Health Benefits and Toxicity Potential of Phytochemical Food Additives

Abstract

There have been increasing consumer preferences for foods and beverages prepared with natural additives. Regular consumption of functional foods that contain significant amounts of bioactive phytochemicals has been associated with a reduced risk of several types of non-communicable diseases. However, under certain circumstances, some phytochemical food additives and ingredients are known to be potentially toxic. This chapter will discuss various categories of phytochemical additives based on their chemical structural classes and mode of action, the claimed health benefits, and the potential toxicity of each class. It will also provide a review of the studies on important natural food additives that are used as preservatives, coloring agents, sweeteners and anti-caking agents. Finally, current challenges and future research directions for phytochemical food additives will be presented.

1. Introduction

The World Health Organization (WHO) defines food additives as substances that are added to food to maintain or improve food safety, freshness, taste, texture, or appearance [1]. It is reported that three-quarters of the western diet comprises various processed foods, with an individual consuming an average of 4–5 kg of food additives per year [2]. Furthermore, factors such as the evolution of human dietary patterns, globalization and civilization, have contributed to the high intake of food additives among populations in developing countries [2]. Based on their functional use, food additives can be classified into preservatives, food colorants, flavoring, texturizing agents such as stabilizers and emulsifiers, and nutritional additives [3]. Another classification for food additives is based on origin and manufacture. They are categorized as natural additives if obtained from animals or plants, synthetic or artificial additives, modified chemically from natural origin, which are similar to natural additives but are produced synthetically by imitating natural ones [4]. Studies conducted in the past decade have reported toxicological effects associated with synthetic food additives. Research on monosodium glutamate, a synthetic flavor enhancing food additive, has shown that the compound displayed toxic effects on different organs and body systems. Osman and colleagues [5] evaluated the toxicological effects of monosodium glutamate in albino rats and the results showed that its chronic use caused hepatotoxicity, histopathological, histochemical, and biochemical changes in a dose-dependent manner. Monosodium glutamate has also been reported to affect adipose tissue and reproductive organs and causes a metabolic disturbance with an increase in insulin, fatty acids and triglycerides in the serum as well as an increase in the several genes expression that involves adipocytes differentiation [6]. Artificial sweeteners such as aspartame and saccharin that are used as sugar substitutes in soft drinks and a wide range of food products have been linked to many hazards. Studies conducted on artificial sweeteners in the last years have indicated that the repeated use of artificial sweeteners even at the permitted level of Food and Drug Agency (FDA) could lead to alteration in the oxidant and antioxidant balance causing oxidative stress and potential toxicity [7]. The potential toxicity of synthetic sweeteners in the body include hepatotoxicity, nephrotoxicity, cytotoxicity, immune disorders, genotoxicity, and cancers [7]. Therefore, literature works that have examined the various effects of food additives on human body have shown that synthetic food additives react with the cellular component of the body leading to various harmful health effects.

Recently, there is a growing interest in dietary additives derived from phytochemicals as an alternative to synthetic substances. Consumer preference studies have shown that most users prefer food prepared with natural additives rather than chemical ones due to the perceived safety of the natural products [4]. Phytochemicals are natural products produced as secondary metabolites and are the bioactive non-nutrient plant compounds found in fruit, vegetables, grains, and other plant foods [5]. It is estimated that over 5000 phytochemicals have been identified from more than 150,000 of the edible plants on the earth [5, 6]. The secondary metabolites can be non-digestible carbohydrates and compounds such as lignin, resistant protein, polyphenols and carotenoids, some of which are considered anti-oxidants while others display anti-microbial activities [8]. Generally, phytochemicals are categorized into five main groups; carotenoids, phenolics, flavonoids, organosulfur compounds, and alkaloids [9]. However, polyphenols, alkaloids and carotenoids represent the major and main compounds of these phytochemicals [4], hence the focus of this review. Thus, the objective of this chapter is to discuss various categories of phytochemical additives based on their chemical structures and mode of action, the claimed health benefits, and the potential toxicity of each of the selected classes.

2. Classes of phytochemical food additives

The dietary phytochemicals found in fruits and vegetables can be classified as carotenoids, phenolics or polyphenols, alkaloids, nitrogen-containing compounds, and organosulphur compounds [9]. This chapter will focus on the chemistry, health benefits and potential toxicity of the most studied phytochemicals: phenolics or polyphenols, alkaloids and carotenoids.

