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Open access peer-reviewed chapter - ONLINE FIRST
Antioxidant and Prooxidant Functions of Carotenoids in Human Health: Trigger Factors, Mechanism and Application
Written By
Aisha Farhana, Yusuf Saleem Khan, Abdullah Alsrhani, Emad Manni, Ayman A.M. Alameen, Wassila Derafa, Nada Alhathloul, Muhammad Atif and Lienda Bashier Eltayeb
Submitted: 07 December 2024Reviewed: 09 December 2024Published: 16 January 2025
Carotenoids are plant-derived compounds that have numerous health benefits, encompassing disease protection, cardiovascular health, mental and physical development, etc. Carotenoids exert their effect by combating oxidative stress, scavenging free radicals and quenching singlet oxidants, hence an effective metabolic antioxidant. Recently, carotenoids have gained a debated interest, wherein research momentum diverges to understand their antioxidant as well as prooxidant functions. Research focuses on investigating the prooxidant function stemming from the ability of carotenoids to induce oxidative damage. Herein, we will discuss the general classification, structure and physiological reactions of carotenoids. The emphasis will lie in understanding the triggers and mechanisms that influence their antioxidant versus prooxidant ability. We aim to outline the likely conditions enabling their antioxidant and/or prooxidant activities. A thorough mechanistic understanding of these highly beneficial nutrients will provide a toolkit for preventing diseases in addition to treating diseases through their exclusive prooxidant abilities.
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Saudi Arabia
Yusuf Saleem Khan
Department of Anatomy, College of Medicine, University of Hail, Saudi Arabia
Abdullah Alsrhani
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Saudi Arabia
Emad Manni
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Saudi Arabia
Ayman A.M. Alameen
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Saudi Arabia
Wassila Derafa
Department of Chemistry, College of Science, Jouf University, Saudi Arabia
Nada Alhathloul
Department of Chemistry, College of Science, Jouf University, Saudi Arabia
Muhammad Atif
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Saudi Arabia
Lienda Bashier Eltayeb
Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Riyadh, Saudi Arabia
*Address all correspondence to: afarhana@ju.edu.sa
1. Introduction
Carotenoids are a class of over 700 fat-soluble pigments, primarily synthesized in plants, algae and certain bacteria and found in some animal products [1]. These lipophilic isoprenoid compounds contribute to the vibrant colors in plants and vegetables, ranging from yellow, orange to red hues [2]. About 20 carotenoids have been found in human blood and tissues, while about 30–40 carotenoids have been identified in the average human diet [3]. Carotenoids play various important roles in plant and animal physiology with significant benefits to human health due to their antioxidant properties [4, 5, 6]. This makes carotenoids the key bioactive molecules in various fields, including nutrition, medicine and biotechnology [7].
Carotenoids are usually thought of as antioxidants because of their ability to neutralize free radicals and lower oxidative stress, but in certain incidences, they may also behave as prooxidants [8, 9]. A number of variables, including chemical composition and concentration of the carotenoid, metal concentration, light exposure, the impact of other biological antioxidants and the intrinsic molecular structure of carotenoids, might influence this functional alteration [8, 10, 11]. Therefore, evaluating their impacts on health underlies the critical assessment of the overall context, which includes dose, environment and the presence of other chemicals [12]. They play essential roles in photosynthesis and photoprotection in plants while offering significant health benefits to humans. Carotenoids are broadly categorized into two classes: carotenes and xanthophylls [8]. Carotenes, such as β-carotene and lycopene, are purely hydrocarbon compounds, whereas xanthophylls, like lutein and zeaxanthin, contain oxygen [12]. These structural variations contribute to their diverse biological functions. In humans, certain carotenoids act as precursors to vitamin A, a crucial nutrient for vision and immune function [13]. They also exhibit potent antioxidant properties, neutralizing reactive oxygen and nitrogen species (ROS/RNS) and mitigating oxidative stress connected to chronic illnesses and aging [14, 15].
Carotenoids encompass major health benefits to human health [16]. Beyond their antioxidant properties, the bioactivity spectrum of carotenoids extends to its potential as prooxidant. Emerging research highlights the potential of carotenoids to reduce the risk of developing chronic illnesses including heart disease, age-related macular degeneration (AMD) and several types of cancer. Some important roles of carotenoids include improving cellular defense mechanisms, regression of malignancy, growth factor and inflammatory pathways modulation. Nonetheless, the effect underlies context-dependence, wherein, under certain conditions, carotenoids switch to prooxidant functions, especially when present in high concentrations or exposed to high levels of oxidative stress, such as in smokers. The scientific community is still debating on safe and effective dietary intake or supplementation of carotenoids because of their dual nature, which highlights the intricacy of their physiological activities. This chapter explores the dual roles of carotenoids, detailing their mechanisms as antioxidants and prooxidants, delving into the intricate dual roles of carotenoids and highlighting their mechanisms of action as both potent antioxidants and, under certain conditions, prooxidants.
