Lab Notes

Antioxidants: The What, Why, and How?

We talk a lot about the important of antioxidants. In this lab note we explain exactly what they are, why they are important, and how they work in the skin.

What are antioxidants?

Environmental aggressors like UV and pollution trigger the defensive immune response in our body which causes the increased formation of free radicals. Free radicals are unstable and highly reactive molecules that steal electrons from other molecules — damaging DNA, intracellular proteins and the extracellular matrix in the process. This creates oxidative stress in our cells leading to the appearance of wrinkles, dry skin and dark spots, all of which are signs of premature skin aging. Antioxidants are naturally occurring and sometimes synthetically-made substances that protect our skin from oxidative damage. Antioxidants combat free radicals and reverse their effects by essentially donating electrons to neutralize them or stop them from forming in the first place. One of the most effective ways to prevent UV-induced free radical damage is to apply broad-spectrum sunscreen daily to protect our cells from the negative effects of UVA and UVB radiation. 

In fact, our body is constantly trying to maintain the delicate balance between the levels of free radicals and antioxidants that are naturally produced in the skin. When that balance is lost, particularly having too many free radicals with an insufficient level of antioxidants (a natural part of aging), we may begin to notice inflammatory conditions in the skin such as eczema, acne, hyperpigmentation, or even skin cancers. This is why in addition to sunscreens, we also recommend serums and creams that are formulated with antioxidants. The goal of antioxidants in skincare is to boost oxidative capacity in our cells and ultimately provide powerful anti-aging benefits, which are often mediated by their anti-inflammatory and photoprotective properties. 

You’ll notice a common feature among the antioxidants found in skincare: the phenolic or polyphenolic ring structure. The phenolics are a class of compounds consisting of one or more hydroxyl groups attached to an aromatic hydrocarbon. The simplest form is phenol where a single hydroxyl group is attached to benzene, Fig 1. This distinct functional group imparts the organic mechanism behind the antioxidant activity of the compound when it encounters free radicals. Phenolic compounds can react with free radicals either by hydrogen atom transfer, transfer of a single electron, sequential proton loss electron transfer, or chelation of transition metals. (1) 

Formulating a product that contains antioxidants is a challenge because of their instability or tendency to degrade. The ingredients must be compatible with each other and contain an adequate amount of the actives in order to demonstrate a notable antioxidative effect. Another factor to consider is whether the product can penetrate the stratum corneum and confer biological activity. Furthermore, antioxidants are classified based on their chemical structure and key functions in the skin. Many products claim to have potent antioxidant power but we recommend looking for formulations that contain a combination of antioxidants as no single antioxidant can tackle all of your skin concerns. Sometimes you can predict the amount of an ingredient in a product based on the colour intensity and possibly scent!

What are the types of antioxidants?

Antioxidants are classified according to their chemical structure. Most of the naturally-sourced antioxidants found in skincare are either polyphenols or carotenoids, which are further divided into different subtypes. Epigallocatechin gallate (EGCG) from green tea and resveratrol from grapes are among the most common polyphenols used to boost hydration and prevent melanin synthesis. Lutein and β-carotene are carotenoids that act as vitamin A precursors to prevent collagen degradation and inflammation. Other antioxidants such as niacinamide and ubiquinone are not under either category, but they also offer potent anti-hyperpigmentation and anti-aging properties.


The phenolic compounds constitute a group of secondary metabolites in plants that exhibit a wide range of antioxidant behaviour when they are absorbed into the dermis. There are about 8000 different structures of plant phenolics, which could be further classified as flavonoid and non-flavonoid compounds. The chemical structure of flavonoid compounds is based on two aromatic rings that are connected by a bridge consisting of three carbons (C6-C3-C6), Fig 2. Subclasses of flavonoids include flavonols, flavones, flavanones, isoflavones, anthocyanidins, and flavan-3-ols. Flavonoids usually exist as glycosides (attached to a sugar) in the physiological state. (2) The non-flavonoid metabolites consist of the phenolic acids, lignans, stilbenes, tannins, and lignins. These antioxidants usually occur as complicated biopolymers. The plant phenolic compounds present a variety of colours from colourless to intense dyes. They are responsible for giving plants some of their vibrant colours such as red and violet. 

