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Review Article

Antioxidant and prooxidant activity of Vitamin C in oral


environment
Aratirika Chakraborthy, Pratibha Ramani, Herald Justin Sherlin, Priya Premkumar, Anuja Natesan
Department of Oral and
Maxillofacial Pathology,
Saveetha Dental College,
Chennai, Tamil Nadu, India

ABSTRACT

Received
: 01-03-14
Review completed : 13-03-14
Accepted
: 28-07-14

Context: Antioxidant properties and Vitamin C.


Background: Vitamin C is a naturally occurring organic compound and a potent antioxidant
preventing oxidative damage to lipids and other macromolecules. It can also exhibit bimodal
activity as a prooxidant at a higher concentration. Vitamin C has a switch over role from being an
antioxidant in physiologic conditions to a prooxidant under pathologic conditions. Asystematic
review of this role would help to elucidate whether it is an antioxidant or a prooxidant in the
oral environment.
Objective: To review studies reported in the literature elucidating the activity of Vitamin C and
determine whether it is an antioxidant or a prooxidant.
Materials and Methods: Articles were searched in PubMed, MEDLINE using appropriate key
words like Vitamin C, antioxidant activity, prooxidant activity, oral health oral disease.
Hand search of journals was also performed. Articles were reviewed and analyzed.
Results: Search strategy reviewed 10 relevant articles which studied the dual role of Vitamin C.
65% of authors analyzed antioxidant action of ascorbic acid compared to 35% of the prooxidant
potential. Vitamin C acts as an antioxidant and a prooxidant by a plethora of mechanisms.
Factors determining its bimodal activity were studied, and the frequencies of their occurrence
in the literature were depicted in percentage.
Conclusion: The data validates the role of Vitamin C as an antioxidant under physiologic
conditions exhibiting a cross over role as a prooxidant in pathological conditions. Further
studies are required to substantiate its prooxidant activity to draw concrete conclusions.
Key words: Antioxidant activity, oral disease, oral health, prooxidant activity, Vitamin C

Vitamin C (chemical name ascorbic acid) is a naturally


occurring water soluble organic compound, obtained
exogenously by various dietary sources owing to the
mutation of gene encoding for Lgulonolactone oxidase
enzyme required for its synthesis.[1]
Reactive oxygen species, both oxygen centered radicals
(superoxide, hydroxyl anions) and oxygen centered
nonradicals (hydrogen peroxide, singlet oxygen) cause tissue
damage.[2] Toxins in cigarette smoke contain numerous
Address for correspondence:
Dr.Pratibha Ramani
Email:dr_pratibha@rediffmail.com
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Website:
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PMID:
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DOI:
10.4103/0970-9290.142547

Indian Journal of Dental Research, 25(4) 2014

free radicals causing tissue damage in the oral cavity.


Vitamin C is one of the several compounds that form part
of the bodys first line of defense against the free radicals
mediated cellular damage, directly neutralizing free radicals,
implicated in the interaction between pathogenic bacteria
and host immune response, contributing an increased risk of
periodontal disease in smokers as compared to their normal
counterparts. It also maintains systemic health by interfering
with the production of free radicals and peroxides by
regulating endothelium derived nitric oxide by its pivotal
vasodilatory role to prevent cardiovascular disorders.[3]
At a higher concentration, it acts as a prooxidant inducing
oxidative stress, either by generating reactive oxygen species
or by inhibiting the antioxidant systems in the presence of
iron, which in turn induces lipid peroxidation.[4] Whether
Vitamin C has a net prooxidant or antioxidant effect
depends on the concentration gradient and redox state of a
cell. As normal tissue receives adequate blood flow and is
rich in antioxidant enzymes, any hydrogen peroxide formed
will be immediately destroyed. Meanwhile, tumor tissue is
often associated with reduced blood flow and antioxidant
499

Chakraborthy, etal.