2. Structural and biochemical foundations of carotenoids
The characteristic hues of carotenoids, which vary from yellow and orange to red, are attributed to a sequence of conjugated double bonds [1]. Within the molecule, these double bonds are usually organized either cyclically or linearly [17]. Since light in the visible spectrum is absorbed by the conjugated system of double bonds, carotenoids are crucial pigments of plants, algae and some microbes [18]. A long sequence of conjugated double bonds, usually organized in a polyene chain, is the primary structural characteristic of carotenoids. The π-electron cloud is extended along the molecule by this conjugation, which causes visible light to be absorbed and gives carotenoids their distinctive coloring [19]. Nonetheless, their electron-rich system makes them a subject of electrophilic attack, thereby imparting greater instability toward oxidation.
2.1 Molecular diversity and functional groups
Based on their chemical structures and functional groups, carotenoids are segregated into two main groups: carotenes and xanthophylls (Figure 1). As hydrocarbons, carotenes are devoid of functional groups with oxygen, solely harboring carbon and hydrogen atoms. This property differentiates carotenes from xanthophylls and also makes them lipophilic. Further classification differentiates carotenoids to be pro-vitamin A (α-carotene, β-carotene and β-cryptoxanthin) and non-pro-vitamin A (lutein, lycopene and zeaxanthin), depending on their ability or inability as precursors of vitamin A (Figure 1).
Figure 1.
Molecular structure of carotenoids. (a) Carotenes and (b) Xanthophylls. The efficacy of carotenoids as antioxidants dependent on the ability of these molecules to bind at the water/lipid interface.
Typical carotenoid examples include β-carotene, α-carotene and lycopene.
β-carotene: It is an efficient electron delocalization tetraterpene made up of 40 carbon atoms with 11 conjugated double bonds (Figure 1). The vivid orange hue of the compounds results from the absorption of visible light by its expanded π-electron system [20]. Its antioxidant qualities are also influenced by this delocalized electron network, efficiently neutralizing free radicals and quenching singlet oxygen [21]. β-Carotenes are present in sweet potatoes, pumpkins and carrots and are a precursor of vitamin A.
α-carotene: The structure of α-carotene is similar to that of β-carotene, except that it lacks one β-ionone ring [22]. It gives green leafy vegetables their yellow-orange hue and is found in large quantities.
Lycopene: Lycopene is a strong scavenger of free radicals due to its open chain polyene structure and absence of β-ionone rings, delineating them from other carotenoids like β-carotene. The linear configuration of conjugated double bonds improves its capacity to neutralize ROS and quench singlet oxygen [23]. Tomatoes, watermelons and pink grapefruits are rich sources of the red pigment lycopene.
Xanthophylls are often classified as lutein, zeaxanthin, β-cryptoxanthin, canthaxanthin and astaxanthin.
Being the derivatives of oxidized carotenes, xanthophylls have conjugated double bonds together with oxygen-containing functional groups like hydroxyl (∙OH) or epoxy (∙O∙) groups [24]. Oxygen atoms provide xanthophylls with special chemical characteristics and biological roles [17]. It makes up 10% of the carotenoids found in nature [25]. Typical xanthophylls include:
Lutein: Eight isoprene units make up the 40-carbon backbone of lutein, an unsaturated polyene hydrocarbon. Its unique structure and functional characteristics are attributed to the two hydroxyl groups that are joined to β-ionone rings [17, 26]. Lutein, which is concentrated in the macula of the retina and is necessary for eye health, is available from egg yolks, marigold flowers and green leafy foods.
β-cryptoxanthin: It contains 11 conjugated double bonds similar to polyisoprenoids (Figure 1). Structurally, it is a bicyclic compound with a hydroxyl group attached to the carbon at position 3 of one of its rings [20]. Retinol, or vitamin A, is produced by the metabolic conversion of β-cryptoxanthin in the human body and is essential for both eyesight and general health.
Zeaxanthin: Nine alternating conjugated double and single carbon bonds make up this extremely reactive and stable polyene molecule [15]. Zeaxanthins have hydroxyl-substituted ionone rings that cap each end of its carbon skeleton enhancing its solubility and biological use [26]. Because of its structure, zeaxanthin can efficiently interact with ROS, which helps to protect cells from oxidative damage and preserve eye health, especially by blocking damaging blue light in the macula [27]. Zeaxanthin is often found in orange peppers, spinach and maize. It is considered an essential carotenoid for maintaining vision and A.
Astaxanthin: This xanthophyll is made up of two terminal rings of the β-ionone type that are joined by a polyene chain. This ketocarotinoids contain β-ionone ring with hydroxyl group (∙OH) at both ends of the molecule and an asymmetric carbon at the 3,3′-position [28]. The ring structure also has oxygen as hydroxyl (∙OH) and keto groups (C〓O) [29]. Its strong antioxidant qualities and functions in the biological systems are facilitated by special structural arrangement [30]. Astaxanthin is a red pigment found in seafood, such as lobster, shrimp and salmon, flamingos and crustaceans that gives them pink color.
2.2 Physiological relevance of carotenoids in human metabolism
The chemical and physical properties of carotenoids dictate their functional role in human metabolism, serving both as antioxidants and precursors to vital biomolecules (Figure 2). β-Carotene, for instance, is converted into vitamin A, which is critical for vision, immune function and cellular differentiation. Carotenoids, lutein and zeaxanthin are concentrated in the retina, particularly the macula, where they prevent oxidative damage, thus supporting eye health and reducing the risk of age-related macular degeneration (AMD) [31]. Additionally, carotenoids have been linked to improved cardiovascular health by reducing lipid oxidation and enhancing endothelial function [32].
