March 2025 Issue

Endogenous Antioxidants
By Heather Davis, MS, RDN, LDN
Today’s Dietitian
Vol. 27 No. 3 P. 24

Antioxidants An In-Depth Look at Their Form and Function

As with many ideas in the field of nutrition, the concept of antioxidants is often oversimplified by popular media in ways that run the risk of leaving out important details. When announcing the virtues of antioxidants in foods, for example, it’s common for the attention to be directed largely at bioactive compounds from plant-based foods, such as flavonoids and other phenolics. However, these bioactive compounds are like drops in the bucket in terms of their contribution to antioxidant activity in the body. The far more influential players are the endogenous antioxidants, encoded by our genes and assisted in their function predominately by multiple micronutrient antioxidants, and to a lesser degree, bioactive compounds.1

Another misconception about antioxidant science is that all free radicals or reactive species are bad for health in every instance. In reality, it’s all about balance. Many healthy, normal processes of metabolism require free radicals for optimal function. The immune system relies on potent reactive oxygen species (ROS) to defend host cells from invaders.2 ROS can also help regulate and mediate other life-sustaining processes, including cell differentiation, proliferation, and migration. They can activate genes, stimulate glucose transport into cells, and affect cell signaling in other helpful ways.2 The problem with these reactive species starts when they overwhelm the body’s ability to maintain redox homeostasis.

Yet another mistaken belief about antioxidants is that if a small dose is helpful, a large dose should be even more beneficial. As will be discussed more in this article, antioxidants have a dual nature, where higher levels or alternate environments may shift the antioxidant into a prooxidant.3

As every dietitian knows, living organisms are frequently exposed to oxidative stress and when this stress overburdens the body, it can damage nucleic acids, proteins, lipid membranes, and other compounds and structures. Reactive species come not only from molecular oxygen (ROS) but also from nitrogen (RNS), chlorine (RCS), bromine (RBS), and even some sulfur-derived varieties have been identified.3,4 Antioxidants are vital for maintaining redox balance in the body and when free radical levels rise, endogenous antioxidants are the first line of defense. Endogenous antioxidants work together with exogenous antioxidants to prevent free radicals from running amok.

Exogenous vs Endogenous Antioxidants
The body’s antioxidant defense system relies on both exogenous and endogenous antioxidants. Exogenous antioxidants come from the diet and include vitamins C, E, and B2; minerals selenium, iron, copper, zinc, and manganese 3; and bioactive compounds such as polyphenols, terpenoids, capsaicinoids, and glucosinolates, among others.5

News about antioxidants is likely to evoke thoughts of berries, coffee, herbs, and, of course, chocolate, due to the presence of bioactive compounds like flavonoids. Though there’s currently no strict consensus on the definition of bioactive compounds, they are considered by many to be secondary plant metabolites capable of impacting physiological processes in the human body without adding any direct nutritional benefit.6 Much research has been published to demonstrate their positive impact on disease risk at certain doses; however, there is ongoing debate about how this is to be reconciled with their notoriously poor bioavailability and tendency to be rapidly metabolized and excreted by the liver’s detoxification processes. Their impact on the microbiome may help answer some of these questions, though many remain.7

With the spotlight on bioactives, it’s sometimes easy to forget about the more powerful exogenous antioxidant contribution coming from foods’ micronutrients like zinc and selenium (found in both plant- and animal-based sources), as well as the dominant endogenous antioxidant systems these micronutrients are working hard to support.

In this article, we’ll shed some light on what endogenous antioxidants are all about, the latest science on how to support them through diet, and whether their direct supplementation is effective, safe, or even possible. We’ll also explore some paradoxes of antioxidants and what that means for practical nutrition recommendations, including supplemental forms of exogenous antioxidants.