2.1 Polyphenols

2.1.1 Chemical diversity of dietary polyphenols

Phenolics are compounds that have one or more aromatic rings bearing one or more hydroxyl groups and are widespread in flowering plants, occurring in all vegetative organs. They are the products of secondary metabolism derived from pentose phosphate, shikimate, and phenylpropanoid pathways in plants; and provide essential functions in the reproduction and the growth of the plants. They act as defense mechanisms against pathogens, parasites, predators and environmental stress [10]. Their structures range from that of a simple phenolic molecule to that of a complex high-molecular weight polymer and, despite this structural diversity, the groups of these compounds are often referred to as “polyphenols”. Phenolics are generally categorized as phenolic acids, flavonoids, stilbenes, coumarins, and tannins [9].

2.1.1.1 Phenolic acids

Phenolic acids consist of two subgroups: the hydroxybenzoic and hydroxycinnamic acids. Hydroxybenzoic acids have a common C6-C1 backbone structure directly obtained from benzoic acid and they include gallic, p-hydroxybenzoic, protocatechuic, vanillic and syringic acids [11]. On the other hand, hydroxycinnamic acids, are aromatic compounds with a three-carbon side chain (C6–C3), with p-coumaric, caffeic, ferulic, and sinapic acids being the most common. They are mainly present in the bound form, linked to cell-wall structural components, such as cellulose, lignin, and proteins through ester bonds and are abundant in fruits, vegetables, cereals and seeds. Figure 1 shows the chemical structures of selected phenolic acids found in various food plants.

Figure 1.

Chemical structures of some phenolic acids found in plants.

2.1.1.2 Flavonoids

Flavonoids are a large group of natural products found inside the cells or on the surface of different parts of plant organs and over 9000 flavonoids have been identified [12, 13]. The structure of flavonoids is based on the flavan nucleus with 15 carbon atoms arranged in 3 rings, C6–C3–C6, which are two benzene rings A, and B connected by a three-carbon, ring C [12]. The basic structure of flavonoids is shown in Figure 2.

Figure 2.

Basic structure of flavonoids.

Flavones, flavanones, flavanols, flavones, anthocyanins and isoflavones are the six main subgroups of flavonoids whose differences in structures are partly attributed to the pattern and degree of hydroxylation, prenylation, glycosylation or methoxylation [14]. Flavones are widely present as glucosides in leaves, flowers and fruits. Belonging to this subclass of flavonoids are luteolin, apigenin and tangeritin which have a double bond between positions 2 and 3 and a ketone in position 4 of ring C [14]. On the other hand, flavanones have a saturated ring C which differentiates them from flavones which have a double bond between positions 2 and 3 of ring C. Flavanones are also known as dihydroflavones, and examples include hesperetin and naringenin. Flavonols have a ketone on position 4 of ring C like flavones but unlike the flavones, they have a hydroxyl group in position 3 of the ring C. The diversity in methylation and hydroxylation patterns as well as the different glycosylation patterns, make the flavonols to be perhaps the most common and largest subgroup of flavonoids in fruits and vegetables [15]. Kaempferol, quercetin, myricetin and fisetin are the most studied flavonols with quercetin being the most widely distributed dietary flavonoid in fruits, vegetables, tea and wine [15]. Flavanols that have a hydroxyl group bound to position 3 of the ring C are referred to as to flavan-3-ols, also called dihydroflavonols or catechins. They are the 3-hydroxy derivatives of flavanones and are a highly diversified and multisubstituted subgroup. Unlike many flavonoids, there is no double bond between positions 2 and 3. Flavanols are found abundantly in bananas, apples, blueberries, peaches and pears [14]. Anthocyanins are a class of flavonoids that are water-soluble and commonly categorized into six groups cyanidin, delphinidin, malvidin, peonidin, petunidin, and pelargonidin. Isoflavones contain hydroxyl group on positions 7 and 4’ but differ from the other flavonoids in the position of benzene ring B in C3 [14]. The backbone structures of the described flavonoid subgroups and their corresponding examples are presented in Figure 3.

Figure 3.

Flavonoid subgroups and their corresponding examples.