Figure 2.
Overview of physical and chemical properties of carotenoids and functional roles.
Carotenoids undergo several key biochemical pathways in human metabolism. Once ingested, carotenoids are absorbed in the intestine, aided by dietary fats and bile salts and incorporated into chylomicrons for transport via the lymphatic system. β-Carotene is enzymatically cleaved by β-carotene-15,15′-dioxygenase in the intestine to yield retinal, which can be reduced to retinol (vitamin A) or oxidized to retinoic acid [33]. These metabolites are indispensable for vision, epithelial cell differentiation and immune regulation, and their deficiencies are linked to conditions like xerophthalmia and increased susceptibility to infections [34, 35, 36]. Non-provitamin A carotenoids, such as lutein and zeaxanthin are concentrated in the macula and create the macular pigment optical density (MPOD) [36]. They reduce oxidative stress and function as blue light filters, which lowers the risk of AMD [36].
Carotenoids play a pivotal role in modulating critical signal transduction pathways that regulate cellular responses to oxidative stress, inflammation and growth regulation. Key pathways influenced by carotenoids include nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) [37]. Through Nrf2 activation, carotenoids, such as lycopene and astaxanthin enhance the expression of antioxidant and detoxifying enzymes, strengthening the defense against oxidative damage. Simultaneously, carotenoids inhibit NF-κB signaling, which reduces the expression of pro-inflammatory cytokines and mitigates chronic inflammation [38]. NF-κB also governs genes associated with embryonic development, skin and bone health and the central nervous system. Specific interactions of carotenoids with signaling pathways such as PI3K/Akt, Wnt/β-catenin, MAPK, JAK/STAT, mTOR, TGF-β and Hedgehog have been well-studied [39, 40, 41, 42]. These pathways are pivotal in regulating cellular stress, growth, metabolism, embryonic development, immune responses, inflammation and the inhibition of cancerous proliferation. By modulating these cascades, carotenoids exhibit remarkable therapeutic potential in the prevention and management of chronic diseases, including cancer, cardiovascular disorders and neurodegenerative conditions, thereby maintaining metabolic homeostasis.
Carotenoids also have the potential to activate nuclear hormone receptor pathways such as retinoic acid receptors (RAR), retinoid X receptors (RXR) and peroxisome proliferator-activated receptors (PPARs) [43, 44]. Both in vitro and animal studies have connected Nrf-2, a transcription factor that activates antioxidant response elements, to carotenoid-mediated oxidative stress reduction [45, 46]. When activated, Nrf2 upregulates the expression of antioxidant enzymes, including glutathione peroxidase, SOD and catalase [47]. These enzymes work synergistically with carotenoids to reduce oxidative stress, mitigate inflammation and protect cellular structures, including lipids, proteins and DNA, from oxidative damage. Carotenoids also play important roles in apoptosis, cellular proliferation, metabolic inflammation and tumor growth. The RAR and RXR receptors also regulate the expression of several genes associated with immunological function and cellular development [48]. Furthermore, RXR/PPARs have been linked to adipocyte differentiation [49]. Studies have also shown that carotenoids activate PPARγ and Nrf-2 [47].
Additionally, carotenoids contribute to cellular communication by enhancing gap junctional intercellular communication (GJIC), a process crucial for maintaining tissue homeostasis and regulating cell growth [50]. It has been particularly demonstrated that carotenoids like β-carotene increase the expression of connexin proteins, which are the structural elements of gap junctions [50]. GJIC is strengthened by this regulatory mechanism, which can subsequently stalls tumor growth through unregulated cell division [51]. The capacity of carotenoids to repair and enhance GJIC underlies their function in preventing cancer and their wider significance in preserving cellular integrity.
2.3 Redox potential and reactivity: The basis of dual functionality as antioxidant and prooxidant
The dual roles of carotenoids as antioxidants and prooxidants are dictated by their redox potential and chemical reactivity (Figure 2). The ability to donate or take electrons in redox processes is a result of the redox potential, which is inherent in their conjugated structure of double bonds [52]. Carotenoids are antioxidants that stabilize free radicals and efficiently quench singlet oxygen by donating electrons or hydrogen atoms; this antioxidant effect is more obvious during mild oxidative stress [41]. Their redox potential is usually within a range conducive of scavenging ROS, which makes them effective at maintaining cellular redox homeostasis. Carotenoids may, however, behave as prooxidants in some instances, adding to oxidative stress. Carotenoid-derived radicals can emerge when the antioxidant action of carotenoids is destabilized by high concentrations of carotenoids, low or high oxygen tension and environments with enhanced ROS [52]. These radicals worsen cellular oxidative damage by interacting with cellular macromolecules and spreading lipid peroxidation. Additionally, the presence of transition metals like iron or copper and prolonged exposure to UV or blue light, can change the redox state of carotenoids, shifting the balance in favor of prooxidant activity [53]. The delicate balance between prooxidant and antioxidant functions is further highlighted by the fact that their oxidative metabolites and coexistence with pre-existing lipid peroxides can enhance prooxidant effects. This dual functionality emphasizes the significance of context such as concentration, oxygen availability and degrees of oxidative stress in deciding whether carotenoids have a protective or detrimental effect on biological systems.
