international journal of nutritional research review article antioxidant … · 2021. 4. 6. ·...

Archives of Life Science and Nutritional Research 1

Kiokias S*

Research Executive Agency (REA), Place Charles Rogier 16, 1210 Brussels, Belgium.

Received: 25 August, 2019; Accepted: 05 September, 2019; Published: 28 September, 2019

*Corresponding Author: Kiokias S, Research Executive Agency (REA), Place Charles Rogier 16, 1210 Brussels, Belgium. E-mail: [email protected]

Abstract Reactive oxygen species as initiators of oxidative stress account for LDL and DNA oxidative

changes that are respectively associated with the development of pathological conditions such as

atherosclerosis and carcinogenesis. This review paper first focuses on specific bio-indicators used to

monitor these harmful oxidative stress conditions and develop health strategies against the associated

human diseases. Subsequently, it provides an overview of the most recent available literature on the

protective role that certain antioxidant vitamins (vitamin C, vitamin E and provitamin A compounds)

have been reported to exert against the biochemical oxidative processes that govern the initiation of

these specific human diseases.

Key words:Provitamin A; Vitamin E; Vitamin C; DNA Damage; Oxidized LDL

Introduction Oxygen free radicals (i.e. as hydroxyl

radicals; superoxide radicals and other active

oxygen species such as singlet oxygen) have

been widely reported to adversely alter lipids

and proteins through biochemical oxidative

reactions and thereby trigger a number of

human diseases [1]. The ability of free radicals

to structurally modify cellular components,

gene expression and protein production has

led to the implication of their involvement in a

variety of health diseases [2]. More specifically,

these harmful oxygen species can generate

oxidative damage and adversely affect biological

membranes with pathological consequences [3].

This review mainly focuses on the following

two resulted pathological conditions:

(i) Oxidative modification of LDL (low- density

lipoproteins) a lipid peroxidation reaction driven

by free radicals that is Considered a key step in the

early stages of atherosclerosis and thereby the

development of cardiovascular diseases [4-6].

(ii) Cellular oxidative DNA damage for which a

body of research is trying to clarify how the

reported repair pathways may influence the cancer

transformation [7, 8].

International Journal of Nutritional Research

Review Article

Antioxidant Effects of Vitamins C, E and Provitamin A

Compounds as Monitored by Use of Biochemical

Oxidative Indicators Linked to Atherosclerosis and

Carcinogenesis

mailto:[email protected]

Antioxidant Effects of Vitamins C, E and Provitamin A Compounds as Monitored by Use of Biochemical Oxidative Indicators Linked to Atherosclerosis and Carcinogenesis Arch Lif Sci Nutr Res: 3(1): 104.


It is also known that the nature has

generously offered a wide range of nutrients

with strong antioxidant activities, among which

certain compounds of vitamin value can act as

radical scavengers in model biological systems

and in the human organism [9]. A large number

of studies have examined the effects of

antioxidant vitamins either individually or in

combination, on ex vivo LDL oxidation and in

vivo DNA damage with most information being

available for the effects of pro vitamins A,

vitamins C and vitamin E [10, 11].

Arvanitoyannis and co- authors (2009) [12]

reviewed the various available methods for the

determination of chain-breaking antioxidant

activity in food and biological systems. The

total peroxyl radical trapping parameter

(TRAP) and the oxygen radical absorbance

capacity assay (ORAC) have served as the most

commonly used methods of evaluating the

antioxidant capacity during the last two

decades [13,14].

This paper first provides an overview

of the link between LDL and DNA oxidative

changes with the development of the specific

harmful pathological conditions. The

biomarkers that are commonly used to monitor

these biochemical processes are also discussed.

Subsequently, building on the knowledge

presented by the most recent clinical studies in

this field, the paper summarises the most

important research findings concerning the use

of certain vitamins against oxidative stress.

More specifically, this work will investigate on

the effect of provitamins A carotenoids,

tocopherols (vitamin E) and ascorbic acid

(vitamin C) against both in vivo oxidative

damage of DNA and ex vivo LDL oxidative

modification.