Tocopherol, commonly known as vitamin E, is an example of a non-flavonoid phenolic antioxidant used in skincare. It is often formulated with ferulic acid and ascorbic acid (vitamin C), a non-phenolic compound, in serums and sunscreens to maximize stability and photoprotection. Chemical modifications (e.g., esterification) of these vitamins yield derivatives with improved stability (= longer shelf life) and skin penetration. This is why you’ll find names like “magnesium ascorbyl phosphate” or “tocopherol acetate” in the ingredients list of your skincare instead of “ascorbic acid” or “tocopherol”. Tocopherol is widely known for its moisturization properties. You might also find it paired with resveratrol. (12) 


The carotenoids are a class of non-phenolic plant antioxidants that also play an essential role in skin health. Similar to the phenolics, carotenoids are pigments responsible for giving plants their bright red, orange and yellow hues. You’ve likely heard of carrots, pumpkins and bell peppers being rich sources of carotenoids. The chemical structure of carotenoids typically consists of a 40-carbon chain backbone composed of eight isoprene molecules. The alternating double bonds allow them to absorb light in the visible range of the electromagnetic spectrum. The two major subclasses of carotenoids are the carotenes, which are made up of carbon and hydrogen atoms, and the xanthophylls, which are oxygenated carotenes. (7) Colourless intermediates in the biosynthesis of carotenoids absorb light in the UV range of the electromagnetic spectrum. Phytoenes are the first compounds to be synthesized in this process, followed by phytofluenes. (8) Carotenoids are potent quenchers of singlet oxygen and scavengers of free radicals. 

Carotenoids are powerful antioxidants that neutralize free radicals, mainly reactive oxygen species (ROS), and are then destroyed. The antioxidant action of topical carotenoids, including phytoenes and phytofluenes, imparts an anti-aging and photoprotective effect in the skin. In vivo studies on human skin show that carotenoids are vital components of the synergistic chain in the antioxidative protective system and could serve as biomarkers for the overall antioxidative status. (7) The carotenes found in human skin include α-, γ-, β-carotene and lycopene and their isomers. The xanthophylls include lutein and zeaxanthin and their isomers. β-carotene and lutein are known as pro-vitamin A carotenoids, which play a critical role in the skin by acting as precursors for the production of retinoic acid. It is thought that retinoic acid stimulates keratinocyte proliferation and reduces inflammation and oxidation. It is also shown to enhance the penetration of other topical ingredients. (8) The antioxidant and anti-inflammatory properties of vitamin A are beneficial for treating acne, wound healing and preventing premature skin aging.

Carotenoids: Conversion to Vitamin A, Concerns for the Topical Use of Vitamin A during Pregnancy 

β-carotene is the most prominent member of the carotenoids. As a tetraterpenoid, it consists of a 40-carbon core with conjugated double bonds substituted with two β-ionone rings. Due to the extensive 9-conjugated double bond feature, β-carotene shows a major absorption peak in the visible spectrum with a maximum at around 450 nm. In biological systems, β-carotene is predominantly found in the trans conformation, which is the most suitable isomer as the precursor for vitamin A. (32) All-trans β-carotene, catalyzed by monooxygenase, yields 2 molecules of trans-retinal upon oxidative cleavage of the central 15,15’ carbon-carbon double bond. All-trans retinal is then enzymatically converted to all-trans retinoic acid and binds as a ligand to the retinoic acid receptor family, which regulates the transcription of genes that are involved in a variety of essential biological activities. (33, 34) 

Topical retinoids, a class of compounds that derive from vitamin A, are common actives used to treat acne. Tretinoin (an alternative term for all-trans retinoic acid) and retinol (a form of vitamin A that requires conversion at the cellular level to retinoic acid via a two-step oxidation process) are among the most common topical retinoids. (35) The teratogenic potential of tretinoin is of particular concern due to its similarity to isotretinoin, a recognized human teratogen with a distinct pattern of malformations. Published case reports have linked topical tretinoin use to retinoid embryopathy, but other studies that examined its use during the first trimester of pregnancy did not find an increased risk of major malformations or evidence of retinoid embryopathy. (35, 36)

Between 1983 and 2003, 106 pregnant women with first-trimester exposure to topical tretinoin were prospectively studied. Birth outcomes including pregnancy loss, major structural defects, and pre- and postnatal growth were compared to 389 women with no topical tretinoin exposure during pregnancy. There were no significant differences between the groups in the proportion of pregnancies ending in spontaneous abortion or infants with major structural defects. The groups were also similar in birth weight, head circumference and length of gestation. Interestingly, the prevalence of one or more retinoic acid-specific minor malformations did not differ significantly between the two groups. It was concluded that the exposure to topical tretinoin in the first trimester was not associated with adverse pregnancy outcome as there was no indication for increased risk for minor malformations that are consistent with retinoid acid embyropathy. (36) The role of topical retinoids in pregnant women remains controversial. However, until more data is collected from larger cohorts, physicians do not recommend the use of topical retinoids during pregnancy. (35)