Endogenous Antioxidants
Considered the main components of the largest and heaviest-hitting antioxidant systems in the body, endogenous antioxidants can be classified as either enzymatic or nonenzymatic. Among the more notable nonenzymatic varieties include metal-binding proteins, glutathione (GSH), uric acid, melatonin, and lipoic acid as well as bilirubin and polyamines.1,4

Nonenzymatic antioxidants work closely with enzymatic counterparts, which include superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), thioredoxin, and peroxiredoxins, among others.4 Both enzymatic and nonenzymatic antioxidants may require nutrients for synthesis and regeneration or as enzyme cofactors. Without those nutrients in balanced amounts, their function may become impaired. For example, nonenzymatic superstar antioxidant GSH requires amino acids cysteine, glutamic acid, and glycine for its structure. GSH also has an intimate relationship with vitamin C, where their dance together amplifies the antioxidant capabilities of each compound. 8 GR, which helps regenerate GSH, needs riboflavin; and GPx, which helps disable dangerous hydrogen peroxide, needs selenium.9-11 Genetics also plays a substantial role in endogenous antioxidant status, as genes encode for antioxidant enzymes, and impairment in the function of these antioxidants at the level of gene expression may exist regardless of dietary intake.1-4

GSH
GSH is considered by many to be the “master antioxidant.”12 It has a major impact on a broad range of cellular functions, including modulating numerous signaling pathways, gene expression, immune response, and influences fundamental elements of cellular adaptation to stress.9,12

As an antioxidant, GSH operates in a cycle with enzymatic partners GPx and GR. These enzymes facilitate the conversion of GSH into its oxidized form (GSSG) and then regenerate the reduced form (GSH) from GSSG. This cycle ensures a continuous supply of reduced GSH ready to go to work. They perform together in a team of antioxidant effort, assisted further by nutrient cofactors like exogenous antioxidant micronutrients C, B2, and selenium.9 A relatively recent addition to the antioxidant micronutrient scene, it wasn’t until 2014 that the evidence for riboflavin, or B2, as an antioxidant was considered more seriously by researchers. Riboflavin plays a key role in the GSH redox cycle through acting as a cofactor for endogenous antioxidant enzyme GR, but doesn’t stop there. Riboflavin also deactivates ROS through the conversion of the reduced form of riboflavin to its oxidized form, and may even help regulate gene expression of many other antioxidant enzymes.11

Glutathione S-transferases, though not specifically related to redox reactions, are another class of enzymes requiring GSH to help carry out important reactions in the liver’s phase II detoxification process that allow for removal of toxins and waste products from the body.9

SOD
SODs provide pivotal oxidative defense in the mitochondria. Because mitochondria take in over 90% of the oxygen used by cells, they are especially at risk for oxidative damage. SODs have been studied extensively for the critical role they play in endothelial and mitochondrial function, including participating in redox signaling to regulate many vascular functions. Impaired SOD activity has been connected to endothelial dysfunction, altered vascular tone, vascular inflammation, vascular remodeling, enhanced vascular permeability, and increased platelet aggregation, which contribute to various diseases such as atherosclerosis and hypertension.13 SODs may also impact other areas of health, including renal, hepatic, neurological, skin, and more.14

In addition, SODs can be classified into four groups: copper-zinc-SOD, iron SOD, manganese SOD, and nickel SOD. SODs require nutrients copper, zinc, and manganese for form and function, and genes encoding for SODs can dictate much about their function. Manganese SOD is the primary antioxidant enzyme in the mitochondria. The superoxide radical is one of the ROS produced in mitochondria during adenosine triphosphate synthesis and manganese SOD helps counter its effects. Once again, it’s all about the middle ground when it comes to manganese dosage, as both manganese deficiency and excess are associated with adverse metabolic effects.15

Although zinc is not involved directly in the enzymatic activity of copper-zinc-SOD, it’s required to maintain the protein structure.14

Catalase
Catalase is an antioxidant enzyme that mitigates oxidative stress by decomposing cellular hydrogen peroxide. Deficiency or malfunction of catalase has been associated with the pathogenesis of many diseases like diabetes, hypertension, anemia, vitiligo, Alzheimer’s disease, Parkinson’s disease, bipolar disorder, cancer, and schizophrenia.16

Catalase enzymes interact closely with SODs, and, like SODs, also have several different variations. The heme-containing catalase variety is the most widespread. There’s another manganese-containing catalase variety, which lacks the heme group. As you can tell from these basic descriptions, adequate availability of nutrients like iron and manganese will be important to support catalase function.16