2.1.1.3 Stilbenes

Stilbenes are a subclass of phenylpropanoids and have 1, 2-diphenylethylene backbone which consists of two aromatic rings of phenyl group linked by ethylene bridge. Some of the biologically active stilbenes include oxyresveratrol, pterostilbene, piceatannol, isorhapotigenin which are trans-stilbenes while resveratrol are the cis-stilbenes (Figure 4).

Figure 4.

Examples of biologically active stilbenes.

2.1.1.4 Coumarins

The basic structure of coumarins is the benzopyrone which is a fused benzene and pyrone ring system. Coumarins can be divided into five classes which are simple coumarins, pyranocoumarins, furocoumarins, dicoumarin, and isocoumarin (Figure 5).

Figure 5.

Chemical structures of simple coumarin and isocoumarin.

2.1.1.5 Tannins

Tannins are high molecular weight, water-soluble polyphenolic compounds with more than 20 hydroxyl groups and are categorized as hydrolyzable and condensed tannins depending on their structures and properties [16]. Hydrolyzable tannins contain a carbohydrate, generally D-glucose as a central core with gallotannins and ellagitannins as examples. On hydrolysis, gallotannins provide sugar and gallic acid while ellagitannins yield ellagic acid in addition to sugar and gallic acid. Condensed tannins, also called proanthocyanidins, consist of flava-3-ol units linked by carbon-carbon bonds and the linkage is between C-4 of one catechin (flava-3-ol) and C-8 or C-6 of the next monomeric catechin. The C-O-C linkages occasionally happen. There are several classes of proanthocyanidins due to variation in hydroxylation pattern with procyanidins as the most common class. The main components in green tea are epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG) and (−)-epigallocatechin gallate (EGCG) (Figure 6) which are largely responsible for the antioxidant activities and astringency on the tongue. Generally, the activities of EGCG and ECG are comparable in potency to the average activities of other tannins [16].

Figure 6.

Examples of dietary tannins.

2.1.2 Health benefits and mechanism of action of phenolics

Plant polyphenols constitute important components of the human diet and are known for their antioxidant activity, free radical scavenging abilities and the capacity to mitigate oxidative stress-induced tissue damage associated with chronic disease [17]. Furthermore, some polyphenols have demonstrated antibiotic, antidiarrheal, antiulcer, and anti-inflammatory activities. Figure 7 provides a summary of the biological activities of the polyphenols. Phenolic compounds can be extracted from natural sources such as olives, grapes, fruits, vegetables, rice, spices, herbs, tea, and algae [18]. These compounds are increasingly popular among consumers due to the fact that they come from natural sources and because they have health biological activities. Antimicrobial phenolic compounds have the capacity of retarding the microbial invasion in some products and avoiding the putrefaction of others, particularly fruits and vegetables. The antimicrobial activities of phenolic compounds are essential for various food preservation applications. Therefore, different kinds of food products can be fortified with phenolic compounds to improve their shelf life [18].

Figure 7.

Biological activities of polyphenolic compounds.

Several researchers have reported the mechanism of action of antimicrobial phenolic compounds. Maqsood et al. [11] studied the activity of polyphenols against microbial enzymes. The results showed that at low concentrations, polyphenols interfered with specific protein sites, whereas at high concentrations they caused denaturation of proteins. An earlier study showed that polyphenols interacted with microbial membrane proteins, enzymes and lipids, thereby altering cell permeability and permitting the loss of protons, ions, and macromolecules [17]. Additionally, it has been reported that polyphenols can cross the bacterial cells and interfere with nucleic acid synthesis thereby causing deformation in the structure and functionality of proteins of microorganisms [11].

