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Review
. 2023 Oct;97(10):2499-2574.
doi: 10.1007/s00204-023-03562-9. Epub 2023 Aug 19.

Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging

Klaudia Jomova  1 , Renata Raptova  2 , Suliman Y Alomar  3 , Saleh H Alwasel  3 , Eugenie Nepovimova  4 , Kamil Kuca  4 , Marian Valko  5
Affiliations
Review

Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging

Klaudia Jomova et al. Arch Toxicol. 2023 Oct.

Abstract

A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or "good stress" and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2-related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress ("bad stress"). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer's and Parkinson's diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.

Keywords: Aging; Antioxidants; Metals; Oxidative stress; ROS; Signaling pathways; Toxicity.

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Conflict of interest statement

We declare no competing interests.

Figures

Fig. 1
Fig. 1
Arrangement of electrons on antibonding π* orbitals of the various forms of molecular oxygen. Radical species containing unpaired electrons are dioxygen and superoxide radical anions. Unpaired electrons are marked as red dots
Fig. 2
Fig. 2
Redox metal-catalyzed Fenton reaction and interaction of redox metals, (copper or iron) with carbonate resulting in the formation of carbonate radical anion (CO3·−). CO3·− can also be formed alternatively starting from the interaction of superoxide radical (O2·−) and nitric oxide (NO·) forming peroxynitrite (ONOO−) which in turn reacts with CO2 finally forming CO3·−. Both CO3·− and ·OH can cause DNA damage
Fig. 3
Fig. 3
The first steps of the lipid peroxidation pathway
Fig. 4
Fig. 4
Main cellular sources of ROS formation
Fig. 5
Fig. 5
Concerted action of Glutathione peroxidase-1, Catalase, and Superoxide dismutase
Fig. 6
Fig. 6
Radical scavenging activity of vitamin C (ascorbic acid). Vitamin C is present under physiological conditions predominantly in the form of an ascorbate anion, AscH−. Following its reaction with radical R·, the hydrogen atom is abstracted from AscH−, and radical AscH· is formed. AscH· is afterward transformed to a more stable ascorbyl radical Asc·−
Fig. 7
Fig. 7
Reaction of vitamin E (α-TOH) with hydroxyl radical resulting in the formation of radical of vitamin E, tocopheryl radical (α-TO·)
Fig. 8
Fig. 8
Structures of reduced (GSH) and oxidized (GSSG) glutathione
Fig. 9
Fig. 9
Antioxidant network of the regeneration of vitamin E by vitamin C and glutathione (GSH). Standard one-electron reduction potentials increase in the order: EΘ (GSSG/GSH) =  − 264 mV, EΘ (Asc·−, H+/AscH−) = 282 mV; EΘ (α-TO·, H+/α-TOH) = 500 mV at pH = 7.4. Antioxidants with lower reduction potentials can regenerate antioxidants with higher reduction potentials
Fig. 10
Fig. 10
Protective role of GSH in the oxidation of protein -SH groups (Adapted from Valko et al. 2006)
Fig. 11
Fig. 11
Examples of carotenoid structures
Fig. 12
Fig. 12
Structure of a flavonoid quercetin and absorption bands of the benzoyl and cinnamoyl systems. (M = chelated metal ion)
Fig. 13
Fig. 13
Interaction of flavonoids with radical R· and regeneration of flavonoid radicals by glutathione (GSH)
Fig. 14
Fig. 14
Structure of ergothioneine (ERG)
Fig. 15
Fig. 15
Structure of melatonin
Fig. 16
Fig. 16
SOD Assay. Xanthine oxidase converts xanthine and O2 to uric acid and H2O2 and generates O2·− which reduces a tetrazolium salt (NBT) to a colored Formazan (NBT-diformazan)
Fig. 17
Fig. 17
Structure of OxiRed™ (1-(3,7-Dihydroxy-10H-phenoxazin-10-yl)ethanone)
Fig. 18
Fig. 18
Action of glutathione peroxidase (GPx) resulting in the formation of oxidized glutathione (GSSG) and regeneration of reduced glutathione (GSH) from oxidized glutathione (GSSG) by glutathione reductase (GR). This reaction uses NADPH as the reducing cofactor and maintains a constant level of GSH
Fig. 19
Fig. 19
Xanthine dehydrogenase (XDH) can be transferred to xanthine oxidase (XO) either irreversibly, by partial proteolysis, or reversibly, during the oxidation of thiols. XO transfers hypoxanthine to xanthine and then to uric acid, as the substrate is used oxygen. XDH maintains the same transformation, however, with NAD+ as the substrate. XDH and XO are collectively referred to as Xanthine oxidoreductase (XOR)
Fig. 20
Fig. 20
Myeloperoxidase catalyzes the reaction between hydrogen peroxide and chlorine ions to form hypochlorous acid
Fig. 21
Fig. 21
Pathways of lipid peroxidation: polyunsaturated fatty acids are susceptible to oxidation (reaction 1) resulting in the formation of carbon-centered radicals 1·. Carbon-centered radicals react with molecular oxygen to form peroxyl radicals at an internal position of fatty acid chain 2· (reaction 2) or at the terminal group 3· (reaction 3). Radical 2· can react by cyclization (reaction 5) to form cyclic peroxide which is then by another cyclization reaction (reaction 7) via an intermediate product (7) transformed (reaction 8) to malondialdehyde (MDA). Peroxyl radicals in the internal position (2·) can alternatively react by hydrogen abstraction (reaction 9) to form lipid hydroperoxides (-OOH). Hydroperoxides can further react with the redox metals [e.g. Fe(II)] to form alkoxyl radicals (RO·) which, following cleavage (reaction 11) may form pentane in the gaseous state, another marker of lipid peroxidation process. Peroxyl radicals located at the end of the conjugated system (3·) are reduced in the absence of redox metals to stable hydroperoxides (-OOH) (reaction 4)
Fig. 22
Fig. 22
Reaction of hydroxyl radical with guanine
Fig. 23
Fig. 23
Polyol (Sorbitol pathway) it is estimated that about one-third of glucose in the body is metabolized by this pathway
Fig. 24
Fig. 24
Structures of selected sirtuin modulators
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