Role of Vitamin C in Skin Diseases

Abstract

Vitamin C (ascorbic acid) plays an important role in maintaining skin health and can promote the differentiation of keratinocytes and decrease melanin synthesis, leading to antioxidant protection against UV-induced photodamage. Normal skin needs high concentrations of vitamin C, which plays many roles in the skin, including the formation of the skin barrier and collagen in the dermis, the ability to counteract skin oxidation, and the modulation of cell signal pathways of cell growth and differentiation. However, vitamin C deficiency can cause or aggravate the occurrence and development of some skin diseases, such as atopic dermatitis (AD) and porphyria cutanea tarda (PCT). Levels of vitamin C in plasma are decreased in AD, and vitamin C deficiency may be one of the factors that contributes to the pathogenesis of PCT. On the other hand, high doses of vitamin C have significantly reduced cancer cell viability, as well as invasiveness, and induced apoptosis in human malignant melanoma. In this review, we will summarize the effects of vitamin C on four skin diseases (porphyria cutanea tarda, atopic dermatitis, malignant melanoma, and herpes zoster and postherpetic neuralgia) and highlight the potential of vitamin C as a therapeutic strategy to treat these diseases, emphasizing the clinical application of vitamin C as an adjuvant for drugs or physical therapy in other skin diseases.

Full text

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REVIEW
published: 04 July 2018
doi: 10.3389/fphys.2018.00819
Edited by:
Jin Wang,
Fudan University, China
Reviewed by:
Simona Martinotti,
Università degli Studi del Piemonte
Orientale, Italy
Marcos Lopez,
Fundación Cardiovascular
de Colombia, Colombia
*Correspondence:
Hongbin Li
196987745@qq.com;
1969877745@qq.com
†These authors have contributed
equally to this work.
Specialty section:
This article was submitted to
Oxidant Physiology,
a section of the journal
Frontiers in Physiology
Received: 26 March 2018
Accepted: 12 June 2018
Published: 04 July 2018
Citation:
Wang K, Jiang H, Li W, Qiang M,
Dong T and Li H (2018) Role
of Vitamin C in Skin Diseases.
Front. Physiol. 9:819.
doi: 10.3389/fphys.2018.00819
Role of Vitamin C in Skin Diseases
Kaiqin Wang1†, Hui Jiang1†, Wenshuang Li2, Mingyue Qiang1, Tianxiang Dong1and
Hongbin Li1*
1Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming, China, 2Bio-ID Center,
School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
Vitamin C (ascorbic acid) plays an important role in maintaining skin health and can
promote the differentiation of keratinocytes and decrease melanin synthesis, leading
to antioxidant protection against UV-induced photodamage. Normal skin needs high
concentrations of vitamin C, which plays many roles in the skin, including the formation
of the skin barrier and collagen in the dermis, the ability to counteract skin oxidation,
and the modulation of cell signal pathways of cell growth and differentiation. However,
vitamin C deficiency can cause or aggravate the occurrence and development of some
skin diseases, such as atopic dermatitis (AD) and porphyria cutanea tarda (PCT). Levels
of vitamin C in plasma are decreased in AD, and vitamin C deficiency may be one of
the factors that contributes to the pathogenesis of PCT. On the other hand, high doses
of vitamin C have significantly reduced cancer cell viability, as well as invasiveness, and
induced apoptosis in human malignant melanoma. In this review, we will summarize the
effects of vitamin C on four skin diseases (porphyria cutanea tarda, atopic dermatitis,
malignant melanoma, and herpes zoster and postherpetic neuralgia) and highlight the
potential of vitamin C as a therapeutic strategy to treat these diseases, emphasizing the
clinical application of vitamin C as an adjuvant for drugs or physical therapy in other skin
diseases.