Other Skin Antioxidants

There are several other antioxidants used in skincare that are not classified as polyphenols or carotenoids. An example of this is niacinamide (vitamin B3), another popular antioxidant vitamin for reducing hyperpigmentation and inflammation. Niacinamide is readily absorbed into the skin and is known for reducing fine lines and redness and yellowing of the skin. It inhibits up to 68% of the melanosome transfer from melanocytes to surrounding keratinocytes. The soothing effect of niacinamide and its ability to improve the skin’s barrier function makes it a suitable active for treating acne and rosacea. (11) Similarly, ascorbic acid is known for reducing dark spots and boosting collagen production. Ubiquinone, or coenzyme Q10, is a lipid-soluble antioxidant that is responsible for maintaining cellular energy and stimulating collagen production. (13) You will likely find Q10 in anti-aging serums and moisturizers used to improve skin elasticity and texture. Ergothioneine is an emerging antioxidant with an imidazole (histidine-derived) chemical structure containing thione and betaine. It is used in skincare with abilities to enable DNA repair in cells that are damaged by UV light and ameliorate UVA-induced skin aging. (30)

What structures in antioxidants correspond to their effect?

Phenols exhibit similar behaviour as alcohols, but due to the aromatic ring they form stronger intermolecular hydrogen bonds which enhance their water solubility and raise their melting and boiling points.

The antioxidant activity of phenolic compounds is associated with the conjugated double bonds and the presence of functional groups (e.g., hydroxyl, methyl, or acetyl groups) in the aromatic rings. The antioxidant ability center of flavonoids and phenolic acids is the phenolic hydroxyl group, hence, the number and position of phenolic hydroxyls are directly related to their antioxidant activity. (14) Specifically, the phenolic ring structures are responsible for ROS scavenging. (2) Phenols reduce the rates of oxidation by transferring an H atom from their hydroxyl (-OH) groups to the chain-carrying ROO* radicals. (15)  The methoxy and carboxylic acid groups of phenolics acids also carry antioxidant ability through electron donation, making them excellent quenchers of excessive free radicals. (14, 16)  

Carotenoids inhibit active free radicals by transferring electrons, donating hydrogen atoms to the radicals or attaching to them. (17) Since carotenoids have non-phenolic chemical structures, their antioxidant activity is primarily a result of conjugation from the alternating carbon-carbon double bonds, which causes electrons of the molecule to move freely within. This phenomenon is described as a resonance structure which is also observed in phenolic rings. Xanthophylls containing hydroxyl groups also participate in the antioxidant action of the compound similarly to phenolics. 

Fun fact: Light absorption is influenced by conjugation. Highly conjugated structures lead to brightly coloured compounds, but the greater the conjugation the darker the compounds will appear. 

Antioxidants as UV Absorbers: Pro-oxidants? 

The inherent conjugated structure of antioxidants enables them to absorb UV to different extents. In chemical assays, antioxidants are shown to significantly absorb light in the UVA (320-400 nm) and UVB (290-320 nm) regions. While antioxidants serve to decrease ROS formation, they could be rendered useless or even become pro-oxidants and increase ROS formation after absorbing energy from UV radiation. For example, silymarin has a dual role in UVA-exposed keratinocytes: it scavenges ROS and induces phototoxicity. This potentially creates photostability concerns in skincare products that contain such antioxidants. (25) Designing a skincare formulation is challenging for this reason because the instability of the ingredients could lead to adverse effects and decrease the product’s shelf life. A product may contain several antioxidants where some of them “resurrect” the “dead” antioxidants as a result of UV exposure. This is a common strategy used in sunscreens where antioxidants are added to also stabilize UVB filters such as octylmethoxycinnanamate. (26) Another technique is to chemically engineer active ingredients with structures that do not allow them for UV absorption. 