Antioxidant and prooxidant role of Vitamin C

enzymes, and consequently formed hydrogen peroxide


remains active leading to cellular damage. This phenomenon
is based on the ability of ascorbate metal dependent
production of hydroxyl radicals by Fenton chemistry,[5]
by reaction of the reduced metal ions like Iron or copper
with hydrogen peroxide. Vitamin C when administered
as a dietary supplements, exhibits a dual role in the oral
environment depending on the concentration gradient.

Database of Abstracts and Reviews of Effectiveness


were searched for systematic reviews. Articles were
searched and selected for the related topic using PubMed;
MEDLINE from 1993 to June 2013. Article search
included only those published in the English literature.
An internet search was also done to obtain the relevant
articles of our interest. The title of the articles and
abstracts were reviewed [Flow chart 1].

Though the importance of Vitamin C is widely accepted,


very few authors in previous studies were able to demark
its action as a potent antioxidant or a prooxidant. Scarce
information is available about its dual pharmacological
effects and actions in the research literature about the
same. Articles were selected on the basis of inclusion and
exclusion criteria for the related topic using PubMed and
published data. The purpose of the systematic review was to
determine whether Vitamin C acts a potential antioxidant
or a prooxidant under physiologic conditions in the oral
environment.

Search methodology

MATERIALS AND METHODS


Search strategy for identification of studies

The search protocol was in consensus with the Cochrane


Oral Health GroupSpecialized Trials Register and the

The search methodology through PubMed was done


using the following keywords: (Vitamin C) OR (ascorbic
acid) OR(sodium ascorbate) OR(dehydroascorbate)
AND(Vitamin C antioxidant) OR(antioxidant potential)
OR(antioxidant property) OR(antioxidant effect)
OR(antioxidant activity) AND(prooxidant activity)
OR (Vitamin C prooxidant) OR (prooxidant potential)
OR(prooxidant property) OR(prooxidant effect)
AND(Oral tissues) OR(oral health) AND(Oral neoplasms)
OR(Oral tumors) OR(oral cancer) OR(gingivitis)
OR(periodontitis). In addition, an internet search was also
done using the key words Vitamin C and ascorbic acid
and antioxidant activity and prooxidant activity and
oral tissues oral disease oral neoplasm and oral tumor
and oral cancer. Journals evaluating the antioxidant and
prooxidant effects of ascorbic acid were referred for review.

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Flow chart 1: Search methodology of the selected articles
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Indian Journal of Dental Research, 25(4), 2014

Chakraborthy, etal.

Antioxidant and prooxidant role of Vitamin C

enzymes, and consequently formed hydrogen peroxide


remains active leading to cellular damage. This phenomenon
is based on the ability of ascorbate metal dependent
production of hydroxyl radicals by Fenton chemistry,[5]
by reaction of the reduced metal ions like Iron or copper
with hydrogen peroxide. Vitamin C when administered
as a dietary supplements, exhibits a dual role in the oral
environment depending on the concentration gradient.

Database of Abstracts and Reviews of Effectiveness


were searched for systematic reviews. Articles were
searched and selected for the related topic using PubMed;
MEDLINE from 1993 to June 2013. Article search
included only those published in the English literature.
An internet search was also done to obtain the relevant
articles of our interest. The title of the articles and
abstracts were reviewed [Flow chart 1].

Though the importance of Vitamin C is widely accepted,


very few authors in previous studies were able to demark
its action as a potent antioxidant or a prooxidant. Scarce
information is available about its dual pharmacological
effects and actions in the research literature about the
same. Articles were selected on the basis of inclusion and
exclusion criteria for the related topic using PubMed and
published data. The purpose of the systematic review was to
determine whether Vitamin C acts a potential antioxidant
or a prooxidant under physiologic conditions in the oral
environment.

