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Abstract
The skin cells continuously produce, through cellular respiration, metabolic
processes or under external aggressions, highly reactive molecules oxidation
products, generally called free radicals. These molecules are immediately
neutralized by enzymatic and non-enzymatic systems in a physiological and
dynamic balance. In situations where this balance is broken, various cellular
structures, such as the cell membrane, nuclear or mitochondrial DNA may suffer
structural modifications, triggering or worsening skin diseases. several
substances with alleged antioxidant effects has been offered for topical or oral
use, but little is known about their safety, possible associations and
especially their mechanism of action. The management of topical and oral
antioxidants can help dermatologist to intervene in the oxidative processes
safely and effectively, since they know the mechanisms, limitations and
potential risks of using these molecules as well as the potential benefits of
available associations.
Keywords: Antioxidants, Carotenoids, Dermatitis, DNA damage, Free radicals, Polypodium, Skin aging
INTRODUCTION
Skin and mucous membranes have a contact and defense barrier role against chemical,
physical and biological aggressions continuously.1
Maintenance of cellular integrity, as well as of all immune mechanisms, whether
inborn (cutaneous lipids and plasma membranes, for example) or specific (cytokine
synthesis, enzymes or cell proliferation), involves a series of chemical reactions
that generate reactive oxygen species – highly reactive molecules that can rapidly
alter molecules fundamental to cutaneous homeostasis, such as proteins, lipids, or
DNA.2 Endogenous or
exogenous antioxidant mechanisms act by neutralizing these reactive molecules. The
imbalance of this neutralization has multiple consequences: free radicals are
implicated in the etiopathogenesis of various dermatoses, as well as in the aging
process and in the onset of cutaneous neoplasias.3
Proper use of antioxidants should be considered in these situations where evidences
of their benefits have been accumulating in the last decades.
OXIDATIVE MECHANISMS AND SKIN PHYSIOLOGY
The main reactive oxygen species (ROS) are the hydroxyl radicals (HO•) and
superoxide (O2•-), peroxyl and alkoxyl radicals
(RO2• and RO•), the singlet oxygen (1O2)3-5, as well as hydrogen peroxide (H2O2) and
organic peroxides (ROOH).4 In
addition to direct damage to molecules such as lipids, amino acids and DNA, ROS can
activate enzymatic and non-enzymatic cellular responses, with the potential to
modify other processes that end up interfering with gene expression.5
Antioxidants are substances that combine to neutralize reactive oxygen species
preventing oxidative damage to cells and tissues.6 The cutaneous antioxidant system consists of enzymatic and
non-enzymatic substances. Among enzymatic antioxidants, glutathione peroxidase
(GPx), catalase (CAT) and superoxide dismutase (SOD) can be highlighted.7
Non-enzymatic or low molecular weight antioxidants also contribute to the maintenance
of cellular redox balance. Here some hormones are grouped such as estradiol and,
melatonin, as well as some vitamins, such as E and C.8
summarizes the main oxidative sources
and their antioxidant systems; participating.9
Diagram of the redox balance in the skin
THE PARADOX OF ANTIOXIDANTS EXCESS
Generation of ROS in physiological conditions, such as respiration or even physical
exercise, is important in the maintenance of cellular functional integrity. These
molecules generally induce intracellular enzymatic processes via transcription
factors (FoxO) that induce the expression of antioxidant enzymes, such as
SOD.9 Increased levels of
FoxO reduce cell proliferation and induce apoptosis. These factors are involved in
cell growth, proliferation, differentiation and longevity.10
Balance of antioxidant systems and the endogenous generation of ROS is dynamic and
tenuous.
There is evidence that situations of mild stress, such as caloric restriction or
physical activity, can modulate the aging process, since they increase mitochondrial
activity, also increasing the generation of ROS – which would provoke an adaptive
response, with improvement of defense mechanisms and consequent better response and
resistance to stress.11
Although this question is not yet studied for skin physiology and pathology, it may
be valid, especially for chronological aging in healthy individuals.
Therefore, the ingestion or application of antioxidant molecules is indicated
in situations in which there is an inability to neutralize,
both by the ROS excess and by the decline of endogenous systems, as occurs in aging
and in some diseases.