Keywords: vitamin C, atopic dermatitis, porphyria cutanea tarda, malignant melanoma, herpes zoster
THE PHYSIOLOGY OF VITAMIN C IN SKIN
Vitamin C (ascorbic acid, ascorbate) is a simple low-molecular-weight carbohydrate that is essential
for the body as a water-soluble vitamin (Lykkesfeldt et al., 2014). As an antioxidant, vitamin C has
both oxidized and reduced forms in the body: L-dehydroascorbic and L-ascorbic acid. Although
vitamin C is an important antioxidant, humans and other primates obtain vitamin C only from
their diet, because they have no ability to synthesize it. With blood circulation to all tissues and
organs, plasma ascorbate acid concentrations can reach up to 10–160 mM (1–15 mg/ml) after
eating a vitamin C diet, and the superfluous vitamin can be excreted by the kidneys (Richelle et al.,
2009). However, there are large differences in the levels of vitamin C in various organs; for example,
the brain, liver, and skeletal muscle have the highest total content, and the content of testis and
thyroid is low (Omaye et al., 1987).
The skin is the largest multifunctional organ on the surface of the human body and consists of
three layers: the epidermis, dermis, and subcutaneous tissue, which forms a complete whole with
tension and elasticity as the body’s first line of defense against harmful external factors (Hunter,
1973). The epidermis is composed of keratinocytes and dendritic cells, and the stratum corneum
can prevent both harmful substances and skin moisture loss and is evolved from keratinocytes and
its lipid matrix (Tagami, 2008); the dermis provides nutrition for the skin and is rich in blood vessels
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Wang et al. Vitamin C in Skin Diseases
and nerve endings (Rittie and Fisher, 2015); and the connective
tissue is composed of collagen fibers and elastic fibers in the
dermis, which maintains the tension and elasticity of the skin
(Carl and Enna, 1979). There is a large difference in the content of
vitamin C in the layers of the skin. The content of ascorbic acid in
the epidermis is 425% higher than the content in the dermis, and
there is a concentration gradient of ascorbic acid in the epidermal
keratinocytes (Shindo et al., 1994;Weber et al., 1999).
It is well known that there are two transport mechanisms for
ascorbic acid in the skin, and they depend on sodium-ascorbate
cotransporter-1 (SVCT1) and sodium-ascorbate cotransporter-
2 (SVCT2). Dermal fibroblasts present two high-affinity and
low-affinity vitamin C transport mechanisms, which may be
related to plasma concentrations of ascorbic acid or stress
conditions (Butler et al., 1991), demonstrating that skin
vitamin C transport characteristics may be associated with skin
healing, antioxidation, and antitumor effects. Sodium-ascorbate
cotransporters (SVCTs), specific sodium-dependent vitamin C
transporters, exist in various tissues and organs for vitamin C
uptake and transport. SVCT1 is primarily responsible for the
transport of epidermal vitamin C, while SVCT2 is responsible
for intradermal transport, both of which are shown in Figure 1.
SVCT2 in dermal cells (such as fibroblasts) diffuses ascorbic acid
transported from the plasma into the epidermis, and SVCT1 in
the epidermis supplies ascorbic acid to keratinocytes (Steiling
et al., 2007). The SVCT2 transporter in fibroblasts in the dermis
transports vitamin C from the blood into the cells (Steiling et al.,
2007). If SVCT2 is inside the fibroblasts, it can bind to Mg2+
but is in a low-affinity state. On the other hand, when SVCT2
is exposed on the fibroblast membrane surface, it can bind to
both Mg2+and Ca2+in high concentrations of sodium solution
and then becomes a high-affinity state and binds to vitamin C
(Savini et al., 2008). Vitamin C can be transported into the cell
after binding to SVCT1 on the membrane of keratinocytes, and
vitamin C and Na+are reversed on the cell membrane at a 1:2
ratio and then discretely distributed in epidermal keratinocytes
(Wang et al., 2000;Steiling et al., 2007;Savini et al., 2008).
The expression of SVCT1 mRNA in mouse skin under UVB
irradiation showed time- and dose-dependent effects, whereas the
SVCT2 mRNA levels did not change significantly, which seems to
explain why the antioxidant capacity of the epidermis is greater
than that of the dermis (Kang et al., 2007).