Search methodology

MATERIALS AND METHODS


Search strategy for identification of studies

The search protocol was in consensus with the Cochrane


Oral Health GroupSpecialized Trials Register and the

The search methodology through PubMed was done


using the following keywords: (Vitamin C) OR (ascorbic
acid) OR(sodium ascorbate) OR(dehydroascorbate)
AND(Vitamin C antioxidant) OR(antioxidant potential)
OR(antioxidant property) OR(antioxidant effect)
OR(antioxidant activity) AND(prooxidant activity)
OR (Vitamin C prooxidant) OR (prooxidant potential)
OR(prooxidant property) OR(prooxidant effect)
AND(Oral tissues) OR(oral health) AND(Oral neoplasms)
OR(Oral tumors) OR(oral cancer) OR(gingivitis)
OR(periodontitis). In addition, an internet search was also
done using the key words Vitamin C and ascorbic acid
and antioxidant activity and prooxidant activity and
oral tissues oral disease oral neoplasm and oral tumor
and oral cancer. Journals evaluating the antioxidant and
prooxidant effects of ascorbic acid were referred for review.

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Flow chart 1: Search methodology of the selected articles
500

Indian Journal of Dental Research, 25(4), 2014

Chakraborthy, etal.

Antioxidant and prooxidant role of Vitamin C

Selection criteria

Published reviews were selected if they met the following


criteria. Cross sectional studies to elucidate the role of
Vitamin C in oral and systemic health of subjects under the
studies and the mechanism by which it exhibits its properties.

Inclusion criteria

Human interventional studies with a follow up period


of 6months
Studies published in English literature
Studies that evaluated the activity of Ascorbic acid as
an antioxidant in oral health
Studies that evaluated the activity of Ascorbic acid as a
prooxidant in oral disease
Studies that analyzed the effects of ascorbic acid in
combination with other antioxidants vitamins
Studies that evaluated the evidence of ascorbic acid
supplementation and combinations of antioxidants as
interventions for the treatment of oral disease.

Exclusion criteria

Studies that have reported the effects of ascorbic acid in


animals
Botanical studies on ascorbic acid
Studies involving more than two simultaneous
interventions of Vitamin C
Studies with missing data that could not be supplied by
the study authors
Studies are not exhibiting the antioxidant and
prooxidant properties of ascorbic acid
Case reports and case series
Letters to editors.

Data extraction and analysis

All the included studies were based on the data extraction


and analysis of the studies of quality and publication

bias. The primary outcome was to elucidate the activity


of Vitamin C on oral health and diseases correlating to
its antioxidant and prooxidant properties. Potentially
relevant articles for systematic review were obtained,
data were extracted from each article was tabulated and
cross checked.

RESULTS
Included studies

The selected articles were divided into subgroups of author


name, journal name, and year of publication, country, and
conclusion are shown in Table1. All included studies have
observed the action of Vitamin C, both as an antioxidant
and a prooxidant depending on various factors. Three
of the authors have found Vitamin C as a potential
antioxidant promoting oral health status of individuals
in various physiologic conditions by its vivid free radical
neutralizing potential. Three authors each have advocated
the strong antioxidant activity of Vitamin C in invivo
studies and glutathione dependent activity in the oral
environment. One author has concluded the moderate
potential of Vitamin C in invivo conditions, whereas one
author each have assessed the strong activity of Vitamin C
among physiologic conditions and smokers, respectively.
Five authors have concluded that Ascorbic acid is a
prooxidant in iron induced Fenton reaction in pathologic
conditions. Two studies have found the prooxidant action
of Vitamin C in Copper induced oxidation. Vitamin C has
been found to be a prooxidant under conditions of high
plasma concentration, and among smokers by one author
each substantiating its activity in various pathologic states.
Three studies showed that Vitamin C acts as a prooxidant
by inhibiting the growth of malignant cells exhibiting its
chemo preventive potential.

Table1: General information of included studies


Author
Padayatty etal.

Name of journal

Year
2003

Schwartz

Journal of American
College of Nutrition
Journal of Nutrition

Herbert

Journal of Nutrition

1996

Carr and Frei

FASEB journal

1999

Retsky etal.

1993
1999

Azmi etal.

Journal of Biological
Chemistry
American Journal of
Nutrition
F1000 Research

Naidu

Nutrition Journal

2003

Nishida etal.

Journal of
Periodontology
The American Journal
of Clinical Nutrition

2000

Carr and Frei

Lee etal.

