
perpigmentation occurs [12]. The use of chemical products to reduce
skin hyperpigmentation by several mechanisms such as reducing the
concentration of melanin is known as whitening of the skin. Nowadays,
brightening the skin is one of the most common procedures to improve
the hyper pigmented parts of the skin [13]. KA and its derivatives are
used to block the formation of pigment by melanocytes as one of the
most popular lightener in cosmetic products [2,14–16].
The kojic acid scaffold has an excellent structure in medicinal

⁎
Corresponding authors at: Mazandaran University of Medical Science, Sari, Iran.
E-mail addresses: msaeedi@mazums.ac.ir (M. Saeedi), microbiologist.eslamifar@gmail.com (M. Eslamifar), Khezripnuchem@yahoo.com (K. Khezri).

https://doi.org/10.1016/j.biopha.2018.12.006
Received 20 September 2018; Received in revised form 25 November 2018; Accepted 2 December 2018
0753-3322/ © 2018 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/BY/4.0/).
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593

chemistry research, due to its vast biological activities. Unnatural Table 1

amino acids, that occur either naturally or synthesized chemically, are Natural sources of kojic acid from different isolates belonging to various species
widely used in ligand design. They represent a powerful tool in drug of fungi [52–55].
discovery when incorporated into therapeutic peptidomimetics and Family Genus Organisms type species
peptide analogs. The incorporation of unnatural amino acids could
enhance the resistance of peptides to enzymatic degradation and in- Pleosporaceae Alternaria Alternaria alternata
Pleospora P. herbarum
crease peptides structural diversity as well as bioactivity. Synthesis of
Pleospora Pleospora allii
novel hybrid molecules containing variety of natural products, such as Chaetomiaceae Chaetomium Chaetomium globosum
novel kojic acid amino acid hybrid natural products has made re- Microascaceae Microascus Microascus brevicaulis
markable progress over the last few years, opening new paths in Stachybotryaceae Stachybotrys Stachybotrys chartarum
Stachybotrys Stachybotrys theobromae
pharmacological approaches. These new amino acid derivatives con-
Torulaceae Torula Torula herbarum
taining kojic acid have several reaction centers for oxidation, reduction, Hypocreaceae Trichoderma Trichoderma hamatum,Trichoderma
alkylation, acylation, and peptide coupling reaction. Also, these com- koningii,T. longibrachiatum,T.
pound will find perfect application as tyrosinase inhibitor [17]. Tran- polysporum
scription factors, are involved in important cellular processes of some Acremonium Acremonium strictum
Nectriaceae Fusarium Fusarium aquaeductuum,
diseases like cancers, autoimmune and inflammatory diseases [18].
F. chlamydosporum
Accumulation of tyrosinase and melanin in cells lead to melasma F. equiseti, F. lateritium
and hyperpigmentation. Tyrosinase is the central enzyme in melanin F. moniliforme, F. oxysporum
biosynthesis. Therefore, illumination of the molecules and pathways F. proliferatum, F. solani
F. subglutinans, F. tricinctum
that regulate tyrosinase activity could identify target areas for the de-
Cunninghamellaceae Cunninghamella Cunninghamella echinulata
velopment of compounds to treat hyperpigmentation in vitro. A major Mucoraceae Mucor Mucor circinelloides,
transcription factor for tyrosinase is the microphthalmia-associated Mucor. fuscus
transcription factor (MITF) that increases tyrosinase expression when Syncephalastraceae Syncephalastrum Syncephalastrum racemosum
upregulated and is involved in the pigmentation, proliferation, and Trichocomaceae Penicillium P. Capsulatum, P. lividum, P. spinulosum
P. funiculosum, P. purpurogenum,
survival of melanocytes. Transcription factors are a class of proteins
P. rugulosum, P. albidum, P.
that regulate gene expression by binding to specific DNA sequences. atramentosum, P. aurantiogriseum
Factors such as ultraviolet radiation, metal ions, free radicals, have P. janthinellum, P. citrinum,
significantly stimulate transcription of tyrosinase gene. the inhibitory P. corylophilum, P. camemberti
effect of melanin formation and tyrosinase activity of kojic acid and P. chrysogenum, P. cyaneofulvum
P. cyclopium, P. digitatum, P. expansum
kojic acid esters was evaluated in B16F1 melanoma cells [19–21]. P. frequentans, P. godlewski,
Kojic acid showed the potential inhibition of cellular NF-κB activity P. nigricans, P. somniferum, P.
in human keratinocytes. NF-κB activation is probably involved in kojic viridicatum
acid induced anti-melanogenic effect [18,22]. Trichocomaceae Aspergillus A. Candidus, A. phoenicis, A. melleus
A. Ochraceus, A. sclerotiorum
During the past decades, fluorescent metal nanoclusters have been
A. Sulphureus, A. fumigatus
widely studied because of their good photo stability, adjustable light A. flavus, A. flavus var. columnaris
emission wavelength, and low bio toxicity. In particular, DNA template A. Oryzae, A. Parasiticus
fluorescent metal nanoclusters have been the center of interest [23]. A. tamarii, A. wentii, A. aculeatus
Luminescent transition metal complexes have also attracted a great deal A. niger, A. terreus, A. flavipes
A. Janus, A. sydowii A. versicolor,
of interest for the detection of biomolecules in scientific projects [9]. A.nidulans
Hybrid probes are highly efficient tools used for locating biological
molecules and signals in living cells. They have great advantages based
on small molecules or fluorescent proteins and are reported to be of 2. Investigating the background and chemical structure of KA
great benefit in live-cell analyses of epigenetic disorders. Yet several
hybrid probes have been utilized by using that fluorescence property in The KA (the name ‘kojic acid’ was derived from “Koji”) is a chemical
response to pH, metal ions, or gas molecules. But, there is paucity of product that is obtained from various types of fungi such as A. flavus, A.
information on the use of hybrid probes for detecting live cells in bio oryzae, A. tamarii, and A. parasiticus (Table 1). It is also produced from
macromolecules. Particularly, there is still unsatisfied demand for the fermentation of some Asian foods (e.g soy sauce and rice wine),
probes for direct visualization of membrane dynamics of live cells which acts as a primer for fungus or inoculum [38–44]. kojic Acid was
[24–26]. first marketed in 1955. The Charles Pfizer and Company, USA, was the
Several substituents are combined into kojic acid at its 2-hydro- first company to try to build this product. In recent years, kojic acid-
xymethyl group. Some kojic acid derivatives are synthesized and producing companies include two in China and three companies in
evaluated for their ability to inhibit D-amino acid oxidase (DAAO). Japan, Switzerland, and the USA. Rapid growth of industries and dis-
These analogs act as beneficial molecular probes to explore the sec- covery of the potential uses of kojic acid and its derivatives, generated
ondary binding site, which could be used in designing more potent great demands for this product. KA (Fig. 1) is classified in the group of
inhibitors [27]. organic acids, which is obtained from different types of fungi during
Human skin exposure to ultraviolet light can cause many skin le- aerobic fermentation process. The common names of KA are presented
sions, such as sunburn, skin cancer, and oxidative stress, all of which in Fig. 2 [39,41,43,45–51].
depend on the intensity and amount of UV light [28,29]. KA can be Its chemical structure is identified as 5-hydroxy-2-hydroxymethyl-γ-
used as a UV protector, with the ability to restrict hyperpigmentation pyron [38–44]. Some of these species are capable of producing KA in
tyrosinase inhibitory effect [2,30–36]. Side effects of hydroquinone
(HQ) as a popular skin lightener has made KA a suitable substitution in
cosmetic products [2,37]. This review describes and discusses the ap-
plication and high capacity of KA, as a lightening agent in cosmetic and
health care preparations.

Fig. 1. Chemical structure of KA.