Health adverse effects of oxidative

damage as monitored by certain

biochemical indicators

Oxidative damage and detrimental health effects

LDL oxidative modification and atherosclerosis

Over the last few years, extensive clinical

and epidemiologic research evidence has been

gathered on the role of oxidized LDL (low-density

lipoproteins) in the development of atherosclerosis

[15]. Atherosclerosis is a progressive disease of the

arterial tree that involves deposition of lipid,

mostly oxidized LDL, in the arterial intima leading

finally to a thickening of the arterial wall and

reduced luminal blood flow [16]. Oxidative

modification of LDL, a lipid peroxidation reaction

driven by free radicals is therefore a key step in the

early stages of atherosclerosis [17]. The

relationship between circulating ox-LDL and

subclinical atherosclerosis has been thoroughly

explored and confirmed in a case control study

performed by Fang and coworkers. [18]

DNA oxidative damage and cancer

It has recently become apparent that generation of

reactive oxygen species from mitochondria first as

the cellular response to oxidative stress and DNA

damage is close linked to carcinogenesis[19]. DNA

damage can take many forms, ranging from

specifically oxidized purine and pyrimidine bases

to gross DNA changes such as strand breaks, sister

chromatid exchange, and the formation of

micronuclei [20]. According to one of the proposed

oxidative mechanisms, hydrogen peroxide can

cause DNA strand breakage, by

generation of the hydroxyl radical (OH-) close to

the DNA molecule, via the Fenton reaction.



Equation (1): H2O2+ Fe2+→OH•+ OH- + Fe3+

This process may result in DNA

instability, mutagenesis and ultimately

carcinogenesis.

Health biomarkers of oxidative damage

Plasma levels of oxidized LDL

A convenient and very frequently used

method for monitoring the level of plasma

oxidized LDL is the process of copper- induced

LDL oxidation through the spectrophotometric

measurement of conjugated dienes (CDs)

absorption at 233 nm [21]. The chronology of

LDL oxidation by Cu2+ ions can be divided into

three consecutive time phases: During the lag

phase, LDL particles become progressively

depleted of its endogenous antioxidants, so

that they subsequently enter the propagation

phase in which the polyunsaturated fatty acids

(PUFAs) are rapidly converted to CDs [22].

In the final decomposition

stage, secondary reactions of LDL oxidation

leading to aldehydes (malondialdehyde,

hexanal, 4- hydroxynonenal etc.), are

accelerated by transition metal ions, such as

Fe2+, which may catalyze decomposition of

lipid hydro peroxides (LOOH) to alkoxyl

radicals (LO·)

Biomarkers of DNA oxidative damage

Among various types of DNA damage

that occur due to Reactive oxygen species

(ROS) and increase cancer risks, the most

studied base damage is 8- oxoguanine (8-

oxoG). Generation of 8-oxoG in DNA is a

mutagenic and potentially carcinogenic event

since the oxidized base has altered hydrogen

bonding or “code specificity”, preferentially

forming base pairs with adenine rather than

cytosine [23]. In addition, the deoxy-nucleoside

derivative 8- OH-dG 8-hydroxy-2’-

deoxyguanosine has been used as useful

marker of oxidative DNA damage [24].

Figure (1) Selective products of DNA oxidative

damage commonly used as biochemical indicators

of oxidative stress: (a) 8-OH-deoxyguanosine (b)

8-oxoadenine (c) 8-oxoguanine(Kiokias,2002)[24]

(a) 8-OH-deoxyguanosine

(b) 8-oxo adenine

(c) 8-oxo-guanine (Kiokias, 2002)[24]

The Japan Institute for the Control of Aging

has developed an in vitro enzyme-linked

immunosorbent assay (ELISA) for quantitative

measurement of the oxidative DNA adduct 8-OH-

dG in tissue or urine samples, thereby enabling a

reliable assessment of DNA oxidative damage.

Furthermore, the well-known COMET assay is an

alternative sensitive and valuable technique that

allows the determination of the level of DNA

damage by making use of repair enzymes to

introduce strand breaks at sites where oxidized

bases are present [25].



Other oxidative bio-indicators

During the last decade, the

development of immunochemical detection of

HNE-histidine cytotoxic adducts (4hydroxynon

enal (4-HNE)), has opened more advanced

methodological possibilities for qualitative and

quantitative detection of lipid peroxidation in

various human and animal tissues [26]. In

addition, the Thiobarbituric acid reactive

substances (TBARs) test is still the most

frequently used test to assess secondary

products of lipid peroxidation such as

malondialdehyde (MDA) that reacts with TBA

reagent on heating under acidic conditions to

give a red chromophore, which is measured by

UV spectroscopy at 532 nm or by fluorescence

at 553 nm [27].