THE ROLE OF VITAMIN C IN SKIN
Vitamin C is involved in the formation of the skin barrier and
collagen in the dermis and plays a physiological role in the skin
against skin oxidation, in antiaging of wrinkles, and in cell signal
pathways of cell growth and differentiation, which are related to
the occurrence and development of various skin diseases (Ponec
et al., 1997b). Vitamin C has a dual role of antioxidation and
pro-oxidation, and this role maintains the balance of the two
reactions in the body (Kim K. et al., 2015). Ascorbic acid and
transition metals, such as Fe2+, produce reactive oxygen species
(ROS) outside of the cell, and high levels of ROS can destroy
the antioxidant defense system of cancer cells (Ohno et al., 2009;
Conner et al., 2012) because the antioxidation system of tumor
cells is incomplete and its balance is destroyed (Kim K. et al.,
2015;Uetaki et al., 2015). High levels of Vitamin C in the cells
lead to oxygen-promoting reactions, which cause DNA damage,
the depletion of ATP reserves, and failure of cellular metabolism
(Tian et al., 2014). Vitamin C is also involved in resistance to
UV-induced oxidative stress, inhibition of melanogenesis, and
promotion of the differentiation of keratinocytes and has been
used for a long time as a clinical treatment reagent. Vitamin C
deficiency leads to many systemic diseases in humans and causes
scurvy in the world’s navies (Carpenter, 2012).
Resistance to UV-Induced Oxidative
Stress
Ultraviolet light, especially UVA, is an important factor that
induces skin oxidative stress (McArdle et al., 2002). UVA
radiation of the skin produces pyrimidine dimers and singlet
oxygen in the body. The former weakens the hydrogen bonding
effects between DNA double strands. The latter can generate the
entire oxygen radical cascade and leads to the alteration of nucleic
acids, proteins and lipids, which may induce skin tumors (Lin
et al., 2005;Rinnerthaler et al., 2015) There is a sophisticated
and complete antioxidant system in the skin, which is used as
a defense to the oxidation reaction induced by UV or ozone.
The antioxidant system consists of two categories, including the
enzyme antioxidant system [superoxide dismutase (SOD) and
catalase (CAT)] and non-enzymatic antioxidant system (vitamin
C, vitamin E, and glutathione). The accumulation of ROS over
the range of antioxidant defenses leads to skin diseases (Godic
et al., 2014). However, vitamin C as a supplement has its
own instability. Moreover, topical vitamin C supplementation
can counteract oxidative stress induced by UVA, which can be
assessed in human skin by the chemiluminescence method (Ou-
Yang et al., 2004). In addition, the mRNA expression level of
matrix metalloproteinase-1 (MMP-1) is significantly increased in
the dermal fibroblast after UVA irradiation (Offord et al., 2002).
Here, vitamin C may prevent collagen degradation and inhibit
the increase of MMP-1, which is the major collagenolytic enzyme
responsible for collagen damage in UV-irradiated skin (Offord
et al., 2002;Brennan et al., 2003). Moreover, the combination of
vitamin E, vitamin C, and ferulic acid can reduce the incidence
of oxidative stress-induced tumors, and their antioxidant effects
are much better than the use of vitamin C alone (Lin et al.,
2005).
Inhibiting Melanogenesis
The synthesis of melanin occurs in the melanocytes of the basal
layer of the epidermis and can be transferred to keratinocytes
so that melanin is distributed throughout the epidermis (Kwak
et al., 2015). Tyrosine and 2-hydroxyphenylalanine (L-dopa) are
oxidized to melanin by tyrosinase, which is the rate-limiting
enzyme in the whole process (Bin et al., 2014). Whether vitamin
C can inhibit melanogenesis is controversial. Most studies have
agreed that although it cannot kill melanocytes, vitamin C
does inhibit melanogenesis; however, some investigators have
demonstrated that the role of vitamin C in the inhibition
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FIGURE 1 | Vitamin C transporters (SVCT1 and SVCT2) and their transport mechanisms in skin.
of melanogenesis is very weak and cannot inhibit tyrosinase
activity (Shimada et al., 2009;Panich et al., 2011). Furthermore,
the combination of vitamin C and vitamin E inhibits melanocyte
production more significantly than vitamin C alone (Choi et al.,
2010a).
Promoting Differentiation of
Keratinocytes
The integrity of the skin barrier may be related to the
differentiation of keratinocytes, which affects the function of the
skin barrier and causes skin diseases. Vitamin C enhances the late
differentiation of keratinocytes, overcomes the differentiation-
dependent oxidative stress, and maintains the integrity of the
entire cuticle (Ponec et al., 1997a;Savini et al., 2002), which is
an important prerequisite for the integrity of the skin barrier,
ensuring the function of the skin barrier and preventing skin
water loss, which in turn can lead to skin disorders.