In addition to antimicrobial activities, dietary polyphenols have exhibited remarkable antioxidant activities through scavenging numerous diverse reactive oxygen species (ROS) including hydroxyl radical, peroxyl radical, hypochlorous acid, superoxide anion, and peroxynitrite [19]. The in vitro cellular models used for characterization of the activities have included human prostate cells, colon cancer cells, hepatocytes, leukemia cells, breast cancer cells, and oral epithelial cells [20]. Some studies have elucidated their mechanisms of action, which included antioxidant effects, cardio- and hepatoprotective effects, anticarcinogenic effects, antimicrobial and antiviral effects, and anti-inflammatory effects [21]. The antioxidant activities of the polyphenols have largely been attributed to soluble or extractable phenolic compounds. However, some reports have suggested that nonextractable polyphenols such as polymeric proanthocyanidins and high molecular weight hydrolyzable tannins are 15–30 times more effective at quenching peroxyl radicals than are simple phenols [19]. Moreover, in vivo and epidemiological data show that low concentrations of the polyphenolic compounds seem adequate to exert potent protective antioxidant activity [20]. Scientific evidence and epidemiological studies have demonstrated that regular consumption of fruits and vegetables provides dietary antioxidants that can reduce cancer risk [22]. The study reviewed 200 epidemiological studies that examined the relationship between intake of fruits and vegetables and cancer of the lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary. The results showed that the consumption of fruits and vegetables was found to have a significant protective effect and it was further observed that the risk of cancer was 2-fold higher in participants with a low intake of fruits and vegetables than in those with a high intake. The benefit of a diet rich in fruits and vegetables could be attributed to the complex mixture of phytochemicals, particularly the polyphenols, present in these and other whole foods [20].

2.1.3 Potential toxicity of dietary phenols

Although most phenolic compounds are considered safe and with health benefits, some in vitro and in vivo animal studies have demonstrated that dietary polyphenols can exhibit many adverse effects on diverse biological systems [17]. For example, several flavonoids inhibit thyroid peroxidase, an enzyme that oxidizes iodide ions to form iodine thereby interfering with thyroid hormone biosynthesis and ultimately thyroid function. The elevated consumption of soy isoflavones has been associated with fertility reduction and retardation of sexual maturation while polyphenols exhibit antinutritional properties through the chelation of transition metals such as iron, which can lead to iron deficiency [23]. Research has also shown that some polyphenols may have carcinogenic or genotoxic effects at high doses or concentrations [24]. Caffeic acid, a phenolic compound synthesized by all plant species but mostly present in foods such as coffee, wine and tea was found to induce forestomach and kidney tumors in rats and mice when administered at 2% [25]. Furthermore, a plant-based antioxidant flavonoid, quercetin, was found to inhibit O-methylation of catecholestrogens and increased kidney concentrations of 2- and 4-hydroxyestrodiol by 60–80%. This suggested that quercetin could enhance redox cycling of catecholestrogens and estradiol-induced tumorigenesis [24] and that the genotoxic effects observed in vitro may be attributable to the high concentrations of the polyphenols. Another report indicated that the intake of green tea catechins at 1% or 0.1% of the diet enhanced tumor development in the colon of F344 male rats [21]. A study of the grapefruit showed that larger molecular weight polyphenols such as tannins can interact with proteins and inhibit several enzymes that are needed for growth [26]. As a result, high polyphenol intake may increase the risk of cardiovascular disease (CVD) through alterations in homocysteine processing of a biomarker for CVD [21]. The polyphenols, specifically naringenin grapefruit, have been associated with the inhibition of drug-metabolizing enzymes such as CYP3A4 involved in xenobiotic metabolism and interact with pharmacological agents thereby increasing the risk of overdose and harm [26]. Evidently, the toxicological data of the dietary polyphenolic compounds suggest that the addition of specific polyphenols, or combinations, to different food products, should be controlled to limit consumption to a dosage window where health benefits and lack of adverse effects have been demonstrated.

2.2 Alkaloids

2.2.1 Structural diversity of alkaloids

Alkaloids are a class of naturally occurring organic compounds that contain at least one nitrogen atom and are widely distributed in various living organisms, such as bacteria, fungi, plants, and animals [27]. Alkaloids derived from plants are secondary metabolites produced in response to environmental modulations and biotic or abiotic stress, which contributes to their chemical structure diversity and variable biological activities [28]. Alkaloids are classified in several ways but the most common one is according to the principal C-N skeleton structure. Based on this classification, alkaloids can be divided into large groups that include pyrrolidine, pyridine, quinolone, isoquinoline, indole and quinazoline (Figure 8).

Figure 8.

Classes of common dietary alkaloids.

