Clinical, Cosmetic and Investigational Dermatology Dovepress

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ORIGINAL RESEARCH

Effects of Skin Lightening Cream Agents –

Hydroquinone and Kojic Acid, on the Skin of
Adult Female Experimental Rats
This article was published in the following Dove Press journal:
Clinical, Cosmetic and Investigational Dermatology

Joshua Oladele Owolabi 1,2 Introduction: Skin bleaching is the act of using steroid- and chemical-containing products
Oluseyi Sunday Fabiyi 1 to lighten the skin. Hydroquinone and kojic acid are often used in skin bleaching creams.
Lola Adeola Adelakin 1 Hydroquinone was suspected to be harmful. This study investigated the effects of kojic acid
Miriammillicent Chinenyenwa and hydroquinone on the skin of adult female Wistar rats and the potential use of aloe vera
for amelioration.
Ekwerike1
Materials and Methods: Eighty [n=80] adult female Wistar rats with an average weight of
1
Department of Anatomy, Ben Carson 120 g were randomly divided into eight groups, marked A, B, C, D, E, F, G, and H. Group
School of Medicine, Babcock University,
Ilishan-Remo, Nigeria; 2Department of A animals served as the control group; group B was treated with 2% hydroquinone, group
Anatomy, University of Global Health C was treated with 2% kojic acid, group D was treated with 4% hydroquinone, group E was
Equity, Butaro, Rwanda
treated with 4% kojic acid, group F was treated with 2% hydroquinone and 2% kojic acid,
group G was treated with 4% hydroquinone and 4% kojic acid, and group H was treated with
4% hydroquinone, 4% kojic acid, and aloe vera. The preparations were applied to the tail
skin and treatment lasted 28 days. Skin samples were excised and processed using H&E,
Masson’s trichrome, and p65 immunohistochemical assays on tissue sections.
Results: Hydroquinone caused structural disruptions of the stratum corneum of the epider-
mis and the overlying keratin. p65 was also prominently expressed in the treated groups.
Hydroquinone reduced skin thickness and caused epidermis disruption.
Discussion: The prominent expression of p65 in the sections indicated deleterious effects of
hydroquinone. Kojic acid was not found to have deleterious effects. Aloe vera prevented
extensive disruption of stratum corneum by hydroquinone. The use of hydroquinone in skin
lightening creams might raise health concerns. Aloe vera could be protective against
hydroquinone.
Keywords: hydroquinone, kojic acid, aloe vera, bleaching products, skin

Introduction
Skin tone is branded as beauty, grace, and high social status in many parts of the world,
and this perception encourages, people, especially women to indulge in skin lightening
products.1,2 Harmful products such as Hydroquinone, Kojic acid, and Mercury are
present in many skin lightening products.2,3 Hydroquinone is considered as a primary
Correspondence: Joshua Oladele topical ingredient for inhibiting melanin production because it reduces the skin’s
Owolabi production of melanin which is responsible for skin color.4 However, because of the
Department of Anatomy, Ben Carson
School of Medicine, Babcock University carcinogenic nature of hydroquinone, it has been banned in some countries in a bid to
Ilishan-Remo, Nigeria reduce the risks of skin cancer.1 Apart from its effects on the skin, hydroquinone has
Tel +2348064884305
Email owolabijo@babcock.edu.ng been found to expose users to acute toxicity from oral exposure and it can also cause