VITAMIN C-RELATED SKIN DISEASES
The effects of food restriction on changes in nutrient intake and
severity of the skin disease have been investigated; with ascorbate
as a prodrug in various skin diseases, clinical treatment strategies
for how to correctly apply vitamin C have become of interest
to many dermatologists. Herein, we summarize the application
of vitamin C as a treatment for a variety of skin diseases,
such as porphyria cutanea tarda (PCT), atopic dermatitis (AD),
malignant melanoma, herpes zoster (HZ), and postherpetic
neuralgia (PHN), in clinic according to well-known levels of
evidence (Table 1).
Porphyria Cutanea Tarda
Variegate porphyria (VP) is an autosomal dominant type
of hepatic porphyria. Women affected by VP appear with
chronic inflammation, plasma oxidative damage and decreased
protoporphyrinogen oxidase (PPOX), CAT and glutathione
reductase (GR) activities that make heme precursors chronically
accumulate in erythrocytes, possibly inducing cellular damage
(Monteiro et al., 1989;Thunell et al., 1995;Ferrer et al.,
2013). PCT is a common type of porphyria in humans and
is characterized clinically by acute and chronic blistering of
the skin when exposed to sunlight, which usually occurs in
the middle and late stages of the disease and causes great
suffering among patients (Patil et al., 2016). The main role
of uroporphyrin deacidification enzyme is the carboxylation
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TABLE 1 | The roles of vitamin C in skin disease.
Skin disease Pathogenesis Clinical lesions feature The roles of vitamin C Reference
Porphyria cutanea
tarda (PCT)
Plasma ascorbate deficiency,
protoporphyrin
decarboxylase activity in
urine and the accumulation
of uroporphyrin in the liver
Acute and chronic
blistering of the skin
exposed to sunlight
Inhibit the catalytic oxidation of
CYP1LA2, reduce the
accumulation of urinary
porphyrins in the liver
Percy et al., 1975;Monteiro et al., 1989;
Sinclair et al., 1993, 1995, 1997a,b;
Thunell et al., 1995;Anderson, 2007;
Gorman et al., 2007;Ferrer et al., 2010;
Ferrer et al., 2013;Patil et al., 2016
Atopic dermatitis
(AD)
Structural or functional
damage of the skin barrier
Erythematous papules
with itching or scaling
Promote keratinocyte
differentiation and the
production of interstitial
material, maintain skin barrier
function
Cook et al., 1997;Forastiere et al., 2000;
Uchida et al., 2001;Arora et al., 2002;
Savini et al., 2002;Bieber, 2008;Kim
et al., 2011, 2013;Kim K.P. et al., 2015;
Assier et al., 2013;Lim et al., 2013;
Sivaranjani, 2013;Park and Zippin, 2014;
Tollefson and Bruckner, 2014;Shin et al.,
2016;Zaniboni et al., 2016
Malignant
melanoma (MM)
Gene mutation, oxidative
stress, epigenetic changes,
tumor microenvironment,
etc.
Blue-black or brown
papules and nodules,
partially papillomatous,
and verrucous-like lesions
with ulcers
Inhibiting the HIF-1α
transcriptional activity,
increasing 5hm content in
melanoma cells and
maintaining tumor capsule
integrity can prevent tumor
invasion and metastasis
Kameyama et al., 1996;Feskanich et al.,
2003;Bedogni and Powell, 2009;Ohno
et al., 2009;Choi et al., 2010b;Cha
et al., 2011;Levine et al., 2011;Cha
et al., 2013;Stojkovic-Filipovic and Kittler,
2014;Hill et al., 2015;
Kaminska-Winciorek et al., 2015;
Gustafson et al., 2015;Kim K. et al.,
2015;Miles et al., 2015;Uetaki et al.,
2015;Yang et al., 2017;Yussif et al.,
2017
Herpes zoster (HZ)
and Postherpetic
Neuralgia (PHN)
Disinhibition, central
sensitization, reactive
oxygen species (ROS), and
neuroinflammation
Clustered small blisters
distributed along the
unilateral peripheral nerves
with acute neuralgia.