2.2.2 Potential health benefits of dietary alkaloids

Alkaloid-containing foods constitute an important component of the human diet, such as tea, coffee, and tomato. The dietary alkaloids possess diverse effects on the human body, either beneficial or not. A large variety of food-produced alkaloids such as caffeine, atropine and cocaine exhibit potent bioactivities whereas lots of other alkaloids such as pyrrolizidine alkaloids (PA) are toxic to humans. This section will highlight the health benefits of dietary alkaloids and their mechanism of action.

Over the past decades, a variety of natural alkaloids derived from plants or medicinal herbs have been extensively studied for their antioxidant and anti-inflammatory properties [29]. Additionally, these alkaloids have been reported to reduce the colonic inflammation and damage in a range of colitic models. The plant species Sophora alopecuroides, widely distributed in western and central Asia, has been used in traditional Chinese medicine for treating bacterial infections, fever, rheumatism, and cardiovascular diseases [30]. Two active quinolizidine, sophocarpine and sophoridine (Figure 9) isolated from the plant have also been associated with the health benefits of the plant species.

Figure 9.

Chemical structures of sophocarpine (1) and sophoridine (2).

Studies of dextran sodium sulfate (DSS)-induced murine colitis have revealed that administration of sophocarpine significantly ameliorates DSS-induced colitis, which was associated with a reduction of serum IL-1b and IL-6 levels and colonic myeloperoxidase (MPO) activity [13]. An earlier study also showed that the treatment with sophoridine had a similar beneficial effect by reducing elevated plasma haptoglobin (HP) and colonic intercellular adhesion molecule-1 (ICAM-1) gene expression, and maintaining the level of cecum immunoglobulin A (sIgA) [31]. Tang et al. [32] reported that the mice that received matrine, a stereoisomer of sophoridine, showed significantly improved TNBS-induced colitis by reducing the up-regulated production of colonic TNF-α. Additionally, the study reported that administration of matrine (10 mg/kg of body weight, p.o.) to developed chronic colitis mice effectively promoted the recovery of colitis by reducing IL-12/23p40, IFN-γ and IL-17 secretion, lowering the proportion of CD4-positive cells, and inhibiting IFN-γ and IL-17 mRNA expression.

The biological properties of indole alkaloids have been reported by various researchers and they include analgesic, regulation of central and peripheral nervous systems, antimicrobial, anti-ulcer, antioxidant, and antimalarial activities [33]. A natural indole alkaloid, isatin, has been isolated from Isatis tinctoria, an anti-inflammatory and dye medicinal plant widely found in Europe and China [34, 35]. The oral treatment of isatin (6 and 25 mg/kg of body weight in rats) showed that the compound was capable of protecting against TNBS-induced gut mucosa injury, which was associated with decreasing colonic TNF-α, COX-2, and PGE2 levels, and MPO activity, and increasing colonic IL-10 and glutathione (GSH) levels. Furthermore, indole-3-carbinol, which is found in cruciferous vegetables, displays valuable cancer-preventive properties [36] and other biological activities including inhibition of inflammation and angiogenesis, decreased proliferation, and promotion of tumor cell death [33]. In the acidic environment of the stomach, indole-3-carbinol is rapidly converted into the digestive product 3,3′-diindolylmethane by the dimerization of two molecules of indole-3-carbinol [33]. Animal studies have suggested that the preventive effects of indole-3-carbinol might be due, at least partially, to the inhibitory effect of 3,3′-diindolylmethane on HDAC activity by inducing proteasome-mediated downregulation of class I HDAC isoenzymes [36].

2.2.3 Potential toxicity of alkaloids

The occurrence of alkaloids in the food chain and possible adverse effects of plant-derived alkaloids have been reported in a number of studies. Research has revealed that some alkaloids known to be present in the modern food chain such as piperine, nicotine, theobromine and theophylline are considered to have low if not negligible risk [37]. However, pyrrolizidine and tropane alkaloids and their derivatives have shown variable levels of toxicity in humans. Natural pyrrolizidine alkaloids (PA) have different chemical structural features (Figure 10), which contribute to their pharmacological activities. The toxicity of PA has mainly been attributed to the nature of the bond in position 1,2 of the pyrrolizidine ring system. The elucidation of the toxicity mechanism indicates that Cytochrome P-450 mediated metabolism of 1,2-unsaturated PAs form pyrroles, which can readily react with proteins to form DNA adducts [13]. However, the 1,2-saturated PA derivatives cannot form such reactive metabolites.