2.3.1 Antioxidant effects of carotenoids: Guardians against oxidative stress
Carotenoids are powerful antioxidants, acting through mechanisms like scavenging reactive species, electron transfer, hydrogen abstraction, radical addition, metal chelation, quenching molecular oxygen and preventing lipid peroxidation. Their chemical composition, interactions with biological membranes and co-antioxidants like vitamins C and E influence their antioxidant activity. The quantity of conjugated double bonds and the type of substituents in the carotenoids, which include cyclic end groups, also influence the quenching activity.
Astaxanthin is ten times more powerful than lutein, canthaxanthin, and β-carotene. It helps stop lipid peroxidation in cellular membranes. [54]. Astaxanthin has scavenging capabilities against ROA, including superoxide anion (O-2) and hydrogen peroxide (H2O2) radicals. The natural astaxanthin found in shrimp shells has antioxidant properties that protect against non-physiological radicals [55]. Astaxanthin lowers ROS formation and reduces ROS in murine cone cell lines in a concentration-dependent manner. It boosts the activity of antioxidant enzymes and decreases MDA levels in human LS-180 colorectal cancer cells. In vivo, it protects the heart from oxidative stress, promotes anti-arthritic effects in rats and provides neuroprotection in the mouse brain [56, 57]. In HR-1 hairless mice, astaxanthin also prevents photoaging, demonstrating its wide-ranging protective benefits in a variety of models that have been investigated thus far [58]. Astaxanthin supplementation was demonstrated to dramatically lower oxidative stress indicators, such as MDA and ROS, in healthy people in clinical research [59]. Further, consumption of astaxanthin improved skin elasticity and reduced the effects of photoaging in those exposed to UV radiation [60]. These findings lend credence to broad-spectrum antioxidant activity of astaxanthin and its capacity to lessen oxidative damage in humans.
Alpha-carotene has shown efficacy in scavenging free radicals, thereby reducing lipid peroxidation in cultured human cells [61]. Supplementation with α-carotene dramatically reduced MDA, a hallmark of oxidative damage, subsequently increasing the activity of antioxidant enzymes including SOD and catalase. Many studies also demonstrate its function in cellular defense. In a clinical trial of people with metabolic syndrome, α-carotene supplementation was found to dramatically lower oxidative stress indicators, such as MDA and ROS metabolites [62]. Higher dietary consumption of α-carotene was linked to decreased oxidative stress and reduced risk of cardiovascular diseases in a Japanese people cohort, according to a study by Hozawa et al. [63]. These studies underscore the beneficial potential of α-carotene in reducing oxidative damage in humans.
β-Carotene is a precursor of vitamin A and illustrates the ability to scavenge free radicals like ABTS˙ + and ROS such as 1O2, ONOO, peroxynitrous acid (ONOOH) and NO2. Its scavenging activity underlies its location and orientation in biological membranes and isomerization states. The lipophilic nature of β-carotene facilitates its efficacy in the lipidic systems. β-Carotene supplementation is shown to decrease oxidative stress in smokers by lowering lipid peroxidation, confirming its protective function against oxidative damage [64]. β-Carotene is shown to increase skin elasticity and decrease UV-induced oxidative damage in humans [65]. This property is further supported by numerous experimental investigations. The capacity of β-carotene to prevent lipid peroxidation in liposomal membranes is dependent on its orientation and location inside the membrane, affecting its radical scavenging capacity [66]. Furthermore, β-carotene confers protection on vascular health by dramatically lowering ROS levels in human endothelial cells [67].
Lutein can scavenge ROS such as ABTS˙+, NO˙ and O2˙. In vitro studies demonstrate the inhibition of lipid peroxidation and scavenging of DPPH radicals [68]. Lutein supplementation in humans enhances antioxidant enzyme system and reduces oxidative stress, particularly in the liver and blood [69]. Lutein also offers protective effects against oxidative damage-associated diseases such as ovarian ischemia-reperfusion injury and cyclophosphamide-induced lung damage [70]. Several in vitro studies have demonstrated that lutein readily neutralizes the ABTS˙ + radical and subdues oxidative stress markers in biological systems. In animal models, lutein has been shown to enhance catalase and SOD activities, while reducing oxidative damage in liver and lungs. In rats with ovariectomies, lutein supplementation raised blood glutathione levels and decreased lipid peroxidation [71]. Lutein supplementation enhances cognitive performance in older persons, especially in domains like memory and attention. fMRI studies have demonstrated that lutein has neuroprotective benefits via increasing brain activity and connection [72].
Lycopene is extremely effective in neutralizing ROS, that is, 1O2, O2˙ and HO˙. It demonstrates greater effectiveness in preventing oxidative damage and scavenging ROS. Lycopene demonstrates greater capacity to quench ROS, reduce ROS formation driven by light exposure in murine cone cell lines, prevent hemoglobin oxidation and lipid peroxidation in human erythrocytes [73]. Additionally, studies show that lycopene protects rats exposed to hepatotoxic chemicals such as aflatoxin B1 and bisphenol A by lowering ROS and MDA levels and increasing total antioxidant capacity [74, 75]. In humans lycopene intake lowers oxidative stress, especially in cardiovascular and neurological disease.