Reduce pain and prevent the
onset of PHN
Kim et al., 2004, 2016;Insinga et al.,
2005;Weaver, 2009;Schencking et al.,
2010;Byun and Jeon, 2011;Chen et al.,
2011;Nalamachu and Morley-Forster,
2012;Gan et al., 2013;Nair et al., 2014;
Chao et al., 2015;Carr and McCall,
2017;Hemilä, 2017;Marrero et al., 2017
of uroporphyrinogen (Sinclair et al., 1993, 1995). Cytochrome
p450, especially cytochrome P450 1A2 (CYP1A2), can catalyze
the oxidation of uroporphyrins to form uroporphyrins (Sinclair
et al., 1995, 1997b). PCT can be caused by a decrease
in protoporphyrin decarboxylase activity in urine and the
accumulation of uroporphyrin in the liver. Plasma ascorbate
deficiency may be a factor that leads to PCT, and a deficiency
in ascorbic acid plays roles in some patients with PCT (Percy
et al., 1975;Sinclair et al., 1997a;Anderson, 2007). Ascorbic
acid as an antioxidant can inhibit the catalytic oxidation
of CYP1LA2. Thus, vitamin C is a good potential drug
for the treatment of PCT. The occurrence and development
of the disease are related to the iron content: the greater
the iron load, the more severe the disease (Sinclair et al.,
1995). On the other hand, ascorbic acid can inhibit the
accumulation of URO at low concentrations of iron, but the
effect of ascorbic acid at high concentrations of iron (300–
500 mg Fe/kg) is offset (Gorman et al., 2007). Ascorbic acid
promotes iron absorption in the intestine, which may be
risky in patients with iron overload. Therefore, solving for
the iron inhibition of ascorbic acid is the main problem
associated with using ascorbic acid as a clinical treatment.
Oral supplementation with vitamin E (50 mg/d) and vitamin
C (150 mg/d) for 6 months reduced plasma oxidative damage
and enhanced the erythrocyte activities of CAT and GR (Ferrer
et al., 2010). Therefore, the use of topical vitamin C for the
improvement of patients with skin symptoms remains to be
studied.
Atopic Dermatitis
Atopic dermatitis (AD) is a chronic relapsing inflammation of
the skin associated with allergies. The lesions are characterized by
erythematous papules with itching or scaling, affecting 15–30% of
children (Bieber, 2008;Kim et al., 2013;Tollefson and Bruckner,
2014). One reason this is important is the structural or functional
damage of the skin barrier (Sivaranjani, 2013;Zaniboni et al.,
2016). Keratinocytes and their intercellular lipids are important
components of the human skin barrier, and vitamin C can
promote keratinocyte differentiation and the production of
interstitial material (Savini et al., 2002;Kim et al., 2011). As
the most abundant lipid in the skin barrier material, ceramide
is generated at the end of keratinocyte differentiation (Uchida
et al., 2001). AD patients lack several nutrients, including vitamin
A and vitamin C. A greater number of food allergens have
shown an association with an increase in the number of deficient
nutrients (Gorman et al., 2007). The ratio of vitamin C intake
is significantly higher in more than three restricted groups
compared to the non-restricted group, which demonstrates that
vitamin C can improve chronic inflammation and positively
influence AD and that the intake of several foods containing
high levels of vitamin C and vitamin A may be related to a
decrease in the risk of AD and asthma diseases (Cook et al., 1997;
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Forastiere et al., 2000;Arora et al., 2002;Lim et al., 2013;Park
and Zippin, 2014). Vitamin C can stimulate ceramide production
in keratinocytes and improve overall epidermal barrier function
(Kim K.P. et al., 2015). With increases in clinical symptoms
of AD, vitamin C and ceramide levels were reduced, which
demonstrated that vitamin C and ceramide levels and the
severity of AD are positively correlated (Shin et al., 2016).
Although vitamin C can be an adjuvant treatment for a variety of
dermatitises, oral vitamin C still causes symmetrical AD (Assier
et al., 2013).