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Owolabi et al Dovepress

diseases such as thyroid disorder, leukemia, and liver Babcock University’s Health Research Ethical Committee
damage.1,3 Chronic occupational exposure to hydroquinone which approved the project (BUHREC 2018). The adult
dust had reportedly resulted in eye injuries, which varied female Wistar rats were divided into eight groups of ten
from mild irritation and staining of conjunctivae and cornea each after the period of acclimatization as follows:
to changes in the thickness and curvature of the cornea, loss Group A: the control group; animals were treated with
of corneal luster, and impaired vision.5 Prolonged exposure only olive oil as a placebo.
could lead to the development of severe ocular effects.4 Group B: This group was treated with 2% hydroqui-
Higher concentrations frequently irritate the skin, and if none and 98% olive oil during the period of the
used for prolonged periods, it could cause disfiguring effects experiment.
including epidermal thickening.2 Oral ingestion of doses Group C: This group was treated with 2% kojic acid
between 5 g and 15 g doses caused convulsions and hemo- and 98% olive oil.
lytic anemia.6 Group D: This group was treated with 4% hydroqui-
Kojic acid on the other hand, known as Koji in Japan, is none and 96% olive oil.
a fungal metabolic product which has the advantage of not Group E: This group was treated with 4% kojic and
being oxidized in skin lotions.1 It is a chelation agent that is 96% olive oil.
produced by several fungi including Aspergillus oryzae. It Group F: This group was treated 2% hydroquinone, 2%
inhibits and prevents the formation of tyrosine and it contains kojic acid, and 96% olive oil.
some antimicrobial properties against several common bac- Group G: This group was treated with 4% hydroqui-
terial stains even in small dilutions.7 A study8 had reported none, 4% kojic acid, and 92% olive oil.
that 4% hydroquinone and 0.75% Kojic when combined for Group H: This group was treated with 4% hydroqui-
typical treatment were effective in treating facial melasma. none, 4% kojic acid, aloe vera gel 4%, and 88% olive oil.
What might not have been adequately investigated would the The required quantities of hydroquinone and kojic acid
possible effects of its prolonged or chronic use on the skin. were dissolved in measured quantities of olive oil under
Skin, the organ of study, is the largest organ of the human mild heat [˂ 50°C]. The treatments lasted 28 days. The
body which accounts for about 15% of the human body animals were sacrificed through the cervical dislocation.
weight and its health could be affected by topical agents.9,10 The tail skins were excised and preserved in 10% formal
The vital functions of the skin include protection, prevention saline for immunohistochemical and histological proce-
of excess water loss from the body and thermoregulation. The dures. The fixed tissues were processed following specific
skin is composed of the superficial epidermis and the under- histological and histochemical protocols. Basic tissue pro-
lying dermis. The hypodermis lies beneath the dermis. Aloe cessing included dehydration [using graded concentration
vera, the plant that was used for the intervention is also known of alcohol], clearing [using xylene], impregnation, and
as Barbadensis miller. It is a shrubby or arborescent, peren- embedding [using molten wax]. The tissue samples were
nial, xerophytic succulent, pea-green color plant that has been sectioned with a rotary microtome (~20 microns). The
known and used in centuries for its health, beauty, medicinal, sections were mounted on glass slides for staining.
and skin care properties.11 The high incidences of skin light-
ening using creams, which is otherwise called bleaching and Staining Techniques
the attendant potential consequences necessitated this study. The H&E staining technique was done following the meth-
Hence, this study also used aloe vera as a possible remedy for ods of Ref. 12 The slides, after dewaxing and rehydration,
the effects of kojic acid and hydroquinone which are found in were placed in hematoxylin for 8–15 minutes for staining.
skin lightening creams.6 The slides were then rinsed in tap water. The slides were
further dipped in a bluing agent for 3–5 long dips. They were
stained with Eosin for a period of 30 seconds and hematox-
Materials and Methods ylin for ~2 minutes. They were also dehydrated in 95% and
Animal Treatment and Tissue Processing 100% alcohol, with 3 changes each for 2 minutes. They were
Eighty adult [n=80] female Wistar rats, with the average then cleared in 3 changes of xylene for 2 minutes each and
body weight of 120 g, were procured for the study from the after which the cover glass was mounted.
institutional animal holding facility. The standard procedures The Masson’s Trichrome staining procedure for collagen
for animal use and handling were followed according to fiber was done following the methods of.13 Tissues were

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284
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Dovepress Owolabi et al