Although iron is typically assumed to pose more of a risk for oxidative stress than a cure, iron deficiency may lead to membrane damage associated with free radical generation.17 Iron is required in the synthesis of heme, and heme-containing enzymes, like catalase, play a powerful role in combating oxidative stress throughout the body. Yet again, it may be all about dose.18

Metal-Binding Proteins
Trace metal elements are essential for enabling normal bodily functions, although a little bit will go a long way. Many trace metal elements combine with proteins in harmful ways and may increase the risk for development of CVD and other diseases. Specialized metal-binding proteins, protecting other vulnerable proteins, are another part of the first level of antioxidant defense in the body.19

Albumin, ceruloplasmin, metallothionein, transferrin, ferritin, and myoglobulin, are all considered types of metal-binding proteins, and all play a part in inactivating transition metal ions and curbing their tendency to drive oxidative stress and free radical formation.19 Metallothioneins are small, cysteinerich heavy metal-binding proteins that participate in a variety of protective stress responses. Although zinc itself has no redox capacity, it’s considered an important antioxidant agent due in part to its earlier described role in SOD structure, its ability to induce metallothionein expression, and influence GSH synthesis.14,20

Ceruloplasmin, a copper-containing ferroxidase, functions as an antioxidant in part by oxidizing toxic ferrous iron to nontoxic ferric iron. This helps prevent ferrous iron from participating in harmful reactions that generate free radicals via Fenton chemistry.21

Melatonin
More of a jack-of-all-trades than many might imagine, melatonin boasts an impressive array of antioxidant activities. It participates in direct detoxification of ROS and RNS and promotes several antioxidant enzymes while suppressing the activity of prooxidant enzymes. It has been effectively used in human trials to combat oxidative stress, inflammation, and cellular apoptosis. Melatonin may also play a part in chelating transition metals involved in the highly damaging Fenton and Haber-Weiss reactions, helping buffer formation of toxic hydroxyl radicals. Found in high concentration in the mitochondria, researchers suggest it be classified as a mitochondria-targeted antioxidant. Melatonin has also been found to reduce the toxicity of certain prescription drugs and even methamphetamine.22

The body makes melatonin from serotonin, which is in turn made from nutrient precursors and cofactors, including tryptophan, vitamin B6, vitamin D, and omega-3 fatty acids EPA and DHA.23

Alpha Lipoate
Lipoic acid, also known as alpha lipoate or alpha lipoic acid (ALA), is bound to certain proteins, which function as part of essential mitochondrial enzyme complexes involved in energy and amino acid metabolism. ALA is one of the most potent antioxidants endogenously synthesized by the body and can also be found in certain foods. It interacts with vitamins C and E and exerts a significant effect on tissue levels of reduced forms of other antioxidants, including GSH. ALA may also help inhibit toxic metal accumulation.24

The richest food sources of ALA are animal tissues with high metabolic activity such as the heart, liver, and kidney. Among the plant-based sources, some ALA is found in spinach, broccoli, tomatoes, peas, Brussels sprouts, and rice. However, consumption of ALA from food has not yet been found to result in detectable increases of free lipoic acid in human plasma or cells and dietary absorption is considered insufficient.24

Uric Acid
Perfectly illustrating the dual and paradoxical nature of many antioxidants, uric acid has been associated with both improved and worsened health outcomes. On one hand, uric acid correlates with the development of obesity, hypertension, and CVD; on the other hand, it may positively impact the central nervous system, particularly in conditions such as multiple sclerosis and Parkinson’s disease. While chronic elevations in uric acid are associated with increased stroke risk, acute elevations in uric acid may provide some antioxidant protection.25

Uric acid, a final product in the breakdown of purine nucleosides in humans, also appears to help prevent lipid peroxidation if vitamin C is also present.25

A Double-Edged Sword: Antioxidants’ Dual Nature
The devil may be in the dose when it comes to antioxidants. The hermetic effect of micronutrients in general has been abundantly demonstrated, where both deficiency and excess can cause detrimental effects and physiological (relatively lower) doses are beneficial, but higher doses may do damage.26 A similar principle can be applied to antioxidants, including bioactive compounds or phytonutrients.27