583
M. Saeedi et al.
Fig. 2. Schematic diagram of Trade Names, Technical Names and Trade Name of KA.
large amounts, but genetic modifications could alter their ability to
greater performance [56]. As mentioned earlier, KA as a skin
whitening, skin lightener or depigmenting agent is used in cosmetic
formulations. It is naturally produced by various species of Penicillium
and Acetobacter and various species of acetic acid bacilli [57–60].
Several methods are suggested for the analysis of KA in various
industries, including voltammetry, spectrophotometry, column chro-
matography with ultraviolet detection, thin-layer chromatography, gas
chromatography with or without flame ionization, mass spectrometry
detection, bio gel P-2 column chromatography [61], and high-perfor-
mance liquid chromatography with photodiode-array or ultraviolet
detection [58,61–73].
3. Melanin synthesis steps and its role in making pigmentation
Melanin is synthesized by melanocytes at the lower layer of epi-
dermis. Melanocytes are classified in the category of specialized den-
dritic cells that are located among epidermal keratinocytes and they
play the primary role of melanin production within an organelle called
melanosomes, and thus spread to surrounding keratinocytes. Each
melanocyte makes contact with melanosomes in different stages of the
dendritic cells and is distributed in many keratinocytes. Melanins are
complex polymers that are derived from tyrosine and other inter-
mediates. They change into black-brown eumelanin and yellow-red
pheomelanin through a multi-stage process of oxidation and complex
reactions that cause variations of color in human population [74,75].
Tyrosinase contain copper ion in the active site. When exposed to UV
rays, the copper ion commands the tyrosinase to become more active.
KA captures the copper ion, preventing that from activating the tyr-
osinase. By inhibiting the activities of tyrosinase, KA can also prevent
creating melanin (Figs. 3 and 4) [76].
More than 80 genes are involved in producing and regulating mel-
anin. Biosynthesis of melanin is controlled by various extracellular
signaling pathways, thus signals are transmitted as a cascade.
Fig. 3. Tyrosinase inhibitory mechanism of KA in melanin biosynthesis for creating melanin by KA.
584
Biomedicine & Pharmacotherapy 110 (2019) 582–593
Fibroblasts are reported to be involved in this signaling. The early
stages of melanin production can occur in the skin by complex genetic
mechanisms, internal and external factors such as aging and ultraviolet
radiation and it can lead to considerable changes in synthesis of pure
melanin [77,78].
4. Transdermal penetration, depigmentation and development of
methods
The topical absorption of KA according to pharmacokinetic ab-
sorption studies in rats and human skin, is estimated to be
0.03–0.06 mg/kg/day. The genotoxic risk of KA as a skin lightening
agent for humans is less. The in vitro percutaneous absorption values of
KA in human skin resulted in 17%, and the maximum potential human
systemic exposure dose (SED) would be 1.7 mg or 0.028 mg/kg/day for
a 60 kg adult human. This SED range is based on the application area of
hands and face [79].
The results of an oral/topical pharmacokinetic study in rats showed
18% of systemic exposure after topical application. Pharmacokinetic
studies in rats after oral and subcutaneous administration to rats,
showed that KA was rapidly absorbed and metabolized. The percuta-
neous absorption of KA in human skin was investigated in vitro and
recovered 14C-equivalents (%) were determined by liquid scintillation
counting in the skin excess (%75.8 ± 9.3), stratum corneum
(%3.7 ± 2.2), epidermis + dermis (%9.2 ± 4.3) and the receptor
fluid (7.8 ± 6.8). KA showed a significant tendency to penetrate into
the dermis and epidermis (penetration rate of 16.98 ± 10.28%, cor-
responding to 3.58 ± 2.38 14C-mgeq/cm2 of treated skin area) [80].
Percutaneous absorption of KA in six healthy postmenopausal
Japanese women was measured before and after applying a cream
containing 1% KA. All the concentrations in plasma were only slightly
above the quantitation limit of 1 ng/ml. So, it was proved that KA had
not the potential role for transdermal penetration into the blood [81].
The inhibition of Eumelanin (black brown) production is usually
M. Saeedi et al.
Fig. 4. Inhibiting the activities of tyrosinase by KA.
considered the main mechanism for depigmentation agents. Cultured B-
16 melanoma cells are excellent material for confirming the melano-
genesis inhibition in vitro. Cultivation of B-16 cells in eagles MEM
containing 10% fetal bovine serum and inserting several concentrations
of depigmenting agents is one of the evaluation methods. After 5 days,
the cells are fixed by formalin and stained by ammoniacal silver nitrate,
then premelanosome stained in black. When the cells are alive, and
premelanosome stain is negative with the presence of depigmenting
agents, melanogenesis have been successfully inhibited. The effects of
melanogenesis inhibition have been established when a depigmenting
agent such as KA was added to the water in which black goldfish were
kept. After 1–2 months the black goldfish turned to yellowish brown
(Fig. 5). Later the goldfish was kept in water without KA, and it turned
back to its original black color. Therefore, KA as a highly effective and
safe ingredient inhibited melanogenesis without damaging cells nor its
function. This demonstrated that melanogenesis was inhibited [82].
5. Cellular and molecular mechanisms of kojic acid
Cosmetic performance that use skin-lightening agents to treat pig-
ment abnormalities are popular worldwide. Yet the molecular and
cellular mechanisms of these agents are mainly unknown. There are
only few skin-lightening compounds with the ability to inhibit tyr-
osinase in addition to activating or inhibiting intracellular signal
leading to the transcriptional inhibition of melanin synthesis genes.
Evidence suggest that most skin-lightening compounds reduce the
synthesis of melanin by inhibiting tyrosinase enzyme activity with low
toxicity on melanocytes. Some skin-lightening agents are believed to
regulate intracellular signaling pathways, leading to a decrease in
585
Biomedicine & Pharmacotherapy 110 (2019) 582–593
Fig. 5. Black goldfish was kept in water containing Kojic Acid,
its color tone fadedIn an initial clinical study, the cream
containing 1% KA had better therapeutic properties than the
cream containing 2.3% KA because KA in the latter crystal-
lized gradually and the effect of the improvement reduced. In
that study, cases of melasma were treated with 1% KA cream
for 6 months. Hyperpigmentation in melasma patient de-
creased significantly after the treatment period. But the
symptoms of melasma returned with exposure to sunlight
[83]. The KA as an iron chelator is applied in treatment of
depigmentation and skin aging. Nanotechnology-based drug
delivery systems, such as liquid crystalline systems (LCSs), can
improve drug permeation through the skin and efficacy of
therapeutic response for a prolonged time [84].
melanin synthesis, or increase in melanocyte cell death [85].
Malignant melanoma generally develops from the transformation
and proliferation of melanocytes in the basal cell layer of the epidermis.
The melanocytes may spread to other organs in the body (metastasis),
and disrupt the function of that organ. To better understand the mo-
lecular and cellular mechanisms of melanoma, human malignant mel-
anoma cells have been extensively used as a skin model for in vitro
examinations because they are highly reproducible, quantifiable and
facility to cultivate. It is a structural cell model that closely equals the
progression of melanoma in vivo, and also a cost-effective alternative to
clinical testing. The anti-apoptotic mechanisms regulating cell death
are involved in drug resistance in tumor cells. Therefore, further
knowledge on the signal transduction pathways leading to tumor cell
death could result in identification of new target molecules to combat
drug resistance and improve melanoma therapy. Tyrosinase catalyzes
three distinct reactions in the melanogenic pathway: hydroxylation of
monophenol (L-tyrosine), dehydrogenation of catechol (L-DOPA), and
dehydrogenation of dihydroxyindole. By contrast, catalase is a potent
inhibitor of tyrosinase that regulates the removal of H2O2. Also, per-
oxidase in the presence of H2O2 and copper ions enhance the conver-
sion of monomers to eumelanin polymers. Thus, enzymatic changes
such as modifications in protein and gene expression, affect melano-
genesis in melanomas. The complex regulatory control of the bio-
synthesis system in melanogenesis includes receptor-mediated path-
ways activated by hormones, neurotransmitters, cytokines, and growth
factors. The biological effects of kojic acid on gene and protein ex-
pression profiles of A375 human melanoma cells and cancer therapy
have been researched. The tumorigenic potential and some genotoxic
effects of kojic acid on human skin cell lines have been widely studied,
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593

Fig. 6. Diagrams of the key function of kojic acid and its derivatives in different industries [55,129–131].

but its effect on gene and protein expression levels in many biological and need for a standardized streamlined protocol to screen melanogenic
functions of human skin has not been exactly reported. Investigating regulatory compounds. Cellular recognition between melanocytes and
the genes and proteins involved in melanoma may consequently im- keratinocytes is an important event involved in melanosome transfer,
prove the development of early diagnostic and therapeutic applications because of their influence on cellular processes including intracellular
[86]. trafficking, endocytosis, and cell-cell recognition [88].
Melanogenesis is a process that is regulated by tyrosinase and tyr-
osinase related protein-1 and -2 (TRP-1 and TRP-2). Tyrosinase plays an
6. Chemical characterizations and applications of KA in various
efficient role in melanin generation by the hydroxylation of tyrosine
industries
into dihydroxyphenylalanine (DOPA) followed by further oxidation of
DOPA into DOPA Quinone. Therefore, inhibition of tyrosinase as a
KA is known as a multi-agent molecule with a reactive gamma-
common method could help in achieving skin hypopigmentation. In
pyrone ring that has poor acidity. KA is reactive on its own ring in any
addition, tyrosinase, TRP-1 and TRP-2 are transcriptionally regulated
situation, therefore, it could be used in production of some products
by a microphthalmia-associated transcription factor (MITF). Skin pig-
with industrial value, including metal chelates, pyridones, pyridines,
mentation is regulated by different types of extrinsic and intrinsic fac-
ethers, azodyes, mannich base, and the products of cyanoethylation.
tors. In particular, extracellular signal-regulated kinase (ERK) nega-
Many functional chemical reactions of KA have been investigated over
tively regulates melanogenesis in melanoma cells. It is also an effective
several decades after its separation. The hydroxyl group in the carbon 5
regulator of the activation of MITF [87].
position from the γ-pyrene ring gives a weak acidic property to the KA
The transcriptional level is the first step by which the expression of
molecule, which leads to the formation of salt by some metals such as
tyrosinase and related melanogenic enzymes may be regulated.
sodium, zinc, copper, calcium, nickel, and cadmium [48–50].
Important factor in this process are the microphthalmia-associated
Kojic acid is well-known for its wide application in various in-
transcription factor (MITF) is a basic helix-loop-helix leucine zipper
dustries such as food, pharmaceuticals, cosmetics, agriculture, and en-
transcription factor that regulates cellular melanocyte as well as the
vironment. It is distributed naturally in traditional Asian food.
transcription of melanogenic enzymes (tyrosinase, TYRP1 and TYRP2)
Moreover, the most striking benefit of kojic acid and its derivatives is
and melanosome structural proteins (MART-1 and PMEL17). There
found in human and animal medicines as biological active compounds
have been substantial advances in our understanding on the cellular
(Fig. 6 and Table 2).
and molecular mechanisms in pigment biology and the processes
causing skin pigmentation. This has led to the development of many
skin lightening agents to reduce skin hyperpigmentation. There has 7. Hyperpigmentation disorders and their causes in human skin
been an increased interest in alternative hypo pigmenting mechanisms
Genetic factors, endocrine abnormalities, injuries, skin cancers,

586
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593

Table 2
Applications of KA in various industries.
Functions Fields References

tyrosinase inhibitor (to inhibit melanin formation) Cosmetic [89]