1996

2013

2003

Indian Journal of Dental Research, 25(4) 2014

Country
Maryland,
USA
Bathesda
MD, USA
NewYork,
USA
Oregon,
USA
Boston,
USA
USA
Detroit,
USA
Mysore,
India
NewYork,
USA
USA

Conclusion
Prooxidant
High plasma
concentration
Strongin vivo
Chemopreventioninhibits
growth of malignant cells
Moderatein vivo
Iron induced Fenton
chemistry
Strongin vitro
Iron induced Fenton
reaction. In vitro
Stronginvivo, in vivo Copper induced
oxidation
Stronginvivo, in vitro Iron induced Fenton
reaction
Strongglutathione
Copper induced
dependent
oxidative damage
Strong under
Iron overload conditions
physiologic conditions
Nonsmokers
Smokers
Antioxidant
Strongin vitro

Strongantioxidant
in vivo

Iron overload
(Fenton chemistry)

Inference
In the oral environment
Prooxidant in pathologic
condition
Antioxidant in physiologic
condition
Prooxidant in pathologic
condition
Prooxidant in pathologic
condition
Antioxidant in physiologic
condition
Antioxidant in physiologic
condition
Paradoxical prooxidant in
the pathological condition
Antioxidant in physiologic
condition
Antioxidant in physiologic
condition
Antioxidant in physiologic
condition
501

Chakraborthy, etal.

Antioxidant and prooxidant role of Vitamin C

Table2 reveals that 65% of authors have analyzed the


antioxidant action of Ascorbic acid when compared to 35%
to the prooxidant potential. It has been found that the
antioxidant activity of Vitamin C is executed by the varied
mechanism of action in physiologic conditions in the oral
environment. The calculated percentage is 36%, 40%, 9%,
9%, 14%, 20%, 25%, 45% and 14% for mechanism of Vitamin
C as an antioxidant by its free radical scavenging property,
redox potential as an electron donor, coadministration
with Glutathione, coadministration with tocopherol,
prevention of lipid per oxidation, prevention of oxidative
DNA damage, prevention of oxidative protein damage,
chemo preventive action in the presence of iron overload,
respectively. While 83%, 42% and 25% of authors have
evaluated the prooxidant action of Vitamin C by the
mechanism of iron induced oxidative damage, copper
induced oxidative damage(Fenton reaction) and higher
pharmacological concentration, respectively, elucidating
its potential activity in pathologic conditions in the oral
environment. Asignificant difference has been observed
in the percentage of studies done to examine the action
of Vitamin C as an antioxidant and a prooxidant, it has
been observed that a greater percentage of studies have
been done in favor of antioxidant property of Vitamin C
under physiologic conditions as compared to that done
for its prooxidant property inducing a compromised oral
health. 70% authors have performed an invivo and invivo
study on antioxidant property under various physiologic
conditions as compared to only 30% done for prooxidant
activity. Similar trend is observed for other study samples,
Table2: Analysis of the percentage of each studied parameter
Antioxidant Parameters studied
Prooxidant
(%)
(%)
65%
Authors
35

Mechanism of action
36
Free radical scavenger

40
Redox potential(reducing agent)

9
Coadministration with glutathione

9
Coadministration with tocopherols

14
Prevention of lipid peroxidation

20
Prevention of oxidative DNA damage

25
Prevention of oxidative protein damage

45
Chemo preventive action

14
Ascorbic acid+iron overload

Iron induced oxidative damage


83
(Fenton reaction)
Copper induced oxidative damage
42
Concentration gradient dependent
25
Type of study
70
In vitro
30
85
In vivo
15
75
Case control
25
53
Cohort study
47
67
Placebocontrolled
33
Study based on the oral environment
73
Health
27
21
Disease
79
Plasma concentration
23
High
30
15
Low
23
502