However, not all molecules of antioxidant potential, from the physiological point of
view, act linearly in cutaneous oxidative stress; an important example of this is
the oral use of beta-carotene.
A randomized, controlled trial to determine whether the impact of the use of
beta-carotene supplementation, associated or not to sunscreens, could delay the
signs of photoaging was developed between 1992 and 1996; no significant effect of 30
mg daily supplementation of beta-carotene was identified.12 Likewise, another carotenoid, lycopene, does not
present a photoprotective effect when ingested orally, both in natura and in
supplementation.13
However, there is evidence that these molecules can also lead to deleterious effects
when used indiscriminately. The risk of hypervitaminosis in older patients, in whom
renal excretory function is reduced, is an example.14
Most emblematic, however, is the issue of vitamin E: tocopherol and its esters are
some of the most documented antioxidants and they are commonly used for their proven
action on induced ultraviolet damage. Its indiscriminate use, however, can inhibit
glutathione-S-transferase, responsible for the removal of cytotoxic compounds
related to tumorigenesis in the skin.15,16
Resveratrol itself, with its recognized antioxidant and anti-inflammatory activities,
has conflicting data regarding its doses: recent data demonstrate its bioactivity in
nanometric doses when derived from phytochemicals in food – and this demonstrates
how it can be difficult to evaluate the synergy, or even antagonism, of the
association between dietary components.17
The administration of antioxidants in smaller doses, but in combination, has been
asserting as the safest alternative for its use. Vitamin E acts in synergy with
vitamin C, which regenerates the radical tocopheryl, a product of alpha-tocopherol
oxidation.18
Supplementation with beta-carotene, this time associated with lycopene and a
probiotic, promoted the prevention of polymorphic light eruption in a study also
randomized.19 Similarly,
another randomized study, conducted with an association of vitamins A, C, E,
selenium, pomegranate extract, quercetin, green tea, coenzyme q10 and carotenoids,
such as lutein, lycopene and zeaxanthin, led to an improvement in the erythematous
dose and absorption levels of free radicals after 4 weeks of use.20
These findings suggest that the use of combinations of multiple antioxidant molecules
allows not only to amplify the antioxidant action in several sites but also to
obtain an amplified action, comparable to a monotherapy in high doses. For this
reason, each association should be ideally evaluated for its clinical
effects.21
MAIN INDICATIONS IN DERMATOLOGY
Photodamage
Currently, there is enough evidence to assert that all solar spectrum favors the
generation of free radicals; this generation possibly favors, to a greater or
lesser extent, photoaging, photoimuniosuppression and
photocarcinogenesis.22
Ultraviolet (UV) radiation, in its UVB range (290-320 nm), is responsible for the
immediate damages of solar radiation, acting mainly on keratinocytes; UVA band
(320-400 nm), which induces cellular changes, particularly compromises
melanocytes and fibroblasts.
In addition to consuming antioxidant systems, UV damage leads to inflammation,
and neutrophil infiltrate activates NAD(P)H oxidase, generating ROS that alter
the production of keratinocytic cytokines.23,24
Use of antioxidants in the prevention and repair of ultraviolet photodamage is
widely studied, being the most known and used indication. Association of
antioxidant molecules, from vitamins to phytoextracts, in photoprotectors and
moisturizers with appeal against aging, is frequent.25-27
A study with the objective of proving the efficacy of an association of
antioxidants with trace elements and glycosaminoglycans in a randomized control
study showed clinical improvement of signs of photoaging after 3 months of
use.28
Oral use of antioxidants does not dispense the use of sunscreens and is therefore
a second line of protection against UV photodamage even when they reduce the
appearance of solar erythema, such as Polypodium
leucotomos.29
Antioxidant action of this phytoextract not only occurs by the neutralizing
effect of ROS, blocking lipid peroxidation, but also by activating natural
antioxidant systems.
Although the indication of Polypodium leucotomos in our scenario
is for polymorphic light eruption, there is consistent evidence of its use in
other dermatoses as well as in photoaging.30
The combination of oral antioxidants at physiological doses recommended daily
intake (RDI) is also able to increase minimum erythemal dose levels (MED).