Anti-inflammatory Cosmetic [17]
Radio protective Cosmetic [90]
Skin-lightening agent in skin creams, lotions, soaps, products Cosmetic [91]
UV protector Cosmetic [92]
Decrease the appearance of scars Cosmetic [93]
Anti-aging effect Cosmetic [94]
Antidermatophytic Cosmetic [94]
Skin whitening or depigmenting agent in cosmetics Cosmetic [79]
Radical scavenging activity Cosmetic [95]
An antioxidant Food and cosmetic [79,96]
Anti-biofilm Food and medical [97]
Anti-convulsant Medical [98]
Anti- HIV Medical [98,99]
Antimicrobial Medical [97]
An inhibitor of the growth of Gram-negative bacteria Medical [100]
antiviral Medical [101]
Biocompatibility Medical [102]
Antitumor Medical [89]
Antidiabetic Medical [103,104]
Anticancer Medical [105]
Antispeck Medical [106,107]
Anti-parasite Medical [108]
Chemo sensitizer to enhance efficacy of commercial antifungal drugs or fungicides Medical [109,110]
Pain killer Medical [55,100]
Anti-proliferative Medical [111]
Antileishmanial activity against Leishmania (L.) amazonensis both in vitro and in vivo Medical [89]
Inducing the activation of murine peritoneal macrophages by increasing reactive oxygen species (ROS) Medical [112]
production without causing cytotoxic effects
Dental care Dentistry [113]
In the preparation of novel derivatives of kojic acid Chemistry and [114,115,116,117,118,119,120,121]
cosmetic
Adhesives between metals and organic materials Chemistry [122]
Metal-adsorbents removing contaminating metals from water or chemicals produced by metal-catalyzed Chemistry [122]
reactions
In chelate-forming resins Chemistry [123]
A metal chelating agent Chemistry [124]
An intermediate in synthesis Chemistry [55]
The prevention of discolouration of crustacean, meat, and fresh (0.2%) vegetables at 1.0% Food [123]
As a preservative Food [125]
As an antioxidant for fats and oils Food [126]
In flavourings at 0.2% to add luster Food [123]
In flour production at 0.1% Food [107]
In syrup at 0.05% Food [123]
Pesticide and insecticide Agriculture [127,128]
As a plant growth regulating agent to increase production Agriculture [123]

Table 3
Melasma therapies using KA alone and in various combinations (Main ingredients of bleaching or depigmenting formulas for melasma and other disorders: GA
(Glycolic acid), KA (Kojic acid), HQ (Hydroquinone), and VC(vitamin C) [135–139].
Treatment formulation given patients Duration Results Reference

2% KA, 5% GA 39 patients 3 months Highly effective in reducing the pigment in melasma patients [140]
2% KA, 10% GA, 2% HQ 40 12 weeks 60% improvement [133]
KA (0.75%), 60 patients 12 weeks 4% HQ and 0.75% KA + vitamin c 2.5% are effective topical hypo pigmenting agents in the treatment of [141]
VC (2.5%), facial melasma
4% HQ
1% KA 80 patients 12weeks 71.87 % [142]
2% HQ improvement
2% KA 50 3 months HQ was more suitable than KA for the treatment of melasma [143]
2% HQ
4% KA 100 women three month KA 4% was found to be more suitable in the treatment of melasma [144]
2% HQ

birth control pills, pregnancies, and medications that affect melanin
production, such as chlorpromazine and hydroxychloroquine, are
amongst the effective factors for hyperpigmentation [132]. Many other
factors can also contribute to the development of hyperpigmentation.
These conditions can be very complicated and may require different
stages of treatment. In more acute cases, surgery or laser therapy may
be the only solution; but stains, melasma, spots, and small patch of light
brown color on the skin caused by post inflammatory hyperpigmenta-
tion can be effectively treated with topical products and also with
cosmetic treatment through the use of skin-whitening products. These
products are made from compounds such as KA and Arbutin, and other
substances with bleaching properties of the skin [132]. Melasma is a

587
M. Saeedi et al.
Fig. 7. Schematic diagram of cosmetic applications of KA.
common hyper pigmentation skin problem on the face which generally
happens in women. One of the most common treatments for melasma is
long-term treatment with topical agents that are used alone, or in
combinations. KA (5-hydroxy-2-hydroxymethyl-4-pyrone) is usually
combined with other agents at a concentration of 1–4% for its skin-
lightening property. The mechanism of its effect might be due to re-
ducing melanin formation in melanocytes by tyrosinase inhibition
[133].Several studies suggested the use of KA with other drugs in
melasma (Table 3). Combination of KA with other agents was also
found to be better than the monotherapy. KA combined with Hydro-
quinone (HQ) 2% showed significantly better results compared with
other formulations. In summary, efficacy of KA in melasma therapies is
yet to be understood due to lack of studies with standard drugs used in
melasma. More detailed and extensive studies on KA remain a necessity
[134].
8. Characteristics and applications of KA in cosmetic and
pharmaceutical preparations
The most important applications of KA are as follows:
a Bleaching properties and skin protection in contrast to ultraviolet
light in cosmetic products
b Dental care products
In some studies, melanogenic inhibitory properties of KA has been
proven in vitro. Due to the carcinogenicity of HQ and its prohibition in
Asia, the FDA has introduced KA as an alternative for HQ. Recently,
chelates of KA and manganese and zinc metals have been introduced as
protective agents against gamma and radio rays [14,15,37,145]. In
many studies, various derivatives of KA such as KA ester, KA laureate,
Table 4
Antifungal Activities of KA.
Properties Antifungal
drugs or fungicides
Antifungal and anti-parasite activities KA
Acrylate monomers
based on KA
Chloro KA derivatives
Amino Acid and Peptide Derivatives of KA
KA derivatives
KA
Chitosan oligosaccharide/ KA grafts
Biomedicine & Pharmacotherapy 110 (2019) 582–593
KA dipalmitate and, KA ethyl phosphonate with aldehyde have been
reported to be more effective than KA [145,146]. A schematic of cos-
metic applications of KA is shown in Fig.7. Moreover, due to the pre-
sence of a pyron ring in the structure of KA, it is used to assess iron in
mineral stones. KA metal chelates are used in controlled release in drug
delivery and catalysts.
Several studies have reported that KA acts as an antibiotic against
human tubercle bacilli, gram-negative and gram-positive microorganisms in
in vitro. In addition, the derivatives of KA called azidometalkojates are
reported to act as antifungal and antibacterial agents on several species
of Bacillus, Staphylococcus, Saccharomyces, Aspergillus, Rhizopus, and
Fusarium [147,148]. Also, zinc derivatives of azidometalkojates have
cytotoxic activity on the hella tumor cells. In addition, other derivatives
of KA act as antifungal agent on several species of Phythium graminicola,
Fusarium oxysporum, and Rhizoctonia solani. In other studies, insecticidal
properties of KA has been shown on Heliothis zea, Spodoptera frugiperda,
Musca domestica, and Drosophila melanogaster insects. It also causes
sterility in male and female species [149–153].
KA and its derivatives have become increasingly important due to
various biological activities, including antimicrobial and antiviral
[101], antitumor [154], antidiabetic [103], anticancer [105], anti-
speck [107], anti-parasitic [108], and pesticidal and insecticidal ac-
tivities [155]. In addition, KA and its derivatives are used as anti-oxi-
dant, anti-proliferative, anti-inflammatory, radio protective and skin-
lightening agent in drug and cosmetic products, due to their tyrosinase
inhibitory activity [37,156–158]. Furthermore, KA could be developed
as a chemo sensitizer to enhance efficacy of commercial antifungal
drugs or fungicides [109].
Potential application of KA and its derivatives has been studied in
veterinary medicine, cosmetic and chemical industry (Table 4–6).
[79,80,147,148,150,152,153,159–185].
9. Safety assessment of KA in cosmetics
Several studies are performed to evaluate the mechanisms of de-
pigmentation and safety of KA [193]. They suggested that the best
range of concentrations for KA topical preparation is 1% or less because
in these ranges, KA melts show effective and safe properties. Clinical
studies have shown effectiveness of 1% KA cream therapy for 6 months
in photo-hypersensitive melasma patients [193,194]. High epidermal
diffusion of KA significantly decreased its remaining in viable epi-
dermis. The absorption was modified by altering the topical preparation
base. Melasma patients who had used 1% KA cream were followed for 2
years and no significant side effect or adverse reaction was observed.
Nowadays, new depigmentation agents such as KA are known as com-
mercial cosmeceutical products and other compounds may be offered in
the future [83,195,196].
Species Disease or References
Infections
Pathogenic yeasts and Human invasive aspergillosis [109]
Filamentous fungi
Candida kefyr Candida infections- [186]
Nosocomial Bloodstream Infections
Candida albicans Invasive and non-invasive fungal infections [101]
C. parapsilosis
Pythium graminicola, Fusarium Seedling [187]
Oxysporum,Rhizoctonia solani blight, fusarium wilt and sheath blight,
Dermatophytic Skin disease [188]
fungi
L. amazonensis Leishmaniasis [108]
Aspergillus niger Aspergillosis [189]
Saccharomyces cerevisiae Crohn's disease
food-borne diseases
588
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593

Table 5
Some commercial applications of KA as an antimicrobial agent.
Properties Compounds Species of bacteria References

Anti Acrylate monomers based on KA Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella typhi [186]
bacterial activities KA crystals Proteus, Staphylococcus, Streptococcus, Pseudomonas, Bacillus, Corynebacterium, Clostridium, [190]
Aerobacter, Escherichia,Klebsiella,
Salmonella
Natural KA Pseudmonas aeuroginosa; E. coli, Proteus vulgaris [191]
Staphylococcus aureus; Streptococcus
pneumoniae, Bacillus subtilis
Metal Chelation of KA analogs S. aureus, E. coli and Ps. fluorescens [161]
Natural KA S. typhimurium, E. coli [80]
Chitosan oligosaccharide/ KA grafts Staphylococcus aureus, Escherichia coli [189]

Table 6
Anticancer and Anti proliferative activity of KA.
Properties Compounds Function Type of cancer cell References

Anticancer activities Pyrone-derived ligands from KA Inhibit dimer formation, Metastatic tumor cell lines [192]
sufficient stability in aqueous solution.
Selenocyanatomethyl derivatives of Induce cellular biological changes, act as an Human skin carcinoma (A431) and [89]
KA immunomodulatory agent, modulatory action on human human breast carcinoma (MCF7) cells
monocytes
KA derivatives, Anti-inflammatory, Brain .
including RHS-0110 anti-proliferative, tumors C6 glioma and SYF cells [105]
anti-oxidative, modulate glioma cell proliferation
and Toll-like receptor
KA Anti-proliferative activity Breast cancer cell line, MDA MB435S [190]
cell lines
(Breast cancer)
KA ATPase, protein binding A375 human malignant melanoma [154]
anti-apoptosis, hetero dimerization activity cells