85%, 75%, 53% and 67%, invivo , case control, cohort


and placebo controlled, studies respectively have been
done in comparison to 15%, 25%, 47% and 33%, studies
respectively done for similar study samples mentioned
above.
A marked potent action of Vitamin C as an antioxidant
in oral health has been observed among authors in the
included studies. The review found that 73% of authors
successfully inferred the response of Vitamin C as an
antioxidant in oral health compared to its nonconcrete
action as a prooxidant which amounts to only about 27%
in the pathologic state. 21% of authors have ascertained
the potency of Vitamin C as a prooxidant in oral diseases
compared to 79% authors who have witnessed the action
of Vitamin C as an antioxidant in physiologic conditions
improving the oral health of individuals. The tendency
of shifting its role from an antioxidant to a prooxidant
under pathological conditions has been observed by 78%
of the authors as compared to 22% authors who have
not observed any transformative role of Vitamin C as
an antioxidant but revealing its individual activity as an
antioxidant and prooxidant in oral health and disease
respectively. Hence, from the previous reviewed literature,
it can be concluded that Vitamin C has a high potential of
transforming from an antioxidant invivo under physiologic
conditions to a prooxidant in pathologic conditions by the
virtue of Fenton chemistry and at a higher pharmacological
concentration.
It is seen from the present review that 23% of authors
have mentioned the antioxidant action of Vitamin C in
high plasma concentration compared to 30% authors in
favor of the prooxidant action of Vitamin C in similar
condition. Whereas 15% and 23%, of authors respectively,
have concluded that Vitamin C is an antioxidant and a
prooxidant, under low plasma concentration. Hence, it is
observed from our review that the majority of studies have
been done by various authors to study the antioxidant action
of Vitamin C than the number of studies done to examine
the prooxidant action of the same. The mechanism of action
by which the antioxidant property of Vitamin C is carried
out in the body is hence better studied and understood than
its prooxidant property. Although its role as an antioxidant
is well documented, there is little evidence that it serves as
a prooxidant under physiological conditions, hence more
studies is required to draw any concrete conclusions.

DISCUSSION
There is a continuing debate over the best dose schedule(the
amount and frequency of intake) of Vitamin C for
maintaining optimal oral health in humans. An average
intake by healthy adults ranges from 90 to 100mg daily;
while there is increased intake in pregnant and lactating
women or individuals under stress.[6]
Indian Journal of Dental Research, 25(4), 2014

Antioxidant and prooxidant role of Vitamin C

Vitamin C is an essential nutrient for humans and a cofactor


for collagen synthesis for maintenance of all oral hard and soft
tissues. The biochemical and molecular roles can be accounted
by its function as a reducing agent. This was observed by
Padayatty etal.[1]in 2003 focusing on its property as an electron
donor to prevent diseases in reduced intake attributing to its
Antioxidant potential by forming ascorbyl radical; which is
comparatively stable and less reactive in nature.
The pathologies that accompany Vitamin C deficiency
have prompted numerous investigators to determine a
possible relationship between ascorbic acid and periodontal
tissue health. Epidemiological studies also demonstrate an
association between Vitamin C intake and pathologies,
affecting the structural integrity of the oral hard and soft
tissues.[7,8] Hence, various authors have extensively viewed
the protective, formative and homeostatic benefits of
Vitamin C in human oral environment.
Vitamin C by its protective role acts as a potent water
soluble antioxidant as observed by 65% of authors from
our systematic review of the literature [Figure 1].[1,2,912]
Antioxidants play a pivotal role as free radical and nonradical
oxidant scavengers. Depending on the circumstances, a
compound may exhibit pro or antioxidant activity. The
protective effect of Vitamin C was further reported by Lee
etal.[13] in 2003, it was also stated that at a higher dosage,
it had induced oxidative damage to DNA promoting to
prooxidant and mutagenic potential in humans.[14]
Ascorbate is a strong antioxidant as suggested by 70%
of authors among the included studies of our review of
the literature, in various invivo and invitro conditions;
however30% of authors among the studies included,
inferred it can also act as a prooxidant invivo by the help
of reducing transition metals; driving a Fenton reaction.[5]
As reported by Joel Schwartz[9] in 1996 the beneficial or
detrimental effect of a nutrient depends on the bimodal
characteristic depending on the inorganic chemistry of
the cell. Herbert[15] in 1996, observed the prooxidant
effects of antioxidant vitamins at a higher concentration,
later supported by Azmi etal.[11] in 2003, linking to their
anticarcinogenic property by generating reactive oxygen
species.