31
Regarding visible light (400-720 nm), it produces about 50% of the total
oxidative stress caused by sunlight. Reactive species such as O2– *
and * * OH CHR are generated by visible light.32
Although there is evidence of cutaneous carotene depletion induced by visible
light, use of topical or oral antioxidants, to reduce free radicals generated by
this range, has not yet been elucidated.33
Lutein, a carotenoid already used in ophthalmology in the treatment of macular
degeneration, has been associated with a protective effect of oxidative damage
from sunlight, particularly by visible light, by absorbing blue light.34
A double blind, placebo-controlled study compared the efficacy of oral
supplementation with topical application of lutein combined with zeaxanthin to
five parameters: epidermal lipids, hydration, photoprotective activity, skin
elasticity and lipid peroxidation under UV radiation. After 12 weeks, both
treatments improved these measures, and oral administration was superior, but
the combination (oral and topical) provided the greatest protection.35
More recently, studies have shown that thermogenic infrared radiation is also
capable of generating free radicals in human skin; its ambiguous effect, since
it is also used therapeutically, depends on two distinct mechanisms: the NF-kB
signaling pathway is responsible for the therapeutic effects, whereas the AP-1
pathway is responsible for the pathological effects.29 AP-1 is responsible for the production of
metalloproteinases that promote collagen breakage, clinically inducing
wrinkles.36,37
The ability of infrared radiation to deeply penetrate favors the generation of
free radicals, as it can cause mutation in mitochondrial DNA.38
Some studies have been conducted with the objective of investigating which
antioxidants would be the most adequate for inhibiting the effect of this
radiation, using combinations of topical use of known molecules; a topical
combination of vitamins C, E, ubiquinone and grape extract showed positive
results in a comparative study.39
Aging
Concomitant with solar radiation and other environmental factors responsible for
oxidative phenomena, skin aging, as well as of all organs, is accompanied by the
decline of the endogenous antioxidant mechanisms.
Clinically, the findings of photoaging are the predominant, and it is difficult –
and often unnecessary in practice – to distinguish the impact of exogenous
factors on the chronological process, but it is known that the main finding of
intrinsic aging is cutaneous atrophy, by the reduction of epidermis, but,
mainly, by the decrease in the collagen content and other dermal
elements.40
In the intrinsic aging process, progressive damage to mitochondrial DNA occurs,
with increased ROS production, which causes cell aging and impairs protein
proliferation.41
The theory of aging from free radicals was developed in the 1950s; later, it was
observed that the cellular organelle responsible for the cellular metabolism,
the mitochondria, was the main generator of free radicals due to the cellular
respiration that occurs in it.42
In its reduced form, ubiquinol (coenzyme Q10) prevents this oxidative activity
and also regenerates alpha-tocopherol. Coenzyme Q10 is the only soluble lipid
antioxidant that animal cells can synthesize and for which there is an
appropriate enzymatic mechanism to regenerate it – which also declines over
time.43 Finally,
coenzyme Q10 has been shown to influence (by mechanism of gene induction) the
synthesis of key cutaneous proteins and to inhibit the expression of some
metalloproteinases, such as collagenase, by preserving the collagen content of
the skin.44
In skin aging, there is a progressive accumulation of proteins, DNA and modified
lipids, reinforcing the association between ROS and intrinsic aging.45
Among the multiple antioxidant mechanisms, SOD plays a central role in the
variety of reactive molecules it neutralizes. Although there is still no direct
correlation, animal models suggest that the lack of SOD leads to degenerative
changes with reduced collagen. Possibly, vitamin C would have a positive impact
on SOD reduction states preventing atrophy due to collagen
degradation.46
The most physiological protective effect against oxidative stress seems to be the
support to the endogenous system, using antioxidants normally present in the
skin. This strategy, however, should not be confused with the permanent use of
high non-physiological doses of isolated antioxidants, nor considered as a
substitute for adequate food.47
Melasma
Induced UV melanogenesis that occurs in melasma is amplified by increasing the
oxidation of dopaquinone; antioxidants such as vitamin C, which reduce
dopaquinone (DOPA), prevent the formation of free radicals.48
The induced UV inflammatory process also favors the increase of
melanogenesis.49
A clinical A clinical trial to study the endogenous the endogenous antioxidant
systems in patients with melasma demonstrating a significant consumption of
superoxide dismutase (SOD) and glutathione peroxidase. This result demonstrates
the rupture of the redox equilibrium.50
Oxidation is a process that may favor melasma, but the exclusive use of
antioxidants in its treatment does not seem to have a relevant effect.