Zeaxanthin, plentiful in dietary and marine sources, is essential for controlling the production of glutathione, enhancing redox equilibrium and reducing cellular damage brought on by H2O2. Zeaxanthin has strong action against hydroxyl radicals (HO•) and effectively scavenges ABTS˙ + and quenches singlet oxygen (1O2) [76]. Additionally, it interacts with oxidized LDL and shields the probe DHR 123 from ONOO− oxidation. Zeaxanthin is less efficient against tert-butyl hydroperoxide-induced lipid damage in human erythrocytes, but it does decrease APPH-induced lipid peroxidation and hemoglobin oxidation. Reduced MDA levels and increased activity of antioxidant enzymes such as glutathione, SOD and catalase are indicators of its protective benefits in acetic acid-induced colitis in rats, according to in vivo studies [77]. Zeaxanthin consumption may help prevent AMD and other oxidative stress-related disorders by lowering oxidative stress and concentrating in the macula, according to human research.
Hypoxic conditions reduce ROS production, thereby minimizing oxidative stress and aiding in cellular protection. Carotenoids such as β-carotene, lutein and lycopene display potent antioxidant activity by scavenging free radicals without transitioning into prooxidant states, more likely at higher oxygen levels. This function is critical for maintaining cellular homeostasis, particularly in oxygen-sensitive tissues like the retina. In this case, lutein and zeaxanthin, which are mostly found in the macula, protect against phototoxic damage by blocking ROS and lipid peroxidation. This keeps the metabolism in balance and keeps cells healthy in oxidative environments.
2.3.2 Mechanisms underpinning the antioxidant activity of carotenoids
Carotenoids interact with free radicals such as superoxide anions (O2− hydroxyl radicals (HO˙) and nitrogen-derived radicals, neutralizing them by electron transfer or by donating hydrogen atoms. For example, β-carotene scavenges the non-physiological ABTS radical cation (ABTS∙+) and neutralizes peroxynitrous acid (ONOOH), an oxidizing agent implicated in cellular damage.
Low oxygen tension and balanced dietary intake lead to the optimal antioxidant activity of carotenoids. Within physiological levels, carotenoids mitigate oxidative stress and inflammation, contributing to cellular redox homeostasis. However, excessive carotenoid concentration, especially in absence of any complementary antioxidant nutrients induces prooxidant effects that tips off the redox balance thereby worsening oxidative damage. Maintaining appropriate carotenoid levels is critical for preserving cellular integrity, preventing oxidative damage and sustaining metabolic health. Carotenoids carry out antioxidant mechanisms in the following ways:
2.3.2.1 Direct free radical scavenging
Carotenoids interact with free radicals such as superoxide anions (O2−), hydroxyl radicals (HO˙ and nitrogen-derived radicals, neutralizing them by electron transfer or by donating hydrogen atoms. As an example, β-carotene gets rid of the non-physiological ABTS radical cation (ABTS˙+) and neutralizes peroxynitrous acid (ONOOH), which is an oxidizing agent that is linked to cell damage. Lycopene, due to its extended conjugation, exhibits higher efficiency in quenching free radicals like hydroxyl radicals compared to other carotenoids [78].
2.3.2.2 Singlet oxygen quenching
Singlet oxygen (O2) is a very reactive type of oxygen that may seriously harm cells, inflicting oxidative damage. Through a physical process called energy transfer, the energy from singlet oxygen is transferred to the carotenoid molecule, quenching singlet oxygen [79]. By releasing the absorbed energy as heat, the carotenoid returns to its ground state and the singlet oxygen is changed into its less reactive triplet state [79]. Carotenoids, lycopene and astaxanthin are essential for avoiding lipid peroxidation and safeguarding cellular membranes because of their long chains of conjugated double bonds, which make them extremely effective quenchers of singlet oxygen. Carotenoids, like lutein or astaxanthin, neutralize the damaging reactivity of singlet oxygen by absorbing its excess energy and dissipating it as heat when they come into contact with it [5]. This method shields cellular structures against oxidative damage, especially in high-exposure organs like the retina, by preventing singlet oxygen from interacting with adjacent molecules like lipids and proteins.
2.3.2.3 Interaction with cellular antioxidant system
Carotenoids function synergistically with intrinsic antioxidant mechanisms. They augment the function of enzymes including SOD, catalase and glutathione peroxidase by diminishing ROS levels and preserving intracellular redox equilibrium [42]. This not only mitigates oxidative stress but also maintains the efficacy of other antioxidants such as glutathione. This emphasize the essential function of carotenoids in safeguarding against oxidative damage, preserving cellular integrity and alleviating chronic illnesses such as cardiovascular diseases, neurological disorders and certain malignancies (Table 1).