deparaffinized and rehydrated through 100% alcohol, 95% more superficial layers of the epidermis, the stratum cor-
alcohol, and 70% alcohol, then washed in distilled water. neum, which observable in Figure 1 photomicrographs.
They were re-fixed in Bouin’s solution for 1 hour at 56°C and This further showed that the cells in this layer were
rinsed under running tap water for 5–10 minutes to remove affected. While the mechanisms of the disruption could
the yellow color. They were then stained in Weigert’s iron either be due to the removal of superficial cells as a result
hematoxylin working solution for 10 minutes and rinsed in of the hydroquinone effects, it might also be due to
running warm tap water for 10 minutes. Furthermore, they retarded formation of the corneum layer cells due to
were washed in distilled water and stained again, in Biebrich alterations in the migration of cells from the deeper layers
scarlet-acid Fuchsin solution for 10–15 minutes. They were of the epidermis. Whichever of the two possible mechan-
washed again in distilled water and differentiated in phos- isms was responsible largely for this observation, the
phomolybdic-phosphotungstic acid solution for 10–15 min- implications are numerous and might include the lesions
utes. Sections were transferred directly (without rinsing) to of the skin, potential fragility of the skin and induced
aniline blue solution and stained for 5–10 minutes, then susceptibility to the ultraviolet (UV) rays and other envir-
rinsed briefly in distilled water and differentiated in 1% onmental hazards. It is also known that increased UV
acetic acid solution for 2–5 minutes. They were again washed exposure is a major risk factor for skin cancer.14 By
in distilled water, then dehydrated very quickly through 95% implication, reduced superficial protection means
ethyl alcohol, absolute ethyl alcohol to wipe off Biebrich increased exposure of the deeper cell layers including the
scarlet-acid Fuchsin staining, and cleared in xylene, after melanocytes to UV radiation15 This has serious implica-
which they were mounted with resinous mounting medium. tions because there are reports that this might increase the
The collagen fibers stained blue, the nuclei stained black, and risk of skin cancer.16
the background stained red. Loss of the superficial cells would mean that the trea-
The p65 immunohistochemistry technique protocol was ted skin was relatively thinner. This means a significant
carried out based on Abcam® specifications. Paraffin sec- loss of the protective stratum corneum. This skin layer is
tions were used for the immunohistochemistry study. very important to skin protection because it is selectively
Antigen retrieval was done though boiling before commen- permeable to chemicals and other agents.17 This also
cing with immunostaining. The slides were washed 2 x 5 would imply that the mechanical strength of the skin to
min in TBS plus 0.025% Triton X-100 with gentle agitation. protect the body from mechanical trauma was reduced or
The sections were blocked in 10% normal serum with 1% compromised. One implication of this might be more
BSA in TBS for 2 hours at room temperature. Slides were frequent or serious skin trauma due to mechanical assaults.
drained for a few seconds. The primary antibody was diluted Hence, the skin that had been affected in such a manner by
in TBS with 1% BSA and applied. Sections were incubated hydroquinone use might have reduced integrity against
overnight at 4°C. Thereafter, sections were rinsed 2 x 5 min mechanical or physical assaults. Another consequence of
TBS 0.025% Triton with gentle agitation; and incubated in such thinness of the skin might be compromised ability to
0.3% H2O2 in TBS for 15 minutes. The slides were mounted perform its function of homeostasis. There might include
using albumin and observed under the microscope. Suitably reduced ability to conserve heat, because of the loss in the
representative photomicrographs were captured. cells that account partly for the thickness of the skin. This
might also be extended to the reduced ability to conserve
water as reduced superficial covering might lead to rela-
Results
tively increased skin vulnerability to losing water, espe-
Results of the study are presented (below) as photomicro-
cially when the environment is hot. A fragile skin is not
graphs of the skin sections as demonstrated using the H and
only susceptible to mechanical trauma but also susceptible
E (Figure 1), Masson’s trichrome technique (Figure 2) and
to penetrations that reach to the deeper structures of the
the p65 immunohistochemistry technique (Figure 3).
skin such as bites from insects for instance. This might
also make it easier for pathogens and toxins to access the
Disruption of the Stratum Corneum Is body through the skin.
Attributable to Hydroquinone Effects Susceptibility to the UV rays and other environmental
A major effect of the application of hydroquinone to the hazards is a major complication that might result from this
skin of the experimental animals is the disruption of the effect. The skin ordinarily has the right thickness to protect

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H&E- A H&E-B H&E- C H&E- D

D ED
1 23 4 G
ED CT
ED CT
G
G
D
D
G
G CT ED D

H&E- E H&E- F H&E- G H&E- H

ED ED
CT D ED CT
CT
D ED D D

Figure 1 Photomicrograph of the skin of the experimental animals in Groups A–H, demonstrating the skin using H and E (H&E A-H; X400). The stratum corneum was
disrupted in Groups B, D, and G (H&E B, D, and G).
Note: Arrows point to specific features that are denoted by letters.
Abbreviations: ED, Epidermis - (1) Stratum corneum (2) Stratum Granulosum (3) Stratum Spinosum (4) Stratum Basale; D, Dermis; G, Gland; C, Connective tissue; K, Keratin.