Malignant Melanoma
Melanoma derived from melanocytes is a kind of skin tumor
that is more malignant and occurs in the skin, skin and mucous
membrane transfer and removal of the eye choroid (Yussif
et al., 2017). Vitamin C may have an effect on the function
and quantity of melanocytes, thereby reducing the synthesis of
melanocytes (Kameyama et al., 1996). The antimelanogenesis
effect of vitamin C is mainly due to its role as a reducing
agent in the various oxidation stages of melanin formation (Choi
et al., 2010b). Vitamin C can indirectly inhibit the activity of
tyrosinase because of its antioxidant capacity, thus reducing
melanogenesis. Furthermore, vitamin C can also reduce the
melanogenesis of melanoma cells stimulated by α-melanocyte-
stimulating hormone (α-MSH) in vitro (Stojkovic-Filipovic and
Kittler, 2014). However, whether this has an effect in the clinical
treatment of melanoma has not yet been determined. Moreover,
cancer patients have been shown to have very low reserves
of ascorbic acid, which is essential for the structural integrity
of the intercellular matrix. Degradation of the extracellular
matrix correlates with the aggressiveness of tumor growth and
invasiveness of a cancer. Vitamin C supplementation significantly
reduced the metastasis of B16FO melanoma in Gulo knockout
(KO) mice and inhibited the growth of 4T1 breast cancer cells in
scorbutic mice (Cha et al., 2013). Surgical resection is effective
only for non-metastatic, early tumors, and there is still not a
good curative chemotherapy for patients with tumor metastasis
(Hill et al., 2015;Kaminska-Winciorek et al., 2015), although
vitamin C has an inhibitory effect on the invasion and metastasis
of melanoma (Bedogni and Powell, 2009;Miles et al., 2015).
Vitamin C can reduce tumor growth, invasion and metastasis of
melanoma in mice by inhibiting the hypoxia inducible factor-1
alpha (HIF-1α) transcriptional activity, which might play a key
role in melanoma carcinogenesis (Cha et al., 2011;Miles et al.,
2015). Posttranslational regulation of HIF-1αrelies on proline
hydrogenase and the inhibition of HIF hydrogenase, both of
which require ascorbate as a cofactor (Cha et al., 2011). The toxic
effects of vitamin C on tumor cells may be related to the induction
of oxidative stress in cells. However, when the antioxidation
system of tumor cells is incomplete, the balance is destroyed, and
the oxygen-promoting effect of vitamin C leads to the death of
tumor cells (Kim K. et al., 2015;Uetaki et al., 2015). Vitamin C
is often used as an adjunct to chemotherapy for tumors. Vitamin
C can also increase 5-hydroxymethylcytosine (5hmC) content in
melanoma cells and cause a decrease in tumor-cell invasiveness
and growth (Gustafson et al., 2015). Thus, vitamin C can be
regarded as a potential antitumor drug for the prevention of
invasion and metastasis of melanoma, which weakens the tumor
capsule integrity and invasiveness and reduces the degree of
malignancy.
However, there is still a lack of understanding about the route
of administration for vitamin C, the dosage of medication and
the complications. We should increase awareness of the fact that
high concentrations of vitamin C induce apoptosis of malignant
melanoma cells, while low concentrations promote the growth
of tumor cells (Yang et al., 2017). However, it is worth noting
that the toxic effects of vitamin C on cancer cells are valid
only with intravenous administration and not in cases of oral
administration (Levine et al., 2011). An increase in vitamin C
levels in the diet of white women increased the risk of melanoma,
also demonstrating that only intravenous vitamin C increased
plasma ascorbic acid concentration and that oral preparation had
no effect on plasma concentration (Feskanich et al., 2003;Ohno
et al., 2009).