Multiple antioxidant micronutrients, including vitamin C, have been shown to take on prooxidative qualities in higher dosages.28 These riskier higher dosages are unlikely to be from antioxidants sourced from whole foods in a balanced diet with intake at physiological levels and more commonly appear with supplementation. According to research, the vitamin C plasma concentration, or tissue saturation (after oral intake) is around 70 to 85 μmol/L, or about 300 mg daily, with the RDA (75-90 mg) being much lower, and both easily met for most through dietary intake.28 In healthy people, amounts greater than the RDA do not appear to be helpful. The demand for vitamin C increases during lactation, with heavy physical exertion, in smokers, alcoholics, the elderly, and those suffering from hypertension and diabetes. For these individuals, needs may be closer to 120 mg per day. In addition to posing an oxidative threat, excess vitamin C can cause excessive iron absorption and impair the absorption of vitamin B12 and copper.28

Excessive vitamin E may also increase oxidative burden. Studies have shown a prooxidant effect of high-dose vitamin E supplementation that may explain the increase in mortality seen in higher-dose intervention studies.29

Zinc is yet another example in our long line of examples. Physiological or adequate levels of zinc have beneficial antioxidant or protective effects against free radicals and oxidative stress, but deficiencies or excess levels of zinc in the body may exert prooxidant effects, increasing oxidative stress.30

A Note About Vitamin A and Carotenoids
For some researchers, preformed vitamin A has earned antioxidant status, even if indirectly, through the role it plays in regulating the transcription of genes that drive the body’s antioxidant responses, including endogenous antioxidants. For other experts, they’re not as ready to grant vitamin A the antioxidant title, and it’s still up for debate.31

Provitamin A carotenoids are considered bioactive-derived antioxidants, though they’re less easily absorbed than preformed vitamin A and must be converted to retinol and other retinoids by the body to accomplish most of vitamin A’s biological activity. The efficiency of conversion of provitamin A carotenoids into retinol is highly variable, depending on factors like food matrix, food preparation, and one’s digestive and absorptive capacities. However, some evidence suggests that carotenoids and/or their metabolites may directly upregulate the expression of endogenous antioxidants and detoxification enzymes in the body.32

An acceptable level of dietary carotenoids for disease prevention has yet to be established, as they can behave harmfully as prooxidants if they accumulate to excess levels. Research indicates that humans are indiscriminate carotenoid accumulators, though it isn’t yet clear why.33 Carotenoids may also act as prooxidants by speeding up the radical chain reaction of lipid peroxidation when they react with oxygen radicals or lipid radicals under specified conditions.33

Endogenous Antioxidant Supplements
Understanding the risks, including, but not limited to, promotion of prooxidant activity, with high-dose micronutrient and/or phytonutrient dosage, it may be wise to take a “food first” approach to supporting exogenous antioxidant status, skipping the high-dose supplements.

But what about endogenous antioxidant supplements? The research offers mixed results.

GSH Supplements
GSH supplements, including oral reduced and liposomal forms, intranasal, transdermal, and intravenous forms have all been studied, though there is a lack of long-term studies in humans. Oral liposomal forms appear to be better absorbed than reduced forms.34 A modified version of topical GSH was developed called glutathione–cyclodextrin nanoparticle complex and one study showed it could increase blood cell levels of GSH.35 Some studies have reported occasional adverse reactions with supplemental GSH use, including skin-related, fatigue, and gastrointestinal upset, though results are inconsistent.36 N-acetylcysteine is a supplement believed to increase GSH levels by way of supplying limiting amino acid cysteine. However, concerns with NAC as well as oral GSH supplementation reference some animal studies suggesting they may accelerate growth of certain tumors, with more research needed.37,38

Genetic single nucleotide polymorphisms impacting GSH building and recycling enzymes can also influence the rate of GSH production from precursors like cysteine as well as impact the performance of intact GSH in the body. Supplementation may fail to overcome some of these limitations, if they exist.37,39-41