Figure1: Pie chart showing percentage of antioxidant and pro-oxidant


studies
Indian Journal of Dental Research, 25(4) 2014

Chakraborthy, etal.

Although few studies have shown the prooxidant effects


of Vitamin C in the presence of Cu2+and/or Fe3+, Retsky
etal.[10] in 1993 contradicted that Vitamin C does not
act as a prooxidant in the presence of transition metal
ions, it rather exhibits its potentiality as an antioxidant
under the same physiologic conditions demonstrating
that Vitamin C was most effective in lipid peroxidation
prevention. The evidence for antioxidant protection
of lipids by Vitamin C, in both iron and noniron
supplementation, was also reported by Carr and Frei[2] in
1999, suggestive of Vitamin C as a potential antioxidant
under physiologic conditions, as also concluded by 73% of
authors in our systematic review, compared to 27% authors
who stated that Vitamin C exhibits a prooxidant by Fenton
reaction[2,11,15] as also seen in studies investigating tumor
growth and cancer inducing a compromised health status.
35% of authors in our review have assessed the prooxidant
action of Vitamin C at high plasma concentration by the
same mechanism.[1]
Nishida etal. in 2000,[16] in reference to NHAHES III
survey, reported higher daily dosage of Vitamin C has the
potential to scavenge free radicals in smokers which helps
to prevent the progression of smoking associated progressive
changes in the oral cavity. However, Naidu[12] in 2003
overviewed the mystical benefits of ascorbic acid in human
health and disease stating that the ascorbic acid at a higher
concentration can exhibits properties of antioxidant.
Carr and Frei[2] on the contrary stated that antioxidants
inhibit the growth of transformed cells thus increasing their
intercellular communication by the oxidative protective
mechanism in a unique manner. Hence, the use of natural
nutrients like Vitamin C is expected to provide the greatest
benefit toward the inhibition of oral carcinogenesis.
Vitamin C plays a switch over from being an antioxidant in
physiologic conditions to a prooxidant under pathological
conditions as observed by 78% of the authors in our, as
compared to 22% authors who have not observed the
same stating the exhibition of its individual activity as an
antioxidant and prooxidant in oral health and disease in
physiologic and pathologic conditions respectively.
To summarize, from the previous review of the literature,
it can be stated that under physiologic conditions, Vitamin
C acts as a potential antioxidant due to its plethora of
mechanisms like free radical and reactive oxygen species
scavenging action, redox potential and prevention
of oxidative damage of lipids, proteins and nuclear
material. However, its switch over role as a prooxidant
is paradoxical, stating the influence of iron and copper by
the virtue of Fenton chemistry in pathological conditions.
Further studies are warranted to explain, understand and
determine its activity as a potential prooxidant in the oral
environment.
503

Chakraborthy, etal.

Antioxidant and prooxidant role of Vitamin C

CONCLUSION
Although the role of Vitamin C as an antioxidant is well
documented, there is little evidence that emphasizes its
prooxidant role in various conditions. Previous research
and our systemic review confirm that under normal
physiological conditions, it acts mainly as an antioxidant;
however, the transition of a healthy oral status to a highly
compromised pathologic state can trigger the prooxidant
activity of Vitamin C. The observations of this systemic
review also reflected the necessity for researchers to
determine stronger theories that would elucidate the
mechanisms and conditions that bring about the prooxidant
attributes of Vitamin C to illustrate and demarcate its
antioxidant and prooxidant properties more precisely.

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How to cite this article: Chakraborthy A, Ramani P, Sherlin HJ, Premkumar P,


Natesan A. Antioxidant and pro-oxidant activity of Vitamin C in oral environment.
Indian J Dent Res 2014;25:499-504
Source of Support: Nil, Conflict of Interest: None declared.

Indian Journal of Dental Research, 25(4), 2014