Herpes Zoster and Postherpetic
Neuralgia
Herpes zoster and its sequelae, postherpetic neuralgia, are
conditions with significant morbidity. HZ is caused by the
reactivation of latent varicella zoster virus (VZV) that lurks in the
body and classically affects adults older than 50 years old (Insinga
et al., 2005;Weaver, 2009). The specific clinical manifestations are
clustered, small blisters distributed along the unilateral peripheral
nerves with acute neuralgia (Nair et al., 2014). PHN refers to
the persistence of neuralgia 4 weeks after the disappearance of
herpes lesions and is a chronic, debilitating neuropathic pain
that can persist long beyond the resolution of visible cutaneous
manifestations (Nalamachu and Morley-Forster, 2012;Gan et al.,
2013;Marrero et al., 2017). Given the different pathogeneses
of HZ and PHN, the symptoms can be divided into stimulus-
induced pain and spontaneous pain. Spontaneous pain can
be persistent or intermittent (paroxysmal). Stimulation-induced
pain is often classified as mechanical, thermal, or chemical (Chen
et al., 2009). Recent studies have proposed that this pain is
related to the participation of oxygen free radicals. Peripheral
inflammation stimulates nociceptors to produce oxygen free
radicals. Oxygen free radicals participate in the stimulation of
pain after they accumulate in the body (Kim et al., 2004). Vitamin
C, as an oxidant, has been reported to have a clinical analgesic
effect (Carr and McCall, 2017). In addition, the incidence of
PHN in patients with HZ who lack plasma vitamin C has been
significantly higher than the incidence in patients with normal
plasma vitamin C levels. When vitamin C supplementation is
given to patients with HZ, the probability of subsequent PHN
in those patients is greatly reduced, demonstrating that vitamin
C has a preventive effect on PHN (Chen et al., 2011). A clinical
case report also mentions that intravenous injection of vitamin C
immediately relieves pain in HZ patients and related symptoms
in PHN patients. In addition, vitamin C can be fully used as a
therapeutic adjuvant for patients who are resistant to analgesics
(Schencking et al., 2010;Byun and Jeon, 2011). Kim et al. (2016)
found that clinical administration of vitamin C supplementation
cannot alleviate the immediate severe pain caused by HZ but
has a better preventive effect on clinical symptoms caused by
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TABLE 2 | The roles of vitamin C as a therapeutic adjuvant in other skin diseases.
Skin disease The roles of vitamin C Combined drugs/physical therapy Reference
Acne Against clarithromycin-resistant P. acnes Zinc and clarithromycin Iinuma et al., 2011;Beylot et al., 2014;
Acne scars Improve skin hardness, smoothness, and
postinflammatory pigmentation
Microneedle treatment Chawla, 2014
Allergic contact dermatitis Reduces the elicitation reaction to a
p-phenylenediamine (PPD)-containing hair dye
Pretreatment of the skin with the
antioxidant ascorbic acid
Basketter et al., 2016;Coenraads
et al., 2016
Psoriatic Make keratinocytes return to normal Atorvastatin combined with
22-r-hydroxycholine female
hormone-treated
Soodgupta et al., 2014
Progressive pigmented
purpuric dermatosis (PPPD)
Protect blood vessel collagen, reduce vascular
fragility, prevent disease recurrence
Aloin Sardana et al., 2004;Schober et al.,
2014
Genital herpes Improve immunity and natural defenses and
reduce the persistence of HPV infection
Vaporization laser treatment, pidotimod Zervoudis et al., 2010
Vitiligo Increase hyperpigmentation at pigment
diminished spots
Short-term UVB irradiation treatment Don et al., 2006
PHN (Kim et al., 2016). In addition, vitamin C directly affects the
immune system to reduce the chance of viral infection in the body
(Hemilä, 2017), similar to the application of vitamin D, which
can affect the immune mechanisms of the human body (Chao
et al., 2015). Therefore, whether the combined use of vitamin
C and vitamin D has a good and comprehensive therapeutic
effect on the presence of HZ or PHN is still a question worth
exploring.
Other Diseases
Vitamin C in other dermatological diseases is seen as an adjuvant
for use in combination with other drugs or for physical therapy.