Figure 10.

Structural features of pyrrolizidine alkaloids: (A) core structural motif; (B) general description of the main base parts of naturally occurring Pas; (C) a core structural motif of otonecine-type PAs; (D) general pyrrolizine structure motif.

The toxicity of PA in humans has been established from various incidences of deaths and poisoning following ingestion of PA-containing herbal medicines, teas and weeds [8], with liver and lung as the main target organs. The acute toxicity of 1,2-unsaturated PAs in humans is characterized mainly by the onset of hepatic veno-occlusive disease (HVOD), associated with high mortality and possibly progressing to liver cirrhosis. Panel expert safety evaluation reports have suggested that the lowest dose of approximately 2 mg/kg bw per day of PA in food and feed is associated with acute toxicity in humans while data on experimental animals indicates that the adverse effects of 1,2-unsaturated PA in include hepatotoxicity, developmental toxicity, genotoxicity and carcinogenicity [13].

Potential health hazards of the ingestion of high doses of tropane alkaloids have been reported in the literature. While tropane alkaloids can be beneficial for medical treatment at low doses, severe unwanted toxic effects have been recorded in case of an overdose. The most common effects reported on humans caused by toxic doses include dizziness, blurred vision, pupil dilation, dry mouth, red skin, vomiting, clouded consciousness, muscle spasms, low body temperature, hallucinations, delirium, tachycardia, and even death [38]. The toxic effects usually occur within 60 minutes after ingestion and the clinical symptoms may persist for up to 24 to 48 hours [38].

2.3 Carotenoids

Carotenoids, also called tetraterpenoids, are organic pigments that are produced by plants, algae, bacteria, and fungi and give the characteristic color of the food products. Carotenoids are the most widespread pigments in nature and have been extensively studied for their provitamin and antioxidant properties [10]. More than 600 different carotenoids have been identified in nature and have variable chemical structures and biological functionalities. For example, lycopene and β-carotene are examples of acyclic and cyclic carotenoids, respectively. Natural carotenoid compounds mostly occur in the all-trans form and the β-carotene, α-carotene, and β-cryptoxanthin function as provitamin A [10]. Recently, plant-based carotenoids have been targeted as potential candidates in fields such as food, feed, nutraceuticals, and cosmeceuticals [39].

2.3.1 Chemistry and classification of carotenoids

The chemistry of carotenoids is characterized by the number of carbons in the structure, degree of saturation, substituents and stereochemistry. Generally, carotenoids in foods consist of C40 tetraterpenes or tetraterpenoids that are formed from eight C5 isoprenoid units joined head to tail, resulting in a symmetrical molecule (Figure 11).

Figure 11.

Structures of selected food carotenes.

The most distinctive structural feature is a centrally located, long system of alternating double and single bonds, in which the π-electrons are delocalized throughout the entire polyene chain [10]. Based on their chemical structures, the following six sub-classes of carotenoids are the most important for human diet: α–carotene, β–carotene, β-cryptoxanthin, lutein, zeaxanthin and lycopene. The most prevalent carotenoids in the human diet are β-carotene and lycopene. The hydrocarbon carotenoids such as β-carotene and lycopene are known as carotenes, and the oxygenated derivatives are called xanthophylls. The common oxygen-containing substituents are hydroxyl, keto, epoxy and aldehyde obtained in β-cryptoxanthin, anthaxanthin, violaxanthin and β-citraurin, respectively. These functional groups largely determine the degree of polarity, solubility, and chemical behavior of the xanthophylls [10].