Function
Mechanism
Trigger factors
Examples of carotenoids
Examples of applications
Antioxidant
Neutralization of free radicals by donating electrons
Adequate oxygen levels, low ROS concentration
Beta-carotene, lutein, zeaxanthin
Prevention of oxidative stress-related diseases cardiovascular diseases, cancer prevention
Prooxidant
Generation of ROS under high concentrations or imbalance
High oxygen tension, excessive carotenoid intake, metal interaction
Beta-carotene, lycopene
Potential use in targeted cancer therapies (inducing oxidative stress in cancer cells)
Synergistic function
Interaction with other antioxidants (vitamin E, C) to enhance effects
Balanced diet with complementary nutrients
Astaxanthin, lutein
Dietary supplements and functional foods
Regulatory role
Modulation of gene expression pathways linked to redox balance
Genetic predisposition, environmental factors
Lycopene, beta-cryptoxanthin
Development of nutraceuticals for personalized medicine
Table 1.
Dual role of carotenoids in human health and influencing factors.
Further, carotenoids exhibit antioxidant action through direct and indirect mechanisms. Directly, they scavenge ROS and lipid radicals, mitigating oxidative stress (Figure 3). Indirectly, they influence cellular signaling pathways related to redox homeostasis, supporting the antioxidant defense system [80]. However, under certain conditions, carotenoids can also behave as prooxidants by interacting with oxygen or lipid radicals, amplifying the lipid peroxidation chain reaction (Table 1) [8].
Figure 3.
The diagram depicts the production and elimination of reactive oxygen species (ROS) in mitochondria, emphasizing the oxidative stress pathway. Molecular oxygen (O2) participates in successive redox processes, yielding superoxide radicals (O2−˙), hydrogen peroxide (H2O2) and hydroxyl radicals (OH˙), whereas singlet oxygen (1O2) also plays a role in the generation of reactive oxygen species (ROS). Antioxidant defense systems encompass catalase, which catalyzes the conversion of hydrogen peroxide (H2O2) into water and oxygen, as well as vitamins C, E and β-carotene, which neutralize hydroxyl and singlet oxygen radicals, so averting oxidative damage. The equilibrium between reactive oxygen species (ROS) generation and detoxification in mitochondria is essential for cellular health; its disturbance may result in aging, degenerative illnesses and many pathologies.
The indirect antioxidant action of carotenoids involves their metabolites, such as electrophilic apocarotenoids, which are cleavage products of parent carotenoids by β-carotene oxygenase 2. These apocarotenoids activate Nrf2, via specific signal transduction pathways [81]. Additionally, ketocarotenoids-oxidative metabolites of xanthophylls with α,β-unsaturated carbonyl structures – exhibit electrophilic properties that may also contribute to this process. The efficacy of carotenoids as biological antioxidants is influenced by their cellular and extracellular distribution, underscoring the importance of their bioavailability and precise interactions in mitigating oxidative stress.
2.4 Prooxidant activities of carotenoids: When protection turns to peril
Carotenoids though known for their antioxidant properties, can paradoxically exhibit prooxidant activities under specific conditions [8]. As discussed earlier, these effects are highly context-dependent [8]. The mechanism by which carotenoids induce oxidative damage is primarily linked to their ability to interact with metal ions, light and oxygen. When carotenoids are exposed to these factors, they may undergo photooxidation or redox cycling [82]. Herein, carotenoids absorb photons, transferring their energy to molecular oxygen, which then produces singlet oxygen or other ROS. Further, at elevated concentrations, carotenoids fail to scavenge free radicals efficiently, leading to the generation of reactive intermediates capable of inducing oxidative stress. This phenomenon is exacerbated under high oxygen tension, where the excessive carotenoid presence can result in autoxidation [83].
The extended conjugated polyene chains of carotenoids make them susceptible to oxidation in the presence of light or transition metals [18]. β-Carotene and lutein can react with molecular oxygen or metal ions to produce singlet oxygen and lipid peroxides. These oxidative reactions, instead of neutralizing free radicals, amplify oxidative damage to cellular components. ROS can initiate lipid peroxidation, damage cellular membranes and disrupt mitochondrial function, leading to apoptosis or necrosis. Redox cycling, on the other hand, involves the repeated oxidation and reduction of carotenoids in the presence of metal ions like iron or copper, which can generate ROS, contributing to cellular damage (Table 1) [8, 84]. Such prooxidant behavior highlights the importance of optimal concentration and environmental conditions to harness their protective effects while minimizing potential oxidative harm.
The process by which lipid peroxyl radicals (LOO˙) and ß-carotene (CAR) combine to generate a variety of carbon-centered radicals, including (LOO)−2.
CAR-(OOL)) (LOO) -CAR-OOL˙, LOO-CAR-OOL and LOO-CAR˙ is represented in equation:
Carotenoids can disrupt the balance between antioxidants and prooxidants in the body. While carotenoids like β-carotene are known to induce antioxidant enzymes under normal conditions, they can act as prooxidants when cellular redox states are altered, or when antioxidants like vitamin E are insufficient. This shift can cause an increase in ROS production, particularly when carotenoid levels are high. In certain pathological states, such as cancer or cardiovascular diseases, this prooxidant activity may accelerate disease progression by promoting inflammation, DNA damage and tumorigenesis. Understanding the delicate balance between antioxidant and prooxidant functions of carotenoids is essential for maximizing their therapeutic potential while minimizing adverse effects.