It has good therapeutic potential in a variety of dermatological
diseases, such as acne, allergic contact dermatitis, psoriasis,
and progressive purpura, especially when used in combination
with other clinical drugs (Table 2). Propionibacterium acne
(P. acne) plays an active pro-inflammatory role in the whole
process of acne and is involved in the skin keratinocytes and
sebaceous glands of the pilosebaceous follicle, resulting in the
generation of acne (Beylot et al., 2014). The combination of zinc
and clarithromycin, along with vitamin C, has an antibacterial
effect against clarithromycin-resistant P. acnes in vitro (Iinuma
et al., 2011), providing a new idea for the clinical use of
antibiotics in the treatment of acne bacteria. Vitamin C,
combined with microneedle treatment for acne scars, improved
skin hardness, smoothness, and postinflammatory pigmentation
(Chawla, 2014). Vitamin C can also reduce allergies often
encountered in dermatology. A case report concluded that it
reduced the allergic contact dermatitis caused by hair dyes
(Basketter et al., 2016). The main component of hair dye is
p-phenylenediamine. Skin pretreated with vitamin C can inhibit
the allergic reaction induced by p-phenylenediamine (Coenraads
et al., 2016). More interestingly, in an experimental study on
the role of LXR-a (liver X receptor alpha) in the pathogenesis of
psoriasis, Soodgupta et al. (2014) demonstrated that ascorbic acid
and atorvastatin combined with 22-r-hydroxycholine returned
female hormone-treated psoriatic keratinocytes to normal.
Collagen is an important component in the connective tissue
of the basement membrane and capillary vessels, and vitamin
C is essential for collagen synthesis. Although the pathogenesis
of progressive pigmented purpuric dermatosis remains unclear,
there are hypotheses that it is associated with increased vascular
fragility (Sardana et al., 2004). Increased vascular fragility is
associated with reduced collagen in vascular connective tissue.
The use of a combined therapy of aloin and vitamin C also
has a good effect on progressive pigmented purpuric dermatosis
(Schober et al., 2014). Regarding vitamin C as an adjuvant
for physical therapy, it has been reported that oral pidotimod
and vitamin C can be combined after laser vaporization for
the treatment of female genital herpes, which can improve
immunity and natural defenses and reduce the persistence
of HPV infection (Zervoudis et al., 2010). Supplementing
patients with high-dose vitamin C significantly improved
the treatment effect of short-term UVB irradiation treatment
in patients with vitiligo, especially in the UVB-irradiated
skin area (Don et al., 2006). However, patients with renal
insufficiency, deficiency in glucose 6-phosphate dehydrogenase
or paroxysmal nocturnal hemoglobinuria should not use vitamin
C because vitamin C can cause poisoning (Padayatty et al.,
2010).
CONCLUSION
In conclusion, nutritional strategies suggest the potential benefits
of a diet rich in vitamin C as a preventive tool for patients with
skin diseases. Vitamin C has low toxicity, is easy to obtain, and
has a low price. Therefore, if it can be applied to clinical treatment
in dermatology, the prospects should be very impressive.
Notably, vitamin C supplementation modulated inflammatory
cytokine secretion, decreased metastasis of melanoma, reduced
tumor growth and enhanced the encapsulation of tumors
resulting from a breast cancer challenge. Following these studies,
investigation into the impact of excessive food limitations on
growth, malnutrition, and skin disease management is needed,
and further studies should investigate the wide and effective
therapeutic potential of vitamin C in dermatology. Although
ascorbate supplementation in cancer patients has been proposed
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fphys-09-00819 July 4, 2018 Time: 12:28 # 7
Wang et al. Vitamin C in Skin Diseases
to reverse their scorbutic symptoms and treat their cancer,
dermatologists should take into consideration the potential risks
of the clinical use of vitamin C to minimize the risk of treatment.
In addition, the route of administration for the use of vitamin
C should receive more attention. It is necessary to increase the
concentration of vitamin C in peripheral blood intravenously
to be toxic to tumor cells. Since vitamin C is a water-soluble
molecule and its transdermal absorption efficiency is low, it
may be of great significance to identify efficient transdermal
drug delivery methods for the stabilization of active compounds,
such as finding lipophilic derivatives of vitamin C to increase
the absorption through the epidermis. Thus, the clinical use of
vitamin C in patients with skin diseases still requires caution.
AUTHOR CONTRIBUTIONS
HL contributed the conception. KW, HJ, WL, MQ, and TD
analyzed the data. KW and HJ wrote the manuscript. HL and KW
revised the manuscript.
ACKNOWLEDGMENTS
This research was supported by a grant (2014FB030) from
the Yunnan Provincial Science and Technology Department –
Kunming Medical University Joint Funding Project, Yunnan,
China.
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Conflict of Interest Statement: The authors declare that the research was
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Frontiers in Physiology | www.frontiersin.org 9July 2018 | Volume 9 | Article 819