Antioxidant molecules employed that have proven utility also have whitening
action by inhibition of tyrosinase (for example, ascorbic acid and ellagic acid)
or anti-inflammatory (for example, pycnogenol).51-53
Non-melanoma skin cancer
Generation of UV induced free radicals in the skin develops oxidative stress when
it exceeds the ability of natural defense: the only skin protection systems are
antioxidant enzymes and melanin, the first line of defense against DNA
damage.54
DNA absorbs ultraviolet light, whose energy can break its molecular bonds; most
of these breaks are repaired by enzymes present in the nucleus itself, however
the remaining damages generate mutations that lead to neoplasia.55
The two main actions of defenses that antioxidants can provide are in relation to
preventing the formation of free radicals or neutralizing the radicals already
generated.56
Epidermal antioxidant capacity is much higher than the dermal: catalase,
glutathione peroxidase and glutathione reductase systems were higher in the
epidermis than in the dermis – both the lipophilic antioxidants (tocopherol,
ubiquinol 9, etc.) and the hydrophilic ones (ascorbic acid and glutathione). The
stratum corneum contains both hydrophilic and lipophilic antioxidants. Vitamins
C and E, as well as glutathione (GSH) and uric acid, were found. Surprisingly,
they are not evenly distributed, but in gradient form, with lower concentrations
in the outer layers and higher concentrations toward the deeper layers of the
stratum corneum.57
It is also confirmed that the acute exposure of human skin to solar radiation
leading to oxidation can be prevented by previous treatments with antioxidants,
reducing the risk of carcinogenesis.58
In contrast, there is evidence that treatment with topical antioxidants after UV
damage can interfere with the cell cycle or apoptosis of damaged cells, not
bringing benefit or even potentiating the damage.59
Therefore, endogenous photoprotection with antioxidants is complementary to
photoprotection with sunscreens, and is currently the most adequate form of
photocarcinogenesis prevention, in addition to, of course, the photoprotection
behavior (seeking shadows, avoiding hours of greater sunshine, etc.).60
Psoriasis
There are consistent systemic signs of oxidative stress in patients with active
psoriasis: plasma levels of malonyldialdehyde (MDA) are significantly elevated,
suggesting the depletion of natural enzymatic and non-enzymatic antioxidant
systems and consequently the prevalence of peroxidation processes in cell
membranes and plasma lipid processes of circulating cells.61 Similarly, SOD is reduced in
erythrocytes of psoriatic patients.62
The inflammatory process itself in the lesion areas induces the formation of
reactive oxygen and nitrogen species.63
On the other hand, classic treatments such as phototherapy or methotrexate are
also capable of generating ROS and RNS.
However, the eventual use of antioxidants should aim to recover the redox
balance, leading to an anti-inflammatory effect, possibly by the activation of
antiproliferative and proapoptotic pathways, both in the local and in the
inflammatory cells.9
Alopecia
The possible benefit of the use of antioxidants in telogen effluvium will be
according to the underlying cause, especially when linked to systemic
inflammatory processes, but there is no direct evidence of any oxidative
mechanism directly linked to this tricose.