2.3.2 Nutritional and health benefits of food carotenoids

Carotenoids are highly lipophilic molecules, therefore, they are considered to be efficient scavengers of reactive oxygen species on the cellular level and have the potential to reduce the overall risk of oxidation [40]. Literature has documented examples of ROS-mediated disorders including atherosclerosis, which result of LDL modification due to oxidation in arterial walls leading to coronary heart disease [41]. The dietary carotenoids derived from plants and vegetables mainly lycopene, α-carotene, β-carotene, zeaxanthin, lutein and β-cryptoxanthin have been reported to efficiently reduce the risk of cardiovascular disease [42]. Studies have further shown that dietary supplementation of β-carotene minimized the mortality due to cardiovascular disease [43] while Hennekens et al. [44] reported that β-carotene supplementation with or without aspirin significantly reduced the risk of myocardial infarction among the study participants. Out of all carotenoids, lycopene is considered the more potent pigment to protect cellular damage caused by ROS [45] and plays an important role in protecting DNA damage from oxidative stress caused by scavenging the oxygen. A study by Singh et al. [33] reported that lycopene can also reduce the risk of cancer, including ovarian, breast, prostate, cervical and liver cancer. Additionally, the study found that higher concentrations of lycopene reduced the chances of cardiovascular diseases and prevented the oxidative damage of skin due to UV-light damage [33].

Another important carotenoid, β-carotene plays a critical role as a precursor of vitamin A, which fights against ROS thereby protecting the body against oxidative stress [46]. Recently, a review study conducted by Elvira-Torales et al. [47] has shown the potential preventive and protective effects of -carotene on hepatic steatosis, fibrosis, oxidative stress, inflammation, and apoptosis. Furthermore, the carotenoid serves as a pre-hormone as it is converted into retinoic acid, which functions as a ligand, regulating the expression of genes involved in metabolic processes [47]. Animal studies have shown that dietary supplementation of carotene had a protective effect on liver damage, demonstrating that rats with monocrotaline-induced steatosis decreased fat accumulation and liver hemorrhages [48]. The study also indicated that β-carotene protects physiological antioxidants against carcinogenesis induced by aflatoxin-B1 in albino rats. A study based on supplementation of experimental animal feed with (9Z)-β-carotene, an isomer of β-carotene, showed a decrease in plasma cholesterol and atherogenesis index and a reduction of fat accumulation and inflammation in the liver of mice fed a diet high in fat [47].

2.3.3 Potential toxicity of carotenoids

According to the United States Food and Drug Administration (FDA), supplements for several carotenoids enriched products including palm oil carotenoids are categorized as Generally Recognized As Safe (GRAS) products [49]. Dietary carotenoids are generally considered safe at levels much higher than those observed in normal food patterns. Therefore, the European Food Safety Authority (EFSA) has made recommendations defining safe daily intakes, including in some cases acceptable daily intake (ADI), of certain carotenoids. Table 1 shows the average daily intake ranges of various dietary carotenoids [49].

Carotenoid	Daily intake ranges [mg]	Sources
α-carotene	0.16–2.43	Palm oil, carrot
β-carotene	0.92–8.80	Carrots, palm oil, gac oil, buriti, mango, sweet potato, apricot, green vegetables
β-Cryptoxanthin	0.04–1.36	Mandarins, tangerines, papaya, red pepper, persimmon, pitanga
Lutein + zeaxanthin	0.83–4.11	Sastra, green vegetables, egg yolk, pumpkin, sea buckthorn, marigold flower (lutein) Sastra, corozo, sapote, quince, orange pepper, red pepper, Chinese wolfberry, buriti, sea buckthorn, marigold flower (zeaxanthin)
Lycopene	0.83–9.43	Tomato, red papaya, red guava, watermelon, sarsaparilla, rose hip

Table 1.

Sources of the main carotenoids and daily intake ranges in humans [49].

3. Conclusions and future research directions

This chapter reviewed the chemistry of dietary additives from three phytochemical classes; polyphenols, alkaloids and carotenoids. The available evidence regarding the potential use of dietary phytochemicals suggests that these compounds are effective in reducing lipid accumulation, insulin resistance, oxidative stress, and inflammation of hepatocytes. Additionally, they have demonstrated antibiotic, antidiarrheal, antiulcer, and anti-inflammatory activities. The evaluation also included the elucidation mechanisms of action of active compounds and in vitro, in vivo and study systems such as in-vitro co-culture cell models. Future research directions should include the conduction of preclinical and clinical studies to evaluate effective doses, a detailed analysis of the bioavailability of different dietary phytochemicals and studies for improved delivery of the compounds through innovations such as nanotechnology.

Acknowledgments

The authors are grateful for the financial support by the Carnegie Corporation of the New York (CCNY) through the University of Pretoria’s Future Africa Institute.

Conflict of interest

The authors declare no conflict of interest.