Table 7 of KA. It is also safe to be used in cosmetics in concentration of 1%

Some main benefits and risks of KA as a lightening agent.
Advantages Lighten effect on visible sun damages, age spots [56]
Anti-aging outcomes [216]
Antimicrobial possessions [125]
Antifungal belongings [217]
Anti-acne properties [218]
Beneficial in treating yeast infections, candidiasis, and ringworm
[219]
Disadvantages Contact dermatitis (especially in sensitive skins) [220]
Long-term use of KA may make skin more susceptible to sunburn
[221]
Using KA on damaged or broken skins can result in cancer
[105,172]
KA is found to be rapidly absorbed and distributed in oral admin-
istration in rats; but, its transdermal administration showed that KA is
slowly absorbed and distributed [79]. In other studies, tyrosinase in-
hibitory activity was evaluated and KA was seen to have a tyrosinase
inhibitory effect in positive control tests [30–36]. In some researches,
KA 1 and 2% not show any allergenic or ocular sensitivity [197–199].
The International Agency for research on cancer introduced KA as a
group 3 carcinogen [200–202] based on in vivo studies on genetic
toxicity of mammals [203–210]. Also, the FDA has not approved KA for
use in pharmaceutical products without prescription, but European
Commission's Scientific Committee has announced that:
1 The dose of KA should be 1% in the formulation of skin care.
2 KA is not a toxicant in acute, chronic, generative, and genotoxicity
form [79,211–215].
10. Effectiveness and risks of KA as a lightening agent
The lightening effect on visible sun damages, age spots, or scars that
lead to anti-aging outcomes on the skin are the main therapeutic effect
according to the Cosmetic Ingredient Review Expert Panel (CIREP).
Besides, KA has exhibited antimicrobial properties that can eradicate
some common types of bacterial strains (E.g. acne caused bacteria) even
in small dilutions. Studies also have shown that KA has potentially
antifungal effect. Furthermore, the treating of yeast infections, candi-
diasis, and ringworm have been reported too.
Some adverse reactions and disadvantages are associated with KA in
cosmetic application. Contact dermatitis (especially for sensitive skins)
is the main side effect of KA which is accompanied by irritation, rashes,
inflamed skin, itchiness, and pain. These side effects can be observed
with a higher concentration more than 1% of KA. Another adverse re-
action may appear in long-term use of KA, such as sunburn in sensitive
skin. KA could also result in skin cancer on damaged skins. But, further
studies are needed to identify other potential benefits or risks of KA.
Table 7. shows some main applications and risks of KA as a lightening
agent.
11. New applications of KA
Different types of technology including various nanoparticles such
as polymeric micelles, noisome, dendrimers, liposomes, carbon nano-
tubes, and metal-based nanoparticles are being effectively used in drug
delivery systems. Nanoparticles coated with polymers have been ap-
plied in different biomedical fields. Biocompatible compounds for drug
delivery systems can also provide the potential to develop new medi-
cines aiming at increased bio-availability, biocompatibility, biode-
gradability, lower toxicity, higher efficiency, and controlled release. KA
products have been studied in combination with polymeric nano-
particles and liposomes. Recently, KA liposomal nano carriers’ delivery
system were designed to enhance the chemotherapeutic efficacy in
tumor cell line. Despite its wide benefits, there are some challenges,
including fast elimination by the reticuloendothelial system, toxicity,
and inflammation of delivery systems [8,222]. In Nano chemical