Effect of vitamins on the oxidative

damage as monitored by LDL and

DNA biochemical indicators Antioxidant activity of Provitamin A

compounds

Provitamin A compounds (α, β-

carotenes and β-cryptoxanthin) belong to the

class of carotenoids (Figure 2). They are 40-

carbon terpenoids widely available in nature

with well-known scavenging activities against

free radicals that are trapped in their

conjugated structure [28]. Carrots and

tomatoes are the main sources of carotene in

the diet, while the daily consumption of leafy

vegetables (spinach, beets, lettuce)

significantly contributes to the

carotenoid daily intake [29]. The antioxidant/p

rooxidant potential of carotenoids is of

particular significance to human health, and a

critical factor in combating the oxidative

processes of various chronic disorders [30].

Figure (2) Structure of the provitamin A carotenoids (Kiokias 2002) [24]

-carotene

-carotene

-cryptoxanthin

Effect of Provitamin A against LDL oxidation

Major non-provitamin A carotenoids

(lycopene, lutein, and zeaxanthin) and provitamin A

compounds carotenoids have different biological

activities and efficacy, depending on their food

content, dietary intake, bioavailability, and

bioconversion [31]. Special attention has been

given to the potential protective role of carotenoids

in atherosclerosis, since these lipid soluble

pigments have shown remarkable antioxidant

capacity against LDL oxidation [32]. The disease-

preventing activity of β-carotene and other

provitamin A carotenoids could be ascribed either

to their conversion into retinoid or to their activity

against LDL oxidation. The molecular mechanisms

in the context of the anti- and pro-oxidant activity

of carotenoids in human are still not fully

understood [33].

It may be that β-carotene and other

carotenoids (e.g. astaxanthin) promote a good



health when supplemented at physiologic

amounts in foods, but could even present

adverse prooxidant harmful activities when

given in high doses and under highly oxidative

conditions. In the well known as “Rotterdam

study” the association between aortic

atherosclerosis and the levels of the major

serum carotenoids including both provitamin A

(α-carotene, β-carotene, α- cryptoxanthin) and

non provitamin compounds (lutein, lycopene,

and zeaxanthin) was investigated in a

subsample of the elderly population (n=108

cases and controls) [34]. In an age- and sex-

adjusted logistic regression model, serum

lycopene (but no other carotenoids) was

inversely associated with the risk of

atherosclerosis.

Effect of provitamin A against DNA oxidative

damage

Lorenzo and coworkers (2009) [35]

have investigated the biological properties of β-

cryptoxanthin, in cell culture model systems,

using the comet assay to measure DNA damage.

They reported that at low concentrations, close

to those found in plasma, β-cryptoxanthin does

not itself cause damage, but rather protects

transformed human cells from damage induced

by H(2)O(2) or by visible light in the presence

of a photosensitizer. Astley and coworkers

(2004) [36] supplemented healthy male

volunteers with lutein, beta-carotene or

lycopene (natural isolate capsules, 15 mg/d, 4

weeks) and observed that both beta carotene

and non provitamin A carotenoids exerted an

antioxidant protection by scavenging DNA-

damaging free radicals and modulation of DNA

repair mechanisms. On the other side, Collins

and Azqueta (2012)[37] stated that studying

reports from the last 5 years, revealed a clear

distinction between effects of pro-vitamin A

carotenoids (α,β-carotenes and β-

cryptoxanthin) and the effects of non- vitamin

A carotenoids (lycopene, lutein, astaxanthin

and zeaxanthin). Whereas the compounds of the

latter group are almost invariably reported to

protect against DNA damage, the provitamin A

carotenoids show a more varied spectrum of

effects, sometimes protecting and sometimes

enhancing DNA damage.