the body from the effects of the sun’s ultraviolet [UV] Connective Tissue of the Skin
rays. A significant loss of the stratum corneum might The agents that were used did not produce any extensive
result in a major compromise of this ability. In addition observable effects on the connective tissues of the skin.
to this, the inability of the skin to replace the loss stratum Thus, the underlying connective tissues were largely pre-
corneum cells might also be extended to the melanocytes served and relatively undisrupted by all the agents that
that are also largely required to protect the skin against the were administered [Figure 2].
UV radiations. To this end, the skin might be vulnerable to
the UV radiation effects. The complications that can arise Prominent Expression of P56 Is
from this might therefore include cancer of the skin.15 Attributable to Hydroquinone Effects
It is worthy of note however that Kojic acid did not The immunohistochemistry method demonstrated p65 which
cause any observable disruption to the stratum corneum as is a REL-associated protein that served as a marker for cell
evident in the photomicrographs in Figure 1 and 2. On the proliferation, degeneration, and inflammation. The promi-
other hand, its effects and interactions with the hydroqui- nent demonstration or expression of p56 in the skin of the
none when both were applied appear to be beneficial, by experimental animals was attributable to the effects of hydro-
mildly ameliorating the effects of hydroquinone. This quinone [Figure 3]. This also strongly suggests inflamma-
might explain why it might often be a co-ingredient of tions or a chemical irritation or assault on the cells or the
certain creams with hydroquinone. Its actions, however, basal layers of the epidermis as well as cells surrounding the
were not potent enough to totally ameliorate the effects of sebaceous glands and the hair follicles. This also implies that
hydroquinone. Thus, this study partly aligns with certain the effects of hydroquinone as associated with the expression
previous studies that kojic acid at prescribed doses might of p56 were not limited to the superficial layers of the skin.
not have deleterious effects when used for skin lightening This might have a number of implications including the
or bleaching because there is no histological evidence of inflammation of the skin as well as links to certain cancers
a potentially deleterious effect of kojic acid on the treated of the skin and other disorders. The expression of p65 in the
skins; however, it would not suffice to support the study skins has significant implications on skin health, espe-
acclaimed multiple health benefits of its uses in certain cially, relative to inflammations and skin cancers. The
reports (18; 19; 20). affected skins, from existing evidences, have increased levels

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Dovepress Owolabi et al

MT- A MT- B MT- C MT- D

D
G ED
ED K D
D D K
ED
G ED

MT- E MT- F MT- G MT- H

G
G D ED
K ED D
ED
D
K ED
D

Figure 2 Photomicrograph of the skin of the experimental animals in Groups A–H demonstrating the skin using the Masson’s trichrome technique (MT A-H; X400). The
connective tissue was relatively generally preserved in the skin layers (MT A-H).
Note: Arrows point to specific features that are denoted by letters.
Abbreviations: ED, Epidermis - (1) Stratum corneum (2) Stratum Granulosum (3) Stratum Spinosum (4) Stratum Basale; D, Dermis; G, Gland; C, Connective tissue; K,
Keratin.

P65- A K P65- B D P65- C p65- D

D
G ED G ED G
D
D ED
K ED
G

p65- E p65- F p65- G p65- H

D ED
G G
D ED
D ED
D
ED G G

Figure 3 Photomicrograph of the skin of the experimental animals in Groups A–H demonstrating the skin using the p65 immunohistochemistry technique (p65 A-H). More
cells in the groups B, D, F, and G expressed p65 which was used as an inflammation marker.
Note: Arrows point to specific features that are denoted by letters.
Abbreviations: ED, Epidermis - (1) Stratum corneum (2) Stratum Granulosum (3) Stratum Spinosum (4) Stratum Basale; D, Dermis; G, Gland; C, Connective tissue; K, Keratin.

of risk. From previous studies, epidermal p65/NF-κB signal- homeostasis; hence, it is protective against spontaneous
ling was essential for skin carcinogenesis.21 Its normal func- dermatitis22. The complications that might arise from its
tion is also associated to the maintenance of skin immune anomalies are therefore of serious skin health consequences.

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A previous study7 had also stated that increased NF-κB

activity caused hyper-proliferation and dysplasia of the References
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