589
M. Saeedi et al.
promotion, liposomes are used as a minute capsule having a particle
size of 100 nm because of its superior biocompatibility and biode-
gradability. It seems to be an ideal DDS in skin and cells. The efficiency
of drug delivery is influenced by the interaction between cell and li-
posome [223–225]. The penetration of kA through skin is found to
improve using HTCC-coating liposomes. The aim of this protocol was to
improve the efficiency of fusion of liposome with cell membrane in
order to increase the absorption of drug [226].
Researchers are trying to improve the disadvantages and challenges
of this system by developing biocompatible products and bio ther-
apeutics. Drug discovery and drug delivery nanoparticles not only in-
crease the effectiveness of active compounds but also improve infection
control, particularly when organisms show multidrug resistant. Coated
magnetic nanoparticles loaded with anticancer drugs such as bio-
compatible product can localize and reduce tumor cells with low side
effects. KA is a poly functional compound without any hazardous side
effects that approve the development of biologically natural compounds
and pharmaceuticals. KA-coated liposome could be used in drug de-
livery in melanoma to its higher fusion ability with cell membrane, high
water solubility and lower toxicity. These liposomal nano carriers can
be applicable for transdermal drug delivery, cancer chemotherapy, and
gene delivery [226,227]. Further researches are suggested to focus on
application of drug-delivery systems with bio therapeutics that include
delivery of several types of nucleic acids such as plasmids, nucleotides
or RNA, antibody–drug conjugates and combination of KA derivate and
liposome, to develop new type of nano carriers for drug delivery in the
future.
12. Conclusion
Generally, KA is popular for its applications in various purposes
such as pharmaceuticals, cosmetics, agriculture, food, and chemical
industry. The most significant advantage of KA is its wide applications
in cosmetics and medical industry. It acts as a brightening ingredient in
whitening creams, skin lotions, and bleaching soaps, and also in dental
and medical care products. In conclusion, and today with massive
growth in this industry, its supply and demand is increasing con-
siderably. Therefore, more clinical studies are needed for designing and
developing new products based on KA.
Acknowledgements
This study is a research project and involves receiving a research
score with approval number 86, supported by Student Research
Committee of the Mazandaran University of Medical Sciences.
References
[1] J.D. Bos, M.M. Meinardi, The 500 Dalton rule for the skin penetration of chemical
compounds and drugs, Exp. Dermatol.: Viewpoint 9 (3) (2000) 165–169.
[2] M. Saeedi, An Overview of Cosmetics and Toiletries, Shelfin Inc, 2013.
[3] S.A. Nasrollahi, et al., Cell‐penetrating peptides as a novel transdermal drug de-
livery system, Chem. Biol. Drug Des. 80 (5) (2012) 639–646.
[4] N. Ookubo, et al., The transdermal inhibition of melanogenesis by a cell-mem-
brane-permeable peptide delivery system based on poly-arginine, Biomaterials 35
(15) (2014) 4508–4516.
[5] K. Khezri, M. Saeedi, S.M. Dizaj, Application of nanoparticles in percutaneous
delivery of active ingredients in cosmetic preparations, Biomed. Pharmacother.
106 (2018) 1499–1505.
[6] J. Akbari, et al., Transdermal absorption enhancing effect of the essential oil of
Rosmarinus officinalis on percutaneous absorption of Na diclofenac from topical
gel, Pharm. Biol. 53 (10) (2015) 1442–1447.
[7] M. Saeedi, K. Morteza-Semnani, Effect of the essential oil of Eryngium caeruleum
on percutaneous absorption of piroxicam through rat skin, J. Essent. Oil Bear.
Plants 11 (5) (2008) 485–495.
[8] T.L. Reddy, et al., Simultaneous delivery of Paclitaxel and Bcl-2 siRNA via pH-
Sensitive liposomal nanocarrier for the synergistic treatment of melanoma, Sci.
Rep. 6 (2016) 35223.
[9] K.-H. Leung, et al., An oligonucleotide-based switch-on luminescent probe for the
detection of kanamycin in aqueous solution, Sens. Actuators B Chem. 177 (2013)
487–492.
590
Biomedicine & Pharmacotherapy 110 (2019) 582–593
[10] F. Oyedeji, G. Hassan, B. Adeleke, Hydroquinone and heavy metals levels in cos-
metics marketed in Nigeria, Trends Appl. Sci. Res. 6 (7) (2011) 622.
[11] K.A. Walters, M.S. Roberts, Dermatologic, Cosmeceutic, and Cosmetic
Development: Therapeutic and Novel Approaches, CRC Press, 2007.
[12] J. Hunter, J. Savin, M. Dahl, Clinical Dermatology, 3rd, Blackwell Science, Oxford,
2002.
[13] K.M. Lewis, et al., Investigating motivations for women’s skin bleaching in
Tanzania, Psychol. Women Q. 35 (1) (2011) 29–37.
[14] Y. Ohyama, Melanogenesis-inhibitory effect of kojic acid and its action me-
chanism, Fragrance J. 6 (1990) 53–58.
[15] J.-M. Noh, et al., Kojic acid–amino acid conjugates as tyrosinase inhibitors, Bioorg.
Med. Chem. Lett. 19 (19) (2009) 5586–5589.
[16] Y. Cho, et al., New cosmetic agents for skin whitening from Angelica dahurica, J.
Cosmet. Sci. 57 (1) (2006) 11–21.
[17] C. Balakrishna, et al., Synthesis of new kojic acid based unnatural α-amino acid
derivatives, Bioorg. Med. Chem. Lett. 25 (21) (2015) 4753–4756.
[18] D.-L. Ma, et al., A highly selective, label-free, homogenous luminescent switch-on
probe for the detection of nanomolar transcription factor NF-kappaB, Nucleic
Acids Res. 39 (10) (2011) p. e67-e67.
[19] A.F.B. Lajis, M. Hamid, A.B. Ariff, Depigmenting effect of kojic acid esters in hy-
perpigmented B16F1 melanoma cells, Biomed Res. Int. 2012 (2012).
[20] Z. Jiang, et al., Sesamin induces melanogenesis by microphthalmia-associated
transcription factor and tyrosinase up-regulation via cAMP signaling pathway,
Acta Biochim. Biophys. Sin. (Shanghai) 43 (10) (2011) 763–770.
[21] D.S.-H. Chan, et al., Structure-based optimization of FDA-approved drug methy-
lene blue as a c-myc G-quadruplex DNA stabilizer, Biochimie 93 (6) (2011)
1055–1064.
[22] K.-Y. Moon, et al., Kojic acid, a potential inhibitor of NF-κB activation in trans-
fectant human HaCaT and SCC-13 cells, Arch. Pharm. Res. 24 (4) (2001) 307–311.
[23] H.-B. Wang, et al., Fluorescent determination of dopamine using polythymine-
templated copper nanoclusters, Anal. Lett. (2018) 1–10.
[24] D.-L. Ma, et al., Crystal violet as a fluorescent switch-on probe for i-motif: label-
free DNA-based logic gate, Analyst 136 (13) (2011) 2692–2696.
[25] H. Wang, et al., Active probes for imaging membrane dynamics of live cells with
high spatial and temporal resolution over extended time scales and areas, J. Am.
Chem. Soc. 140 (10) (2018) 3505–3509.
[26] Y. Hori, et al., Synthetic-molecule/protein hybrid probe with fluorogenic switch
for live-cell imaging of DNA methylation, J. Am. Chem. Soc. 140 (5) (2018)
1686–1690.
[27] M. Raje, et al., Synthesis of kojic acid derivatives as secondary binding site probes
of D-amino acid oxidase, Bioorg. Med. Chem. Lett. 23 (13) (2013) 3910–3913.
[28] M.A. Ebrahimzadeh, et al., Correlation between sun protection factor and anti-
oxidant activity, phenol and flavonoid contents of some medicinal plants, Iranian
journal of pharmaceutical research: IJPR 13 (3) (2014) 1041.
[29] N.S. Pour, et al., Sun protection for children: a review, J. Pediatr. Rev. 3 (1)
(2015).
[30] J. Cabanes, S. Chazarra, F. Garcia–Carmona, Kojic acid, a cosmetic skin whitening
agent, is a slow‐binding inhibitor of catecholase activity of tyrosinase, J. Pharm.
Pharmacol. 46 (12) (1994) 982–985.
[31] E.V. Curto, et al., Inhibitors of mammalian melanocyte tyrosinase: in vitro com-
parisons of alkyl esters of gentisic acid with other putative inhibitors, Biochem.
Pharmacol. 57 (6) (1999) 663–672.
[32] Y.M. Kim, et al., Oxyresveratrol and hydroxystilbene compounds inhibitory effect
on tyrosinase and mechanism of action, J. Biol. Chem. 277 (18) (2002)
16340–16344.
[33] K. Sasaki, F. Yoshizaki, Nobiletin as a tyrosinase inhibitor from the peel of Citrus
fruit, Biol. Pharm. Bull. 25 (6) (2002) 806–808.
[34] M. Ishikawa, I. Kawase, F. Ishii, Combination of amino acids reduces pigmentation
in B16F0 melanoma cells, Biol. Pharm. Bull. 30 (4) (2007) 677–681.
[35] P. Donsing, N. Limpeanchob, J. Viyoch, Evaluation of the effect of Thai bread-
fruit’s heartwood extract on melanogenesis-inhibitory and antioxidation activities,
J. Cosmet. Sci. 59 (1) (2008) 41–58.
[36] O. Abdel-Halim, et al., A new tyrosinase inhibitor from Crinum yemense as po-
tential treatment for hyperpigmentation, Die Pharmazie-An International Journal
of Pharmaceutical Sciences 63 (5) (2008) 405–407.
[37] S. Emami, et al., Kojic acid and its manganese and zinccomplexes as potential
radioprotective agents, Bioorg. Med. Chem. Lett. 17 (1) (2007) 45–48.
[38] Kitada, M., et al., Studies on Kojic Acid Fermentation:(I) Cultural Conditions in
Submerged Culture. 醗酵工學雑誌, 1967. 45(12): p. 1101-1107.
[39] A. Ariff, et al., Aeration and yeast extract requirements for kojic acid production
by Aspergillus flavus link, Enzyme Microb. Technol. 19 (7) (1996) 545–550.
[40] Y. Wakisaka, et al., Development of a cylindrical apparatus for membrane-surface
liquid culture and production of kojic acid using Aspergillus oryzae NRRL484, J.
Ferment. Bioeng. 85 (5) (1998) 488–494.
[41] S. El-Aasar, Cultural conditions studies on kojic acid production by Aspergillus
parasiticus, Int. J. Agric. Biol. 8 (4) (2006) 468–473.
[42] T. Yabuta, LXXIII.—the constitution of kojic acid, a γ-pyrone derivative formed by
Aspergillus oryzæ from carbohydrates, J. Chem. Soc. Perkin Trans. I 125 (1924)
575–587.
[43] R. Megalla, H. Polasa, Inhibition of growth of kojic acid biosynthesis in Aspergillus
by some chlorinated hydrocarbons, Indian J. Microbiol. 25 (1985) 21–25.
[44] V. KAHN, P. LINDNER, Y. ZAKIN, EFFECT OF KOJIC ACID ON THE OXIDATION