Antioxidant activity of Vitamin E

compounds Vitamin-E comprises a category of eight

monophenolic compounds (known as Tocopherols

and tocotrienols) with strong reported antioxidant

activities in food and biological systems. α-

Tocopherol is the most common compound found

in European dietary sources such as olive and

sunflower oils, while γ-tocopherol is frequently

present in the American diet because of higher

intakes of soybean and corn oil [38]. Vitamin E has

been reported to exert a role in reducing

inflammation and muscle soreness and protect the

cell membrane from oxidative damage [39].

Tocopherols mainly act as chain breaking

antioxidants that inactivate free radicals via their

hydrogen donating character [40].

Effect of vitamin E against LDL oxidation

Hodis and co-authors (2012) [41] reported

that α-tocopherol supplementation (400 IU/day)

significantly raised plasma vitamin E levels

(P<0.0001) whereas reduced circulating oxidized

LDL and LDL oxidative susceptibility. Studies that

included vitamin E supplementation support a

significant protection of LDL usually at doses higher

than 400 IU/day. As noted by Rizvi and co-workers

(2014) [42] Vitamin E is the major lipid-soluble

component in the cell antioxidant defense system

with numerous important roles within the body

because of its antioxidant activity. However, it has

also been suggested that when accompanying

antioxidants such as ubiquinone and vitamin C are

not available (to react and quench the vitamin E

radicals) a pro-oxidant tocopherol effect could be

induced [33]. Actually Niki (2010) [43] noted that



recent human clinical trials with vitamin E

have not yielded positive results against LDL

oxidative deterioration on the contrary to in

vitro experiments.

Effect of Vitamin E against DNA oxidative

damage

Makpol and coworkers (2010) [44]

observed that α-tocopherol protected against

H(2)O(2)-induced DNA damage and this

modulation was affected by donor age.

Another human trial [45] showed that an

intake of food rich in α-tocopherol could

decrease levels of DNA oxidative adducts.

Asgard (2014) [46] reported a significant

decrease of catechol- induced (1 mM) general

DNA damage in the presence of 20 μM of α-

tocopherol. On the contrary, Barcelos and co-

authors (2011) [47] supported that dietary

supplementation with α-tocopherol can even

induce DNA oxidative stress.

Antioxidant activity of Vitamin C compounds

L-Ascorbic acid (AH2) is an essential

nutrient, known as vitamin C, widespread

vitamin in nature in many fruits and

vegetables [48]. Although its role is not limited

to being an antioxidant, arguably its

antioxidant activity and its redox properties

are key to its over all biological function [49].

Ascorbic acid is commonly reported to act

synergistically with chain breaking

antioxidants (e.g. tocopherols, flavonoids)

resulting into enhancing effects against food

and biological oxidative deterioration [50].

Effect of Vitamin C against LDL oxidation

Ascorbic acid is a water-soluble

antioxidant, and as such is expected to be

removed from LDL during isolation. An earlier

study [51], did not find any significant effect of

dietary supplementation with vitamin C on LDL

oxidation in smoking volunteers. On the

contrary Harats [52], reported a beneficial

effect of dietary supplementation with 500

mg/d for 2 months [31] against LDL oxidative

deterioration. In addition, McRae (2008) [53] noted

that Vitamin C supplementation reduced serum

LDL and triglycerides levels. More recently, Shariat

and coworkers (2013) [54] noted a strong

antioxidant effect of vitamins C against the low

density lipoprotein oxidation mediated by mye-

lopero-xidase.

Effect of Vitamin C against DNA oxidative damage

A protective effect of vitamin C

supplementation in humans with plasma

levels>50μmol/l was observed by Sram (2012) [55]

in terms of 8-oxodG levels. More recently, Kontek

and coworkers (2013) [56] noted that vitamin C (in

a concentration range10- 100 μm) caused a clear

protecting effect against DNA damaging. More

specifically, they concluded that vitamin C

modulates DNA damage induced by hydrogen

peroxide in human colorectal adenocarcinoma cell

lines (HT29), estimated by COMET assay in vitro

(decrease ∼ 30%). Asgard (2014) [46] reported

that high plasma levels of ascorbate reduced the

levels of oxidative DNA damage (8-oxodG) in

mononuclear white blood cells. Overall, Konopacka

(2004) [57] highlighted that data concerning the

influence of vitamin C on oxidative DNA damage are

conflicting and some of the discrepancies can be

explained by the different experimental

ethodologies employed.