In alopecia areata, there is evidence of increased plasma SOD activity and in the
affected tissue, however the studies are still controversial.64
Other dermatoses
Many inflammation conditions demonstrate redox imbalance and significant
consumption of their antioxidant systems in local cells, such as atopic
dermatitis or burned skin, as well as in the scarring process, in which the
excess of ROS hinders dermal and epidermal repair, especially in the moment of
acute inflammation.65
Observational studies of melanoma patients demonstrate a correlation between the
lower incidence of the disease and the daily consumption of carotenoid and
vitamin C-rich tea and vegetables, as well as the high consumption (at least
three portions/week) of dark green vegetables rich in lutein; however, there is
no elucidation whether the antitumor mechanism involved would be
antioxidant.66
Polypodium leucotomos extract has demonstrated a complementary
effect on the limitation of melanoma cell growth, but the impact of the
antioxidant mechanism on this effect is unclear.67 There is also evidence of oxidative stress in
dermatoses such as vitiligo, lichen planus, acne vulgaris, seborrheic dermatitis
and pemphigus foliaceus, but there are no clinical studies demonstrating the
impact of the use of antioxidants in the control of these diseases, both oral
and topically.68-72
PRACTICAL ASPECTS ON THE USE OF ANTIOXIDANTS
Use of oral or topical antioxidants in the treatment of dermatoses basically seeks to
neutralize excess free radicals, reducing or preventing the attack on cellular
structures. As the preservation or reestablishment of the redox balance is the goal
in these situations, the use of antioxidants should always be in line with
treatments or other preventive measures, as in the case of
photoprotection.73
In this context, the use of concentrations close to the physiological ones is
preferential, since they adjust more easily to the cellular physiology, in addition
to reducing risks of toxicity or even of drug interaction with any drugs that the
patient uses. Effects of antioxidants can vary considerably depending on the
concentrations.74
It is important to note that the use of oral or topical antioxidants does not replace
a diet with fruit and vegetable consumption, in which the combination of the active
elements expands its effects, and does not involve any risk. Lycopene, for example,
readily found in tomato paste, ingested on the order of 55 g/day for 12 weeks, led
to a significant reduction of MMP-1 expression in a randomized controlled
study.75
Rich and varied diet should be encouraged in normal individuals; however, groups such
as patients after bariatric surgery, elderly, and people with dietary restrictions
may have vitamin deficiencies, in which reposition in physiological doses would be
indicated.
Use of antioxidants in long-term pharmacological concentrations should only be
considered in situations where there is a diagnosed need under
strict medical supervision.76,77
Association of antioxidants with complementary mechanisms allows a broader
neutralizing action, with adequate safety of use during the period of oxidative
stress – which can be from a simple sun exposure to extensive and acute phase
dermatosis.78,79
Use of supplements without indication, or ingested in high doses, or even for a
prolonged time can, in thesis, cause adverse events precisely in the physiological
antioxidative balance. Hence the importance of medical monitoring.11
It is important to highlight that, among the exogenous antioxidants available on the
market, the scientific evidence regarding the actual effect on skin cell lines is
varied.
Likewise, the proposed associations may have varied responses according to the
concentrations and molecules involved. The evaluation of clinical response should be
made in order to better understand the effects in relation to the proposed
indication.
Another important point is that the in vitro effect does not necessarily correspond
to the clinical effect, influenced by route of administration, level of
concentration in administration and target cell, level of degradation etc. lists the major antioxidants with
action on the skin by oral or topical administration and their mechanisms of
action.
Chart 1
Main molecules with antioxidant action, both topical and oral, of
prescription in Dermatology
| Molecule | Mechanism of antioxidant action |
|---|---|
| Vitamin E | Neutralization of singlet oxygen in the cell membrane; involvement with membrane stabilization, preventing lipid peroxidation – oxidation of unsaturated fatty acids, such as arachidonic acid from membrane phospholipids, which may lead to rupture of the cell membrane80,81 |
| Vitamin C | Extensive removal of free radicals and repair of oxidized vitamin E bound to the cell membrane82 |
| Polypodium leucotomos | Inhibition of UV induced ROS generation, including superoxide anion30,83 |
| Lycopene | Carotenoid of greater biological action in the neutralization of singlet oxygen84 |
| Lutein | Carotenoid that protects the fibroblasts from UVA-induced oxidative action, also preventing the decrease of the antioxidant enzymes catalase and superoxide dismutase (SOD)85,86 |
| Resveratrol | Inhibition of UV-induced oxidative and mutagenic action to DNA87,88 |
| Epigallocatechin gallate (green tea) | Flavonoid with broad scavenging action of free radicals, inhibiting the production of ROS and lipid peroxidation products, in addition to protecting the endogenous antioxidative systems89,90 |
| Lipoic acid | Repair of endogenous antioxidant systems, free radical neutralizer91 |
| Delphinidin | Inhibition of lipid peroxidation and formation of 8-hydroxy-2′-deoxyguanosine (8-OHdG), marker of oxidative stress to DNA and carcinogenesis92 |
| Coenzyme Q10 | Reduction of the production of free radicals and regeneration of vitamin E; reduction of keratinocyte DNA damage and UVA-induced metalloproteinase production in the fibroblasts; reduction of mitochondrial oxidative damage43,93 |
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