OF o‐DIHYDROXYPHENOLS BY MUSHROOM TYROSINASE, J. Food Biochem. 18
(4) (1994) 253–271.
[45] T.E. Gottschalck, International Cosmetic Ingredient Dictionary and Handbook,
Cosmetic, Toiletry, and Fragrance Assoc, 2004.
M. Saeedi et al.
[46] S. Basappa, V. Sreenivasamurthy, H. Parpia, Aflatoxin and kojic acid production
by resting cells of Aspergillus flavus Link, Microbiology 61 (1) (1970) 81–86.
[47] M.Y. Kwak, J.S. Rhee, Controlled mycelial growth for kojic acid production using
Ca-alginate-immobilized fungal cells, Appl. Microbiol. Biotechnol. 36 (5) (1992)
578–583.
[48] K. Takamizawa, et al., Optimization of kojic acid production rate using the Box-
Wilson method, J. Ferment. Bioeng. 82 (4) (1996) 414–416.
[49] B.S. Gould, The metabolism of Aspergillus tamarii Kita. Kojic acid production,
Biochem. J. 32 (5) (1938) 797.
[50] K. Coupland, W.G. Niehaus Jr, Effect of nitrogen supply, Zn2+, and salt con-
centration on kojic acid and versicolorin biosynthesis byAspergillus parasiticus,
Exp. Mycol. 11 (3) (1987) 206–213.
[51] T. Laird, Directory of World Chemical Producers Chemical Information Services:
Dallas, Texas. 2004. 2200 pp.(GBP) 615. ISSN 1093-2933, Org. Process Res. Dev. 8
(6) (2004) p. 1084-1084.
[52] I.A. El-Kady, A.N.A. Zohri, S.R. Hamed, Kojic acid production from agro-industrial
by-products using fungi, Biotechnol. Res. Int. 2014 (2014).
[53] A.-N.A. Zohri, et al., Optimization of kojic acid production conditions from cane
molasses using Plackett-Burman design, Eur. J. Biol. Res. 8 (2) (2018) 56–69.
[54] A. Moharram, A. Zohri, N. Seddek, Production of kojic acid by endophytic fungi
isolated from medicinal plant in Egypt, Int. Invent. J. Biochem. Bioinf. 3 (3) (2015)
28–31.
[55] R. Mohamad, et al., Kojic acid: applications and development of fermentation
process for production, Biotechnol. Mol. Biol. Rev. 5 (2) (2010) 24–37.
[56] Z.D. Draelos, Skin lightening preparations and the hydroquinone controversy,
Dermatol. Ther. 20 (5) (2007) 308–313.
[57] A. Beélik, Kojic Acid, in Advances in Carbohydrate Chemistry, Elsevier, 1956, pp.
145–183.
[58] M.B. Pildain, et al., Two novel aflatoxin-producing Aspergillus species from
Argentinean peanuts, Int. J. Syst. Evol. Microbiol. 58 (3) (2008) 725–735.
[59] M.O. Masse, et al., Identification and quantitative analysis of kojic acid and ar-
butine in skin‐whitening cosmetics, Int. J. Cosmet. Sci. 23 (4) (2001) 219–232.
[60] N. Agha, et al., Kojic acid from Penicillium simplicissimum (Oud.) Thom, Biologia
23 (6) (1968) 466–467.
[61] R.G. Owens, R. Welty, G. Lucas, Gas chromatographic analysis of the mycotoxins
kojic acid, terreic acid, and terrein, Anal. Biochem. 35 (1) (1970) 249–258.
[62] P. Scott, J. Lawrence, W. Van Walbeek, Detection of mycotoxins by thin-layer
chromatography: application to screening of fungal extracts, Appl. Microbiol. 20
(5) (1970) 839.
[63] A.A. Qureshi, N. Prentice, W. Burger, Separation of potential flavoring compounds
by high-performance liquid chromatography, J. Chromatogr. A 170 (2) (1979)
343–353.
[64] H. Tanigaki, H. Obata, T. Tokuyama, The determination of kojic acid using the
stopped-flow method, Bull. Chem. Soc. Jpn. 53 (11) (1980) 3195–3197.
[65] S. Yang, C. Wei, C. Chou, Kojic Acid Content in the Fermented Foods Produced in
Taiwan, Yen chiu pao kao.= Memoirs of the College of Agriculture, National
Taiwan University-Kuo li T’ai-wan ta hsueh, Nung hsueh yuan, 1980.
[66] M. Manabe, et al., Fluorescent compound in fermented foods. VI. High-perfor-
mance liquid chromatographic analysis of kojic acid, Nippon Shoyu Kenkyusho
Zasshi 10 (1984) 146–150.
[67] J. Dobias, J. Brtko, Quantitative determination of kojic acid in fermentation broth
of fungi using diffusion in agar plates and by spectrophotometry, Kvas. Prum. 31
(11) (1985) 260–262.
[68] J.C. Frisvad, High-performance liquid chromatographic determination of profiles
of mycotoxines and other secondary metabolites, J. Chromatogr. A 392 (1987)
333–347.
[69] M. Manabe, et al., Fluorescent constituents in fermented foods. VIII. Gas–liquid
chromatographic analytical system for kojic acid, Nippon Shoyu Kenkyusho Zasshi
14 (1988) 183–186.
[70] T. GoTo, M. MATSUI, T. KITSUWA, Analysis of Aspergillus mycotoxins by gas
chromatography using fused silica capillary column, Mycotoxins 1990 (31) (1990)
43–47.
[71] 苅田修一, et al., Bio Gel P-2 カラムによる米麹中の麹酸の定量. 日本醸造協会誌,
1991. 86(11): p. 884-885.
[72] K. KIMURA, et al., Determination of kojic acid in various commercial foods by
HPLC, J. Food Hyg. Soc. Jpn. 41 (1) (2000) p. 70-73_1.
[73] M.S. Piantavini, Desenvolvimento e validação de um método espectrofotométrico
para a quantificação de ácido kójico por complexação com alumínio e
caracterização do complexo, (2010).
[74] V.J. Hearing, Biochemical control of melanogenesis and melanosomal organiza-
tion, in Journal of Investigative Dermatology Symposium Proceedings (1999).
[75] K.U. Schallreuter, Advances in melanocyte basic science research, Dermatol. Clin.
25 (3) (2007) 283–291.
[76] L. Saghaie, et al., Synthesis and tyrosinase inhibitory properties of some novel
derivatives of kojic acid, Res. Pharm. Sci. 8 (4) (2013) 233.
[77] M. Cario‐André, et al., In vivo and in vitro evidence of dermal fibroblasts influence
on human epidermal pigmentation, Pigment Cell Melanoma Res. 19 (5) (2006)
434–442.
[78] G.-E. Costin, V.J. Hearing, Human skin pigmentation: melanocytes modulate skin
color in response to stress, Faseb J. 21 (4) (2007) 976–994.
[79] C.L. Burnett, et al., Final report of the safety assessment of kojic acid as used in
cosmetics, Int. J. Toxicol. 29 (6_suppl) (2010) 244S–273S.
[80] G.J. Nohynek, et al., An assessment of the genotoxicity and human health risk of
topical use of kojic acid [5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one], Food
Chem. Toxicol. 42 (1) (2004) 93–105.
[81] D.V. Belsito, et al., Tentative Safety Assessment, (2011).
591
Biomedicine & Pharmacotherapy 110 (2019) 582–593
[82] P. Elsner, H.I. Maibach, Cosmeceuticals, Marcel Dekker, New York, 2000.
[83] M. Nakagawa, K. Kawai, K. Kawai, Contact allergy to kojic acid in skin care
products, Contact Derm. 32 (1) (1995) 9–13.
[84] M. Gonçalez, M.A. Correa, M. Chorilli, Skin delivery of kojic acid-loaded nano-
technology-based drug delivery systems for the treatment of skin aging, Biomed
Res. Int. 2013 (2013).
[85] K. Martinson, et al., A novel stilbene-like compound that reduces melanin through
inhibiting melanocyte differentiation and proliferation without inhibiting tyr-
osinase, Cosmetics 5 (3) (2018) 45.
[86] J.-F. Hsieh, S.-T. Chen, S.-L. Cheng, Molecular Profiling of A375 Human Malignant
Melanoma Cells Treated With Kojic Acid and Arbutin, in Breakthroughs in
Melanoma Research, InTech, 2011.
[87] J. Zhou, et al., Oleoylethanolamide inhibits α-melanocyte stimulating hormone-
stimulated melanogenesis via ERK, Akt and CREB signaling pathways in B16
melanoma cells, Oncotarget 8 (34) (2017) 56868.
[88] J. Ebanks, R. Wickett, R. Boissy, Mechanisms regulating skin pigmentation: the
rise and fall of complexion coloration, Int. J. Mol. Sci. 10 (9) (2009) 4066–4087.
[89] J.P. Da Costa, et al., Biological effects of kojic acid on human monocytes in vitro,
Biomed. Pharmacother. 101 (2018) 100–106.
[90] G. Lima, et al., Novel Kojic acid-based functionalized silica nanoparticles for tyr-
osinase and ache inhibition and antimicrobial applications, Chem. Eng. Trans. 64
(2018) 175–180.
[91] J.J. Faig, et al., Biodegradable kojic acid-based polymers: controlled delivery of
bioactives for melanogenesis inhibition, Biomacromolecules 18 (2) (2017)
363–373.
[92] K. Wang, et al., Protective effects of kojic acid on the periphery blood and survival
of beagle dogs after exposure to a lethal dose of gamma radiation, Radiat. Res. 182
(6) (2014) 666–673.
[93] K. Gupta, N. Agarwal, Assessment of response of microdermabrasion with 2% kojic
acid in melasma, Int. J. Res. Med. Sci. 4 (6) (2017) 1868–1872.
[94] Aytemir, M., et al., Kojic acid-derived mannich bases with biological effect. 2018,
Google Patents.
[95] K. Syamsul, et al., Evaluation of tyrosinase activity and radical scavenging activity
of Kojic acid and Kojic acid monooleate, Adv. Sci. Lett. 23 (5) (2017) 4742–4744.
[96] M. Sheikhshoaie, I. Sheikhshoaie, M. Ranjbar, Analysis of kojic acid in food
samples uses an amplified electrochemical sensor employing V2O5 nanoparticle
and room temperature ionic liquid, J. Mol. Liq. 231 (2017) 597–601.
[97] Y. Wu, et al., Evaluation of antibacterial and anti-biofilm properties of kojic acid
against five food-related bacteria and related subcellular mechanisms of bacterial
inactivation, Food Sci. Technol. Int. (2018) p. 1082013218793075.
[98] K. Wang, et al., Kojic acid protects C57BL/6 mice from gamma-irradiation induced
damage, Asian Pac. J. Cancer Prev. 15 (1) (2014) 291–297.
[99] R. Tanaka, et al., Novel 3α-methoxyserrat-14-en-21β-ol (PJ-1) and 3β-methox-
yserrat-14-en-21β-ol (PJ-2)-curcumin, kojic acid, quercetin, and baicalein con-
jugates as HIV agents, Bioorg. Med. Chem. 17 (14) (2009) 5238–5246.
[100] A. Ariff, et al., Kinetics and modelling of kojic acid production by Aspergillus
flavus Link in batch fermentation and resuspended mycelial system, World J.
Microbiol. Biotechnol. 13 (2) (1997) 195–201.
[101] M.D. Aytemir, B. Özçelik, A study of cytotoxicity of novel chlorokojic acid deri-
vatives with their antimicrobial and antiviral activities, Eur. J. Med. Chem. 45 (9)
(2010) 4089–4095.
[102] M.L. Gonçalez, et al., Structural characterization and in vitro antioxidant activity
of kojic dipalmitate loaded w/o/w multiple emulsions intended for skin disorders,
Biomed Res. Int. 2015 (2015).
[103] X. Xiong, M.C. Pirrung, Modular synthesis of candidate indole-based insulin mi-
mics by Claisen rearrangement, Org. Lett. 10 (6) (2008) 1151–1154.
[104] Y. Wei, et al., A new salicylic acid-derivatized kojic acid vanadyl complex:
synthesis, characterization and anti-diabetic therapeutic potential, J. Inorg.
Biochem. 105 (8) (2011) 1081–1085.
[105] D.S. Yoo, et al., A modulatory effect of novel kojic acid derivatives on cancer cell
proliferation and macrophage activation, Die Pharmazie: Int. J. Pharm. Sci. 65 (4)
(2010) 261–266.
[106] H.A. Ammar, et al., Identification and characterization of genes involved in kojic
acid biosynthesis in Aspergillus flavus, Ann. Microbiol. 67 (10) (2017) 691–702.
[107] K. Uchino, et al., Kojic acid as an anti-speck agent, Agric. Biol. Chem. 52 (10)
(1988) 2609–2610.
[108] A.P.D. Rodrigues, et al., A novel function for kojic acid, a secondary metabolite
from Aspergillus fungi, as antileishmanial agent, PLoS One 9 (3) (2014) p. e91259.
[109] J.H. Kim, et al., Enhancement of commercial antifungal agents by kojic acid, Int. J.
Mol. Sci. 13 (11) (2012) 13867–13880.
[110] J.H. Kim, et al., Synergism of antifungal activity between mitochondrial respira-
tion inhibitors and kojic acid, Molecules 18 (2) (2013).
[111] B.S. Reddy, et al., Enantioselective 1, 4-addition of kojic acid derivatives to β-
nitroolefins catalyzed by a cinchonine derived sugar thiourea, RSC Adv. 4 (18)
(2014) 9107–9111.
[112] A.P.D. Rodrigues, et al., Kojic acid, a secondary metabolite from Aspergillus sp.,
acts as an inducer of macrophage activation, Cell Biol. Int. 35 (4) (2011) 335–343.
[113] J.-Y. Kim, et al., Patches for teeth whitening. 2014, Google Patents.
[114] Y. Kobayashi, et al., Synthesis of amino acid derivatives of kojic acid and their
tyrosinase inhibitory activity, Biosci. Biotechnol. Biochem. 59 (9) (1995)
1745–1746.
[115] S. Nagai, T. Izumi, Cosmetic composition containing kojic acid ester. 1981, Google
Patents.
[116] N. Ishak, et al., Kinetics and optimization of lipophilic kojic acid derivative
synthesis in polar aprotic solvent using lipozyme RMIM and its rheological study,
Molecules 23 (2) (2018) 501.
M. Saeedi et al.
[117] A.F.B. Lajis, et al., Lipase-catalyzed synthesis of kojic acid derivative in bioreactors
and the analysis of its depigmenting and antioxidant activities, Cosmetics 4 (3)
(2017) 22.
[118] S.W. Yu, et al., Construction of Novel Kojic acid fused furans by domino reactions
of a Kojic acid derivative with (Z)‐bromonitroalkenes, ChemistrySelect 3 (17)
(2018) 4827–4830.
[119] R. Teimuri-Mofrad, et al., Eco-friendly one-pot, three-component synthesis of
novel derivatives of kojic acid by the Mannich-type reaction under solvent-free
ball-milling conditions, Res. Chem. Intermed. 42 (4) (2016) 3425–3439.
[120] H.-Y. Zhang, et al., A magnetic metal–organic framework as a highly active het-
erogeneous catalyst for one-pot synthesis of 2-substituted alkyl and aryl (indolyl)
kojic acid derivatives, New J. Chem. 41 (15) (2017) 7108–7115.
[121] M. Zirak, B. Eftekhari-Sis, Kojic acid in organic synthesis, Turk. J. Chem. 39 (3)
(2015) 439–496.
[122] B. Ochiai, M. Kamiya, T. Endo, Synthesis and Fe (III)‐complexation ability of
polyurethane bearing kojic acid skeleton in the main chain prepared by poly-
addition of aliphatic hydroxyl groups without protection of phenolic hydroxyl
groups, J. Polym. Sci. Part A: Polym. Chem. 50 (17) (2012) 3493–3498.
[123] R.M. Saleh, et al., Screening and production of antibacterial compound from
Trichoderma spp. Against human-pathogenic bacteria, Afr. J. Microbiol. Res. 5
(13) (2011) 1619–1628.
[124] S. Katoh, et al., Protective action of iron-chelating agents (catechol, mimosine,
deferoxamine, and kojic acid) against ischemia-reperfusion injury of isolated
neonatal rabbit hearts, Eur. Surg. Res. 24 (6) (1992) 349–355.
[125] X. Liu, et al., Synthesis, characterization, and antimicrobial activity of kojic acid
grafted chitosan oligosaccharide, J. Agric. Food Chem. 62 (1) (2013) 297–303.
[126] B.-H. Yi, D.-H. Kim, Antioxidant activity of maltol, kojic acid, levulinic acid, fur-
fural, 5-hydroxymethyl furfural, and pyrazine, Korean J. Food Sci. Technol. 14 (3)
(1982) 265–270.
[127] J. Marui, et al., Kojic acid biosynthesis in Aspergillus oryzae is regulated by a Zn
(II) 2Cys6 transcriptional activator and induced by kojic acid at the transcriptional
level, J. Biosci. Bioeng. 112 (1) (2011) 40–43.
[128] P.F. Dowd, Kojic acid and esters as insecticide synergists. 1990, Google Patents.
[129] J. Chaudhary, A. Pathak, S. Lakhawat, Production technology and applications of
kojic acid, Annu. Res. Rev. Biol. 4 (21) (2014) 3165.
[130] M.D. Aytemir, G. Karakaya, Kojic Acid Derivatives, in Medicinal Chemistry and
Drug Design, InTech, 2012.
[131] H.A. Ammar, S.M. Ezzat, A.M. Houseny, Improved production of kojic acid by
mutagenesis of Aspergillus flavus HAk1 and Aspergillus oryzae HAk2 and their
potential antioxidant activity, 3 Biotech 7 (5) (2017) 276.
[132] J.-P. Ortonne, et al., Hypomelanoses and hypermelanoses, Fitzpatrick’s Dermatol.
Gen. Med. 1 (2003) 839–848.
[133] J.T.E. Lim, Treatment of melasma using kojic acid in a gel containing hydro-
quinone and glycolic acid, Dermatol. Surg. 25 (4) (1999) 282–284.
[134] D. Bandyopadhyay, Topical treatment of melasma, Indian J. Dermatol. 54 (4)
(2009) 303.
[135] P.-C. Kuo, et al., Isolation of a natural antioxidant, dehydrozingerone from
Zingiber officinale and synthesis of its analogues for recognition of effective an-
tioxidant and antityrosinase agents, Arch. Pharm. Res. 28 (5) (2005) 518–528.
[136] Y.M. Olumide, et al., Complications of chronic use of skin lightening cosmetics,
Int. J. Dermatol. 47 (4) (2008) 344–353.
[137] M. Gallarate, et al., On the stability of ascorbic acid in emulsified systems for
topical and cosmetic use, Int. J. Pharm. 188 (2) (1999) 233–241.
[138] S.-C. HUANG, et al., Simultaneous determination of magnesium ascorbyl phos-
phate, ascorbyl glucoside, kojic acid, arbutin and hydroquinone in skin whitening
cosmetics by HPLC, J. Food Drug Anal. 12 (1) (2004).
[139] P.G. Engasser, H.I. Maibach, Cosmetics and dermatology: bleaching creams, J. Am.
Acad. Dermatol. 5 (2) (1981) 143–147.
[140] A. Garcia, J.E. Fulton Jr, The combination of glycolic acid and hydroquinone or
kojic acid for the treatment of melasma and related conditions, Dermatol. Surg. 22
(5) (1996) 443–447.
[141] R.C. Monteiro, et al., A comparative study of the efficacy of 4% hydroquinone vs
0.75% kojic acid cream in the treatment of facial melasma, Indian J. Dermatol. 58
(2) (2013) 157.
[142] K.S. Deo, et al., Kojic acid vis-a-vis its combinations with hydroquinone and be-
tamethasone valerate in melasma: a randomized, single blind, comparative study
of efficacy and safety, Indian J. Dermatol. 58 (4) (2013) 281.
[143] Harshini, S., The comparative study of Hydroquinone and kojic acid in treatment
of Melasma in Shadan Institute of Medical Science Teaching Hospital and Research
Centre, Himayathsagar road, Hyderabad (Telangana State).
[144] N. Espahbodi, A. Abbasi, R. Feizi, A comparative study of kojic acid cream and
hydroquinone in treatment of melasma, J. Shahrekord Uuniv. Med. Sci. 10 (2008).
[145] Y.S. Lee, et al., Synthesis of tyrosinase inhibitory kojic acid derivative, Arch.
Pharm. (Weinheim) 339 (3) (2006) 111–114.
[146] S.E. Ashari, et al., Optimization of enzymatic synthesis of palm-based kojic acid
ester using response surface methodology, J. Oleo Sci. 58 (10) (2009) 503–510.
[147] T. Tamura, et al., Absence of in vivo genotoxic potential and tumor initiation
activity of kojic acid in the rat thyroid, Toxicology 222 (3) (2006) 213–224.
[148] M. March, MHW Ordinance No. 331, Appendices 2-4. Restricted lists, Ministry of
Health, Labor and Welfare, Pharmaceutical and Medical Safety Bureau, Inspection
and Guidance Division, 2005 p. 2-2.
[149] M.D. Larrañaga, R.A. Lewis, Hawley's Condensed Chemical Dictionary, John Wiley
& Sons, 2016.
[150] R. Saruno, F. Kato, T. Ikeno, Kojic acid, a tyrosinase inhibitor from Aspergillus
albus, Agric. Biol. Chem. 43 (6) (1979) 1337–1338.
[151] K. Buchta, Organic Acids of Minor Importance in Biotechnology Biomass,
592
Biomedicine & Pharmacotherapy 110 (2019) 582–593
Microorganisms For Special Application, Microbial Products, Energy From
Renewable Resources, Bioehringer, Ingelheim Federal Republic of Germany, 1982,
p. 447.
[152] F. Prignano, et al., Therapeutical approaches in melasma, Dermatol. Clin. 25 (3)
(2007) 337–342.
[153] A. Synytsya, et al., Conjugation of kojic acid with chitosan, Carbohydr. Polym. 72
(1) (2008) 21–31.
[154] J. Nawarak, et al., Proteomics analysis of kojic acid treated A375 human malig-
nant melanoma cells, J. Proteome Res. 7 (9) (2008) 3737–3746.
[155] M. Uher, V. Konecny, O. Rajniakova, Synthesis of 5-hydroxy-2-hydroxymethyl-4H-
pyran-4-one derivatives with pesticide activity, Chem Pap 48 (1994) 282–284.
[156] S.J. Hosseinimehr, et al., Radioprotective effects of kojic acid against mortality
induced by gamma irradiation in mice, Saudi Med. J. 30 (4) (2009) 490–493.
[157] X. Li, et al., γ-Pyrone derivatives, kojic acid methyl ethers from a marine-derived
fungusaltenaria sp, Arch. Pharm. Res. 26 (7) (2003) 532–534.
[158] L. Novotný, et al., Kojic acid–a new leading molecule for a preparation of com-
pounds with an anti-neoplastic potential, Neoplasma 46 (2) (1999) 89–92.
[159] B.J. WILSON, Miscellaneous Aspergillus toxins. Microbes toxins, Fungal Toxins,
(1971), pp. 235–250.
[160] K. Buchta, Organic acids of minor importance, Biotechnol.: A Compr. Treaties 3
(1982).
[161] T. Kotani, et al., Bacteriostatic activities and metal chelation of kojic acid analogs,
Agric. Biol. Chem. 40 (4) (1976) 765–770.
[162] H. Lee, B. Boltjes, W. Eisenman, Kojic acid as an inhibitor of tubercle bacilli, Am.
Rev. Tuberculosis Pulmonary Dis. 61 (5) (1950) 738–741.
[163] D. Hudecová, et al., New azidometalkojates and their biological activity, Folia
Microbiol. (Praha) 41 (6) (1996) 473–476.
[164] H. Kayahara, et al., Amino acid and peptide derivatives of kojic acid and their