Antioxidant activity of Vitamin mixtures Effect of

vitamin mixtures against LDL oxidation

A growing body of human clinical

investigation has focused into combination of

various antioxidants in order to explore the

potential of interactions because of varying modes

and mechanisms of antioxidant action [10].

Interestingly, a few studies that were designed to

supplement subjects with mixtures of antioxidant

vitamins in generally observed an enhanced

beneficial effect on oxidative stability of LDL,

presumably resulting from a synergistic action

between the vitamins [58, 59].) A recently



conducted cross-sectional study [60] observed

that the total daily carotenoid intake of

provitamin A carotenoids (β cryptoxanthin, β

and α carotene lycopene) mixture with

xanthophylls (lutein plus zeaxanthin,) was

inversely associated (p<0.05) with

the plasma oxidized-LDL concentrations.

Kiokias and Gordon (2003) [61]

supplemented for 3 weeks 30 healthy

volunteers with a mixture of provitamin A

(palm oil carotenes) and xanthophylls

(paprika, lutein, bixin)providing in a total

amount of 30mg active carotenoid/day. The

authors reported an increased resistance

of LDL to oxidation

(monitored by CD at 233 nm) accompanied by

enhanced plasma carotenoid levels for the

supplemented groups compared with placebo

[61]. Boushehri and coauthors (2012) [61]

examined the effect of antioxidant vitamins on

serum oxidized LDL levels in male subjects

with cardiovascular disease risk factors. They

reported that a diet enriched in a combination

of vitamin C (500 mg), vitamin E (400 IU) and

ß-carotene (15 mg), was strongly associated

with lower serum oxidized LDL levels.

Similarly in an earlier study [63], a daily

supplementation for 2 months with a mixture

of vitamin E (200 mg) together with vitamin C

(400 mg) and β- carotene (20 mg) significantly

decreased the susceptibility of LDL to oxidative

deterioration.

Effect of vitamin mixtures against DNA

oxidative damage

An earlier study [64], had examined the

effect of antioxidant vitamin supplementation

on DNA damage and repair in human -

lymphoblastic cells. After a 24-hour

supplementation period with a mixture of

ascorbic acid and α-tocopherol, (60 micro M in

total) the level of endogenous DNA damage

was significantly lower than in the non-

supplemented culture, as assessed by the

comet assay. In addition a human clinical trial [65]

reported that supplementation of smokers and non-

smokers with an antioxidant mixture

(vitamin C-100 mg+vitamin E-280 mg +and β-

carotene-25 mg per day) significantly (p<0.002)

reduced base damage in lymphocyte DNA.

These findings agree with another human

trial [66] in which 23 healthy subjects (after 2

weeks of washout) were supplemented daily with

40 mg lycopene (weeks 3 and 4), 22.3 mg β-

carotene and 15.7mg α-carotene (weeks 5 and 6),

and 11.3 mg lutein (weeks 7 and 8) This

intervention has resulted into a significantly

decreased DNA damage in lymphocytes. Kiokias &

Gordon (2003) [61] conducted a double-blind,

placebo-controlled cross over study with 30

healthy subjects. Following a dietary

supplementation with 30 mg carotenoid mixture

/day (,-carotenes, lycopene, paprika, lutein,

bixin, total amount) they reported a significant

effect against production of urinary 8-OHdG

estimated by use of ELISA test. Zou and co-authors

(2014) [66] also highlighted that there could be a

synergistic effect when carotenoids are mixed

together because various compounds tend to

arrange in different sites of membranes and

lipoproteins, adding an enhanced protection

against oxidative damage. More recently, a cross-

sectional study [60] supplemented 296 healthy

middle-aged men with a mixture of all 3 provitamin

A compounds and two more carotenoids (lycopene

and lutein). In conclusion, the total daily carotenoid

intake based on five investigated carotenoids was

inversely associated with the production of urinary

8-OH-dG as oxidative stress biomarker

(p<0.05). Very recently, Ahmed and co-authors

(2018) [67] concluded a protective effect of

curcumin and α-tocopherol against propoxur-

induced oxidative DNA damage in human

peripheral blood mononuclear cells. An overview

on the most recent human trials (individually or in

mixtures) that reported protective effects of

vitamins against LDL and DNA oxidative changes is

given in (Table 1).