SOD Supplements
One study demonstrated the effective oral delivery of SOD without chemical modification or encapsulation. Authors noted antiaging efficacy of their highly stable SOD with evidence in organ, tissue, cell, and molecular levels from both in vivo testing and in vitro experiments.42 However, these results have not been replicated and other studies emphasize clinical evidence for SOD’s efficacy is limited and far from being demonstrated.43 Back to the discussion of hormetic effects, in some cases, the benefits of supplemental SOD are either murky at best or even harmful in exacerbating cell injury and death. Advanced understanding of optimal dosage to avoid these risks will likely take much longer to establish and will be required before SOD can be taken seriously as a therapeutic agent.43

Melatonin Supplements
As a supplement, melatonin is typically used to help improve sleep; however, melatonin receptors are found throughout the brain, adipose tissue, coronary arteries, pancreatic cells, myometrium, and testis, and likely have other complex effects beyond promoting sleep initiation. Researchers say that the effects of supplemental melatonin are not yet fully understood and could be expected to affect many physiological processes in unknown ways. Randomized trials show mixed results in terms of risk for adverse effects and great variability in the dosage used in trials may be partly to blame. Melatonin at doses of 1 mg to 10 mg has been shown to worsen glucose tolerance and insulin sensitivity compared to placebo in men as well as in pre- and postmenopausal women after a single dose and persisting after up to three months.44 Some studies have noted a genetic component to this tendency as well as the possibility that the timing of supplementation and meals may be helpful in attenuating this effect.45

ALA Supplements
Since food-sourced ALA is unlikely to have a significant impact on endogenous levels, the question of supplementation is of strong interest. High supplemental oral doses of free ALA (≥50 mg) significantly, yet transiently, increase the concentration of free ALA in plasma and cells. Pharmacokinetic studies in humans have found that only about 30% to 40% of an oral dose of a racemic mixture of R-lipoic acid and S-lipoic acid is absorbed. Oral ALA supplements are better absorbed on an empty stomach than with food and taking ALA with food (vs without food) decreased peak plasma ALA concentrations by about 30% and total plasma ALA concentrations by about 20%. In studies, a liquid formulation of R-lipoic acid was found to be better absorbed and more stable in the plasma, suggesting that it might be more effective than the solid form in the management of conditions like diabetic neuropathy.24

Research suggests that the highest tissue concentrations of free ALA likely to be achieved through oral supplementation are at least 10 times lower than those of other intracellular antioxidants, such as vitamin C and GSH. Free ALA is also rapidly eliminated from cells, so any increases in direct radical scavenging activity are unlikely to be sustained.

Though supplementation may boost endogenous levels, however transiently, some believe there may still be cause for caution. The chemical structure of biotin is similar to that of ALA and there’s some evidence that high concentrations of ALA may compete with biotin for transport across cell membranes. In animal studies, researchers noted that administration of high doses of ALA via injection to rats decreased the activity of two biotin-dependent enzymes by about 30% to 35%. However, it’s unknown whether this impact would translate to humans or how high oral doses may or may not behave similarly.46

Wrapping It Up: Recommendations for RDs
Endogenous antioxidants are the primary antioxidant systems involved in maintaining redox balance in the body; however, both exogenous and endogenous antioxidants work in interdependent synergy. An individual’s oxidative status is influenced by dietary or exogenous antioxidants, genetic factors directly impacting endogenous antioxidant enzyme expression and activity, and environmental factors adding reactive species burden over time. For supporting redox homeostasis in their patients and clients, RDs should recommend dietary-derived antioxidants as a primary nutrition intervention, as antioxidant supplements are relatively more likely to trigger undesirable hormetic effects driving paradoxical reactions that may increase oxidative stress. Ensuring broad micronutrient adequacy at physiological levels through a diverse and nutrient-dense diet is likely to be far more beneficial and less risky than administering high doses of any single supplemental antioxidant.

— Heather Davis, MS, RDN, LDN, is the editor of Today’s Dietitian. Her background includes nutrition research, education, integrative and functional clinical nutrition, and medical/technical writing and editing in the health sciences.

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