antifungal properties, Agric. Biol. Chem. 54 (9) (1990) 2441–2442.
[165] Š. Balaž, et al., Relationship between antifungal activity and hydrophobicity of
kojic acid derivatives, Folia Microbiol. (Praha) 38 (5) (1993) 387–391.
[166] P.F. Dowd, Toxicological and biochemical interactions of the fungal metabolites
fusaric acid and kojic acid with xenobiotics in Heliothis zea (F.) and Spodoptera
frugiperda (JE Smith), Pestic. Biochem. Physiol. 32 (2) (1988) 123–134.
[167] S. Sehgal, Effectiveness of Kojik Acid in Inducing Sterility in Trogoderma gran-
arium Everts.(Coleoptera), Ciencia e cultura, 1976.
[168] R.L. Beard, G.S. Walton, Kojic acid as an insecticidal mycotoxin, J. Invertebr.
Pathol. 14 (1) (1969) 53–59.
[169] J. Dobias, P. Nemec, J. Brtko, The inhibitory effect of kojic acid and its two de-
rivatives on the development of Drosophila melanogaster [insecticidal effect],
Biologia (1977).
[170] B.J. Wood, Microbiology of Fermented Foods, Springer Science & Business Media,
2012.
[171] C. Tatsumi, et al., Production of comenic acid from kojic acid by microorganism, J.
Ferment. Technol. 47 (3) (1969) p. 178-&.
[172] G.A. Burdock, M.G. Soni, I.G. Carabin, Evaluation of health aspects of kojic acid in
food, Regul. Toxicol. Pharmacol. 33 (1) (2001) 80–101.
[173] J.S. Chen, et al., Inhibitory effect of kojic acid on some plant and crustacean
polyphenol oxidases, J. Agric. Food Chem. 39 (8) (1991) 1396–1401.
[174] L. Novory, et al., Kojic acid–a new leading molecule for a preparation of com-
pounds with an anti-neoplastic potential, Neoplasma 46 (1999) 2.
[175] A. Garcia, J.E. Fulton, The combination of glycolic acid and hydroquinone or kojic
acid for the treatment of melasma and related conditions, Dermatol. Surg. 22 (5)
(1996) 443–447.
[176] E. Guibal, Interactions of metal ions with chitosan-based sorbents: a review, Sep.
Purif. Technol. 38 (1) (2004) 43–74.
[177] M.N.R. Kumar, A review of chitin and chitosan applications, React. Funct. Polym.
46 (1) (2000) 1–27.
[178] T. Takizawa, et al., Hepatocellular tumor induction in heterozygous p53-deficient
CBA mice by a 26-week dietary administration of kojic acid, Toxicol. Sci. 73 (2)
(2003) 287–293.
[179] M. Moto, et al., Absence of liver tumor-initiating activity of kojic acid in mice,
Arch. Toxicol. 80 (5) (2006) 299–304.
[180] T. Watanabe, et al., Induction of hepatocellular proliferative lesions in CBA mice
by a 26-week dietary administration of kojic acid, J. Toxicol. Pathol. 18 (3) (2005)
159–165.
[181] T. Watanabe, et al., Lack of initiating activity of kojic acid on hepatocarcinogen-
esis in F344 rats, J. Toxicol. Pathol. 18 (2) (2005) 79–84.
[182] A. James, et al., Annexe D. Deposition of inhaled particles, Ann. ICRP 24 (1-3)
(1994) 231–299.
[183] G. Oberdörster, E. Oberdörster, J. Oberdörster, Nanotoxicology: an emerging
discipline evolving from studies of ultrafine particles, Environ. Health Perspect.
113 (7) (2005) 823.
[184] M. Index, Whitehouse Station, Merck & Co. Inc., NJ, 2001.
[185] M.D. Larrañaga, R.J. Lewis, R.A. Lewis, Hawley's Condensed Chemical Dictionary.
John Wiley & Sons, 2016.
[186] M. Saraei, et al., Novel functionalized monomers based on kojic acid: snythesis,
characterization, polymerization and evalution of antimicrobial activity, Des.
Monomers Polym. 20 (1) (2017) 325–331.
[187] H. Kayahara, et al., Amino acid and peptide derivatives of kojic acid and their
antifungal properties, Agric. Biol. Chem. 54 (9) (1990) 2441–2442.
[188] Š. Baláž, et al., Biologically important physicochemical properties of kojic acid
derivatives, Collect. Czech. Chem. Commun. 58 (3) (1993) 693–701.
[189] X. Liu, et al., Effect of kojic acid-grafted-chitosan oligosaccharides as a novel an-
tibacterial agent on cell membrane of gram-positive and gram-negative bacteria, J.
Biosci. Bioeng. 120 (3) (2015) 335–339.
M. Saeedi et al.
[190] Devi, K.B.D., et al., Screening of anti-cancerous compound kojic acid by a novel
fungal isolates from economically inexpensive nutritive sources.
[191] S. El-Aasar, Cultural conditions studies on kojic acid production by Aspergillus
parasiticus, Int. J. Agric. Biol. 8 (4) (2006) 468–473.
[192] J.H. Kasser, et al., Mannich products of kojic acid and N-heterocycles and their Ru
(II)–arene complexes: synthesis, characterization and stability, J. Organomet.
Chem. 695 (6) (2010) 875–881.
[193] P. Elsner, H.I. Maibach, Cosmeceuticals: Drugs vs. Cosmetics Vol. 23 CRC Press,
2000.
[194] Y. Mishima, et al., Inhibitory action of kojic acid on Melanogensis and its ther-
apeutic effect for various human hyper-pigmentation disorders, Skin Res. 36 (2)
(1994) 134–150.
[195] A. Breathnach, Melanin hyperpigmentation of skin: melasma, topical treatment
with azelaic acid, and other therapies, Cutis 57 (1 Suppl) (1996) 36–45.
[196] K. Jimbow, N-Acetyl-4-S-Cysteaminylphenol as, Arch. Dermatol. 127 (1991)
1528–1534.
[197] T. Shino, Irritation Test of Kojic Acid Aqueous Solutions Against the Eye Mucosa of
Rabbits, Department of Dermatology, Kyushi University-14.11, 1978.
[198] M. Suzuki, M. Yoshimura, I. Kojso, Eye Mucosa Irritation Test of Kojic Acid, Pola
Chemical Research Institute, 1978, pp. 1–3 Unpublished data.
[199] S. Kynoch, M. Liggett, Irritant Effects of Kojic Acid on Rabbit Skin, Huntingdon
Research Centre study number 9556/14D/78, 1978, pp. 1–5 Unpublished data.
[200] W.H. Organization, IARC Monographs on the Evaluation of Carcinogenic Risks to
Humans. Volume 79: Some Thyrotropic Agents, World Health Organization, 2001.
[201] Y. Ota, et al., A 55-week chronic toxicity study of dietary administered kojic acid
(KA) in male F344 rats, J. Toxicol. Sci. 34 (3) (2009) 305–313.
[202] T. Shibusawa, et al., Carcinogenesis-modifying Action of Kojic Acid in the Rat
Liver, Unpublished data (2002).
[203] L. Bjeldanes, H. Chew, Mutagenicity of 1, 2-dicarbonyl compounds: maltol, kojic
acid, diacetyl and related substances, Mutat. Res. Toxicol. 67 (4) (1979) 367–371.
[204] S. Iwahara, K. Sakamoto, Mutation Induction Test of Kojic Acid-Ames Test, Hatano
Research Institute study number 54-079, 1980, pp. 54–119 Unpublished data.
[205] C. Wei, et al., Mutagenicity studies of kojic acid, Toxicol. Lett. 59 (1-3) (1991)
213–220.
[206] S. Ishikawa, et al., Characterization of genotoxicity of kojic acid by mutagenicity
in Salmonella and micronucleus induction in rodent liver, Genes Environ. 28 (1)
(2006) 31–37.
[207] D. Marzin, Mutagenicity Test on Bacteria (Salmonella Typhimurium His-) Using
BN Ames Technique With 53 758, Institut Pasteur de Lille report number IPL-R
970118/53 758, 1997 Unpublished data.
[208] H. Wollny, Salmonella Typhimurium and Escherichia coli Reverse Muation Assay
With Kojic Acid, RCC-CCR project number 612701, 1998 Unpublished data.
[209] H. Wollny, Salmonella Typhimurium Reverse Muation Assay With Kojic Acid,
RCC-CCR project number 696301, 2001 Unpublished data.
[210] S. Iwahara, Mutagenicity Study on Kojic Acid-mutation Induction Test in Chinese
593
Biomedicine & Pharmacotherapy 110 (2019) 582–593
Hamster V79 Cultured Cells, Hatano Research Institute study number 56-234-1,
1981 Unpublished data.
[211] A. Palmer, J. Edwards, R. Clark, Effect of Kojic Acid on Fertility and Early
Pregnancy of the Rat, Huntingdon Research Centre study no, 1979 SSO/21/79429.
Unpublished data.
[212] A. Palmer, J. Edwards, R. Clark, Effect of Kojic Acid on Pregrancy of the New
Zealand White Rabbit, Huntingdon Research Centre study number SS0/22/79320,
1979 Unpublished data.
[213] D. Choudhary, G. Sahay, J. Singh, Effect of some mycotoxins on reproduction in
pregnant albino rats, J. Food Sci. Technol. 29 (4) (1992) 264–265.
[214] D. Choudhary, G. Sahay, J. Singh, Antifertility and cannibalistic properties of some
mycotoxins in albino rats, J. Food Sci. Technol. (Mysore) 31 (6) (1994) 497–499.
[215] J. Richard, Preliminary Study for Effects on Embryo-Fetal Development by Oral
Administration (gavage) in Rats. CIT Study Number 16699 RSR, Unpublished data
(1998).
[216] J. Rivers, The role of cosmeceuticals in antiaging therapy, Skin Therapy Lett. 13
(8) (2008) 5–9.
[217] B.S. Reddy, et al., Indium (III) chloride catalyzed three-component coupling re-
action: a novel synthesis of 2-substituted aryl (indolyl) kojic acid derivatives as
potent antifungal and antibacterial agents, Bioorg. Med. Chem. Lett. 20 (24)
(2010) 7507–7511.
[218] R.B. Aronsohn, Skin formulation. 1986, Google Patents.
[219] J.E. Nett, et al., Reduced biocide susceptibility in Candida albicans biofilms,
Antimicrob. Agents Chemother. 52 (9) (2008) 3411–3413.
[220] E. Serra‐Baldrich, M. Tribo, J. Camarasa, Allergic contact dermatitis from kojic
acid, Contact Derm. 39 (2) (1998) 86–87.
[221] Y. Shih, J.-M. Zen, Voltammetric determination of kojic acid in cosmetic bleaching
products using a disposable screen-printed carbon electrode, Electroanalysis 11 (4)
(1999) 229–233.
[222] M.A. Obeid, et al., Delivering natural products and biotherapeutics to improve
drug efficacy, Ther. Deliv. 8 (11) (2017) 947–956.
[223] M. Mezei, V. Gulasekharam, Liposomes-a selective drug delivery system for the
topical route of administration I. Lotion dosage form, Life Sci. 26 (18) (1980)
1473–1477.
[224] M. Mezei, V. Gulasekharam, Liposomes—a selective drug delivery system for the
topical route of administration: gel dosage form, J. Pharm. Pharmacol. 34 (7)
(1982) 473–474.
[225] N. Kojima, et al., Oligomannose-coated liposome as a novel adjuvant for the in-
duction of cellular immune responses to control disease status, Biomed Res. Int.
2013 (2013).
[226] Y.-W. Wang, et al., Cellular fusion and whitening effect of a chitosan derivative
coated liposome, Colloids Surf. B Biointerfaces 90 (2012) 169–176.
[227] S.H. Hussein-Al-Ali, et al., Novel kojic acid-polymer-based magnetic nanocompo-
sites for medical applications, Int. J. Nanomedicine 9 (2014) 351.