Fenton Reaction

While plant phenolics play a critical role in the regulation of redox homeostasis, they also have the capacity to become pro-oxidants and increase the concentration of ROS to undesirable levels. The antioxidant activity of flavonoids depends heavily on the redox properties of the phenolic hydroxyl groups, especially on those of the catechol or pyrogallol moieties. These structures are easily oxidized to semiquinones or quinones and add to the pro-oxidant tendency of the compound. (27) Additionally, the reduction of molecular oxygen to superoxide anion radical and Fe3+ to Fe2+ also causes pro-oxidant activities. This phenomenon is described by the Fenton reaction, which produces hydroxyl radicals (HO). Quercetin and myricetin are examples of antioxidants that show pro-oxidant activity with iron and hydroxyl radical species that are produced by the Fenton reaction. However, the myricetin-iron complex is able to exhibit antioxidant activity in the presence of ascorbic acid; pro-oxidant activities prevail in ascorbic acid-free systems. (27) While myricetin is able to substitute for ascorbic acid as a radical scavenger in this assay, it is less efficient on its own than together with the vitamin antioxidant. In a separate assay, caffeic acid, which also acts as an iron chelator, is demonstrated to have comparable radical scavenging ability as ascorbic acid. (28)

The most notable antioxidants that are also considered pro-oxidants include tocopherol, ascorbic acid and polyphenols such as EGCG and caffeic acid. Phenolics, in particular, display pro-oxidant effects in systems that contain redox-active metals such as copper and iron. The presence of these transition metals catalyzes the redox cycling and may lead to the formation of phenolic radicals which damage DNA and lipids. The flavonoids quercetin and kaempherol are shown to induce DNA damage and lipid peroxidation in the presence of transition metals. β-Carotene, though its chemical structure doesn’t contain a catechol or pyrogallol group, may lose its effectiveness as an antioxidant and become a pro-oxidant depending on the oxygen tension and its interaction with ascorbic acid.29 Besides the presence of transition metals, an excessive level of antioxidants also induces pro-oxidant activities.

Mechanisms of Action

Organic Mechanisms 

Antioxidants undergo several chemical reactions when they encounter free radicals, either through a predominant mechanism or through multiple mechanisms. These include hydrogen atom transfer (HAT), single electron transfer (SET), sequential proton loss electron transfer, or chelation of transition metals. (1,18) Phenolic compounds inhibit free radicals by transfer of a hydrogen atom from its hydroxyl group. When a phenolic antioxidant reacts with a peroxyl radical (ROO•), the transfer of a hydrogen cation from the phenol to the radical forms a transition state of an H-O bond with one electron. The fate of the antioxidant is influenced by the molecular environment. In vitro studies show tocopherol, caffeic acid and epicatechin are likely to undergo HAT, while resveratrol and kempferol are subjected to SET. (18)  

During inflammation, arachidonic acid is released from the cell membrane phospholipids and is transformed by either the cyclooxygenase (COX) or lipoxygenase (LOX) pathways. Polyphenols inhibit both pathways either by binding to the active site of the enzyme and disrupting the hydrogen bonding system, or by chelating metal ions that are required for the function of the enzyme. 

Most carotenoids have a characteristic symmetrical tetraterpene backbone. This linear 40-carbon structure is susceptible to chemical modifications like the addition of functional groups. The chemical basis behind the antioxidant action of carotenoids lies within the conjugated polyunsaturated chain, which is primarily responsible for inhibiting free radicals. The presence of hydroxyl groups in some carotenoids substantially modify their reactivity and antioxidant ability. Similar to phenolics, the fate of carotenoids is dependent on the molecular environment, with the potential to become pro-oxidants. (18) 

Carotenoids are characterized as excellent peroxyl radical scavengers. They have a high capacity for electron donation and act as antioxidant agents through three mechanisms: SET, formation of an adduct, and HAT. For example, β-Carotene reacts with NO2• via SET. In other cases, carotenoids undergo SET and then adduct formation or the other way around. The polyunsaturated chain of carotenoids attributes to their lipophilic character, which contributes to their role in protecting cell membranes and lipoproteins against peroxyl radicals. (18) 

Other antioxidants that don’t have a phenolic ring or polyunsaturated chain can also be effective ROS scavengers due to the presence of delocalized electrons in the resonance structure of the compound. Vitamin C undergoes HAT, the inactivation of singlet oxygen, and the elimination of molecular oxygen when it encounters ROO•. (18) 

Biochemical Mechanisms

At the macromolecular level, the result of antioxidation is to prevent photodamage and signs of premature skin aging. This is achieved by inhibiting the production of molecules that stimulate inflammation, apoptosis, melanogenesis and collagen degradation. Moreover, antioxidants promote the gene expression of molecules that retain moisture, boost collagen synthesis and keratinocyte proliferation. 