3. Redox dynamics of carotenoids: Molecular mechanisms
The redox dynamics of carotenoids are central to their dual role as antioxidants and, under specific conditions, prooxidants. These compounds can directly scavenge ROS and quench singlet oxygen, effectively neutralizing oxidative stress and protecting cellular components. Their ability to interact with free radicals is largely dependent on their conjugated polyene structure, which allows the delocalization of unpaired electrons [82]. This antioxidant activity is influenced by factors such as oxygen tension, carotenoid concentration and the presence of other antioxidants. At physiological levels, carotenoids stabilize redox balance, reducing ROS accumulation and preventing lipid peroxidation [82]. However, under high concentrations or in environments with excessive ROS, carotenoids may adopt prooxidant behavior, facilitating oxidative chain reactions [85]. This shift occurs due to their interaction with ROS or lipid radicals, particularly when the antioxidant network is overwhelmed or unbalanced. Thus, the redox dynamics of carotenoids are tightly regulated, emphasizing the importance of maintaining their levels within physiological limits to support cellular homeostasis and mitigate oxidative damage.
3.1 Key pathways of redox cycling and ROS regulation
Carotenoids regulate redox dynamics primarily through their ability to quench ROS and modulate redox homeostasis. They efficiently neutralize singlet oxygen (1O2) and other reactive species by undergoing redox cycling, which involves electron transfer, hydrogen abstraction or physical quenching [85]. For instance, lycopene exhibits high singlet oxygen quenching efficiency, while β-carotene and lutein scavenge free radicals via their polyene chains. This redox activity prevents lipid peroxidation, protein oxidation and DNA damage in cellular systems [82]. Additionally, carotenoids can act as prooxidants under high oxygen tension, generating reactive intermediates that influence oxidative stress depending on cellular context.
3.2 Crosstalk with cellular signaling pathways and gene expression
As mentioned in Section 2, carotenoids interact with key cellular signaling pathways to regulate antioxidant responses and stress signaling. They activate nuclear factor erythroid 2–related factor 2 (Nrf2), a transcription factor that upregulates genes encoding antioxidant enzymes like glutathione peroxidase, SOD and catalase [71]. This cascade enhances cellular resilience against oxidative damage. Simultaneously, carotenoids suppress nuclear factor-kappa B (NF-κB), reducing inflammation and ROS-mediated damage. Lycopene, for example, has been shown in human studies to inhibit NF-κB activity, decreasing pro-inflammatory cytokine production in metabolic syndrome patients [86, 87]. These molecular interactions underscore the dual role of carotenoids as both direct antioxidants and modulators of gene expression.
3.3 Apoptosis, autophagy and carotenoid-mediated oxidative modulation
Carotenoids influence apoptosis and autophagic responses of the cell, the two critical processes for maintaining cellular homeostasis. By alleviating ROS levels, carotenoids like astaxanthin provide protection against oxidative stress-induced apoptosis in neuronal cells, as demonstrated in in vitro and in vivo studies [88]. Under specific situations, carotenoids can induce apoptosis via activating oxidative stress pathways, as well as mitochondrial or death receptor-mediated pathways. This way, carotenoids trigger apoptosis in cancer cells, hence facilitating tumor reduction [89, 90]. Moreover, carotenoids control autophagic flow, enhancing the clearance of damaged organelles and proteins. Zeaxanthin demonstrates the potential to subdue autophagic indicators in oxidative stress models, hence enhancing cytoprotection [91]. This dual modulation underscores their function as redox-sensitive regulators in both health and illness.
Carotenoids restore cellular homeostasis under stress by controlling autophagy via pathways including AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) [92]. In clinical studies, dietary carotenoid supplementation has been linked to decreased markers of oxidative stress and apoptosis, especially in conditions such as cardiovascular disease and metabolic syndrome. Consequently, diets abundant in carotenoids have been associated with enhanced autophagic activity, particularly in older populations, potentially postponing age-related cellular deterioration [93]. This dual role in modulating apoptosis and autophagy underscores the importance of carotenoids as redox-sensitive regulators. Their context-dependent effects highlight their potential for therapeutic applications in managing oxidative stress-related diseases, including neurodegeneration, cancer and aging.
4. Translational applications of carotenoid bioactivity
Carotenoids hold significant promise in translational medicine owing to their antioxidant, anti-inflammatory and redox-regulatory properties, making them valuable for preventing and managing chronic diseases. Their ability to modulate apoptosis and autophagy positions them as potential adjuvants in cancer therapies, selectively targeting tumor cells while protecting healthy tissues.
4.1 Nutraceuticals and functional foods: Increasing dietary antioxidants
Because of their strong antioxidant qualities and related health advantages, carotenoids are being used more and more in functional foods and nutraceuticals. ROS can be scavenged and oxidative damage can be decreased by these bioactive chemicals, which are found in large quantities in fruits, vegetables and marine sources. Carotenoids such as lutein, β-carotene and lycopene are used in functional food formulations to enhance skin, eye and cardiovascular health. According to clinical research, diets high in carotenoid-rich foods increase blood antioxidant capacity and lower oxidative stress indicators. Drinks fortified with lutein have been demonstrated to increase the optical density of macular pigments, which may reduce the risk of AMD. These developments emphasize the importance of carotenoids in contemporary dietary therapies.