Table (1) An overview of most recent human clinical evidence confirming positive effects of dietary

supplementation with vitamins against LDL and/or DNA oxidative changes.

Authors/studies(in date order)

Condition of Human Clinical trials

Protective effect of the vitamin mixture

Effect against LDL oxidation

Effect against DNA damage

Sram et al (2012) [55]

Vitamin C supplementation in

humans

---------- Protective effect of vitamin C

supplementation against DNA damage in terms of 8-oxodG levels

Hodis et al (2012) [41] reported

α-Tocopherol

supplementation (400 IU/day)

Supplementation significantly raised plasma

vitamin E levels (P< 0.0001) and reduced circulating

oxidised-LDL (P= 0.03) and LDL

oxidative susceptibility (P< 0.01).

----------

Boushehri et al (2012) [61]

Male subjects followed a diet enriched with a

combination of vitamin C (500 mg),

vitamin E (400 IU), ß- carotene (15 mg),

The antioxidant treatment resulted into significantly lower serum oxidized LDL

levels.

----------

Kontek et al (2013)[56] Vitamin C supplementation in

humans (in a concentration range

10-100 μm)

----------

Modulation of DNA damage estimated

by COMET (decrease ∼ 30%)

Asgard (2014)

[46]

47 type-2 diabetes subjects supplemented

for 12 weeks with 16 capsules/day (mixture of β- carotene + α- tocopherol)

----------

Significant decrease of catechol-

induced (1 mM) DNA damage in the presence of 20 μM of α-tocopherol.

Cocate et al. (2015)[60]

296 healthy middle- aged subjects were supplemented with a carotenoid mixture

(β-cryptoxanthin, lycopene, lutein plus

zeaxanthin α- β carotenes)

The carotenoid

supplementation resulted into reduced plasma

oxidised-LDL concentrations. (p<0.05)

----------

Ahmed et al (2018) [67]

Propoxur-induced oxidative DNA damage

in human peripheral blood

mononuclear cells:

----------

Protective effects of curcumin mixtured with α-tocopherol



Conclusions/future work in this

scientific field Based on the analysis presented in the previous

section of this review, the following conclusions

can be drawn:

a) The association between plasma oxidized

LDL and DNA oxidative adducts with the

eventual risk of developing a cardiovascular

disease or cancer respectively are not

completely elucidated yet. Further

investigation is required in this field to

obtain more recent and valid clinical

intervention data further to the existing

epidemiological data. To this end, the set-up

of new methods and biomarkers to monitor

the level of DNA and LDL oxidative damage

is very essential and the use of innovative

technologies (e.g. Nano science and Nano-

tools) can be decisive in the development of

new monitoring tools. Such bio- indicators

can be used to test the efficiency of natural

antioxidants against oxidative stress and

thereby offer new strategies to combat

again the progression of atherogenesis and

certain types of cancer.

b) A recent body of clinical research evidence

has concluded that dietary combinations of

vitamins (e.g. vitamin E, vitamin C and

provitamins A) can be more effective

against oxidative damage of either LDL or

DNA than the supplementation of each

individual vitamin. Such an enhanced effect

of vitamins mixtures may relate to the

different mode of activities of the individual

compounds thereby allowing a synergistic

effect when combined in the diet. In

particular for carotenoids, a better

antioxidant effect against oxidative damage

has been reported when provitamin A

compounds (mainly hydrophobic α-and β-

carotene) are supplemented together with

preparations of more polar xanthophylls

(e.g. lutein or paprika) in recent human

clinical studies.

c) In order to design a new generation of

dietary supplements based on natural

vitamins with clear antioxidant activity, it is

essential to first explore and elucidate the

bioavailability of the individual compounds.

This would help to establish a clear

relationship between dietary intake and

health impact thereby facilitate

further optimization studies on the clinical

effects of vitamins supplementation against

oxidative pathological conditions.

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Citation: Sotirios K (2019), Antioxidant Effects of Vitamins C, E and Provitamin A Compounds as Monitored by Use of Biochemical Oxidative Indicators Linked to Atherosclerosis and Carcinogenesis. Int J Phar Inft Thrp; 3(1): 01-13.

DOI: 10.31829-2765-8368-alsnr2019-3(1)-104

Copyright: © 2019 Sotirios K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.














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