What is the difference between radical scavengers vs physical quenchers?

The terms “radical scavenger” and “radical quencher” describe different outcomes when an antioxidant reacts with a free radical. The proposed mechanisms of radical scavengers are HAT, single electron transfer followed by proton transfer (SET-PT), and sequential proton loss electron transfer (SPLET). (23)

Fun fact: Tocopherol is one of the most abundant radical scavengers in our skin, but it also has a higher pro-oxidant capacity when ascorbic acid is present. When designing a skincare formulation that contains both of these antioxidant vitamins, the structure of tocopherol is stabilized by the addition of ferulic acid. 

Radical Quenching

The term “radical quenching” usually applies to the neutralization of singlet oxygen (1O2). One of the mechanisms behind this is related to energy transfer and physical quenching. The quencher molecule deactivates 1O2 to the triple unreactive ground state, gains energy to a triple excited state, then readily loses this energy to the environment and returns to its original state. (24) Carotenoids are known for being physical quenchers of singlet oxygen, but they can also undergo chemical reactions with the free radicals they encounter. While physical quenching involves harmless thermal energy dissipation, chemical quenching involves the oxidation of carotenoids. The latter mechanism can produce a variety of aldehydic or ketonic cleavage products that contain a reactive carbonyl group - an example being β-cyclocitral, which triggers changes in the expression of 1O2-responsive genes leading to an enhancement of photo-oxidative stress tolerance. (37) In other words, chemical quenching of 1O2 by β-carotene generates oxidized metabolites with signaling functions that are able to stimulate photoprotective activities.

Chemical quenching, or scavenging, of 1O2 by carotenoids is believed to play a minor role in radical quenching compared to the physical mechanism. (24) Chemical quenching only occurs as a much slower process and leads to mainly carotene endoperoxides. (38) When the quencher molecule is oxidized after it reacts with 1O2, it is either consumed (= destroyed) or it must be enzymatically recycled, as in the case with ascorbate by glutathione. (24, 37) The reaction by which tocopherols and tocotrienols remove 1O2 is oxidized by singlet oxygen α-tocopheroxyl radicals, which can be recycled back to the active reduced form through reduction by other antioxidants such as ascorbate, ferulic acid, retinol, or ubiquinol. (39) A synergistic effect is also seen with quercetin and a number of antioxidants. After exerting its scavenging properties, quercetin is oxidized into reactive products such as semiquinone and quinone. These compounds can be recycled by antioxidants like ascorbate and glutathione. In fact, if ascorbate and glutathione levels are reduced in vivo, semiquinone and quinone can bind protein thiols and produce transient toxic compounds. (40, 41) Hence, the recycling of quercetin has an immunomodulatory effect. In most cases, the degraded quencher is replaced instead.24

 Abbreviations and Definitions




Activator protein 1; a transcription factor that regulates gene expression during an immune response


Programmed cell death, a process that is involved in the elimination of damaged cells or cancer cells, and aging


Proteases (enzymes which break down proteins) that initiate apoptosis

CD1a-expressing cells

Cells that contain the CD1a protein used for antigen presentation (immune function)


Cyclooxygenase-2; an enzyme that is expressed during an inflammatory response (pro-inflammatory)


A small protein that is secreted during an inflammatory response to facilitate cell signaling and immune function


A gene that is responsible for expressing filaggrin


Hyaluronic acid synthases; a group of enzymes responsible for the synthesis of hyaluronic acid


Heme oxygenase 1; an inducible enzyme that breaks down heme, contains antioxidant properties


Hyaluronidase; an enzyme that hydrolyzes and degrades hyaluronic acid (HA)


Interleukins; cytokines that are secreted in response to inflammation 


Inducible nitric oxide synthases; a group of enzymes that catalyze the synthesis of nitric oxide in response to inflammation


5-Lipoxygenase, an enzyme that is expressed during an inflammatory response (pro-inflammatory) 


A product of lipid peroxidation and biomarker of oxidative stress


Matrix metalloproteinases; proteinases that play a central role in wound healing and tissue remodeling


Natural moisturizing factors; molecules that are responsible for skin moisture retention


Nuclear factor kappa B; a transcription factor that regulates the expression of genes important for cell survival and cytokine production


Transglutaminase-1; an enzyme involved in providing strength and stability to the epidermis


Tumor necrosis factor alpha; a cytokine produced during inflammation to promote necrosis or apoptosis


An enzyme responsible for the synthesis of melanin



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