4.2 Therapeutic potential in managing oxidative stress-associated disorders
Carotenoids are regarded as adjunctive therapy owing to their therapeutic efficacy in addressing oxidative stress-related conditions, including cancer, neurological disorders and cardiovascular illnesses. Research has shown that lycopene decreases MDA, improves lipid profiles and mitigates oxidative damage in persons with metabolic syndrome. Astaxanthin may traverse the blood-brain barrier and mitigate ROS-induced neuronal damage, demonstrating neuroprotective advantages in conditions such as Alzheimer’s disease. Research indicates that β-carotene supplementation reduced oxidative markers and inflammation in individuals with rheumatoid arthritis, suggesting that carotenoids also affect inflammatory pathways. These therapeutic advantages endorse its potential application in adjunctive therapy methods.
Despite the fact that carotenoid supplementation has potential health advantages, its safety and efficacy warrant a careful evaluation in clinical contexts (Figure 4). Clinical research underscores the need for proper doses to mitigate prooxidant dangers and enhance therapeutic advantages. Furthermore, formulations that integrate carotenoids with synergistic nutrients, like vitamins C and E, have shown improved absorption and effectiveness. Research indicates that carotenoid-enriched soft gels normalize oxidative stress indicators in non-alcoholic fatty liver disease (NAFLD) without eliciting deleterious consequences. These findings highlight the significance of evidence-based methodologies in clinical practice.
Figure 4.
(A) Multifaceted roles of carotenoids in disease prevention, treatment and immunomodulation, including their effects on cancer, neurodegenerative and infectious diseases. (B) Mechanistic actions of carotenoids, such as antioxidant activity, anti-inflammatory effects, immune regulation and cell cycle modulation.
4.3 Bridging research and clinical utility
The incorporation of carotenoids into healthcare frameworks requires a multidisciplinary strategy, merging knowledge from molecular biology, pharmacology and clinical nutrition. Innovative technologies, including nanocarriers and bioengineering, are utilized to improve carotenoid bioavailability and stability, therefore expanding their therapeutic relevance. Furthermore, progress in omics technology enhances comprehension of individual reactions to carotenoid supplementation, enabling the development of individualized nutrition plans. Longitudinal investigations and extensive clinical trials are essential for determining the long-term safety, effectiveness and appropriate use of carotenoids in disease prevention and therapy (Figure 4). These advancements indicate a potential for the extensive use of carotenoid-based therapies in clinical and public health sectors.
5. Innovations and future directions in carotenoid research
Recent advances in carotenoid metabolism have brought attention to the intricate interactions that these compounds have with cellular signaling and redox mechanisms [4]. Targeted therapies that take advantage of these interactions to prevent chronic diseases linked to oxidative stress have been made possible by advancements in the use of mass spectrometry and isotopic tracers, nanotechnology and bioinformatics, which have also allowed for a deeper understanding of the in vivo conversion of carotenoids and their impact on cellular redox states [94].
5.1 Cutting-edge techniques for investigating carotenoid bioactivity
Investigation of carotenoid bioactivity has advanced due to sophisticated analytical methods that provide improved accuracy in elucidating their physiological functions. High-resolution mass spectrometry (HRMS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) have facilitated the precise identification and quantification of carotenoid metabolites in biological tissues. Moreover, the application of sophisticated imaging methodologies, including confocal microscopy, has enabled researchers to monitor carotenoid dispersion and localization inside certain cellular compartments in real time. These improvements have yielded novel insights into the interactions of carotenoids with lipophilic membranes, their impact on gene expression and their modulation of cellular processes. Methods like CRISPR-Cas9 gene editing and RNA sequencing have been utilized to investigate the molecular processes by which carotenoids affect cellular signaling pathways and metabolic networks, enhancing our comprehension of their therapeutic potential.
5.2 Future prospects: Personalized approaches in nutrition and therapeutics
Carotenoid research offers the potential for personalized nutrition and therapeutics as individual differences in carotenoid metabolism are becoming more recognized. Genetic polymorphisms in carotenoid-metabolizing enzymes can modulate the bioavailability and effectiveness of carotenoids [7]. Nutrigenomics is advancing to determine ideal carotenoid consumption levels based on an individual’s genetic composition and health state. Personalized carotenoid supplementation can be used in clinical practice to target specific oxidative stress-related conditions like cancer, AMD and cardiovascular disease [95].
In summary, carotenoids provide a double-edged sword in health management; hence, their advantages must be harnessed judiciously. By bridging the gap between basic research and real-world application, scientists and medical professionals can fully unlock the potential of carotenoids to prevent illnesses linked to oxidative stress and improve human health. Nonetheless, the realization of their full potential as therapeutic and functional agents depends heavily on strategic, evidence-based approaches. Future research should focus on uncovering the molecular mechanisms behind carotenoid redox dynamics, their effects on cellular signaling and gene expression and their therapeutic applications. Advances in biotechnology, nanotechnology and analytical tools will be pivotal in unlocking their full potential in health and disease management.
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Written By
Aisha Farhana, Yusuf Saleem Khan, Abdullah Alsrhani, Emad Manni, Ayman A.M. Alameen, Wassila Derafa, Nada Alhathloul, Muhammad Atif and Lienda Bashier Eltayeb
Submitted: 07 December 2024Reviewed: 09 December 2024Published: 16 January 2025
Open access peer-reviewed chapter - ONLINE FIRST
