Possible Side Effects of Polyphenols and Their Interactions with Medicines

Reactive oxygen species (ROS) play an important role in many biological processes in the human body (e.g., cellular signalling, fighting pathogens, and regulating blood pressure) [ 19 , 20 , 21 , 22 ]. They are naturally produced in animals’ body or plant tissue in various physiological processes, and can also be of exogenous origin [ 23 , 24 , 25 ]. The imbalance between the production and accumulation of ROS in cells and tissues and the ability of the cell/organism to deactivate them is called oxidative stress. It can be caused both by excessive ROS generation and by the impairment of antioxidant mechanisms. Usually, excessive activity of ROS can result in cells damage and the development of various diseases; therefore, it is usually considered undesirable and harmful [ 26 , 27 , 28 , 29 , 30 , 31 ]. However, in some cases, oxidative stress which was intentionally triggered can be used to treat cancers [ 32 ]. Many organisms have developed various strategies that provide antioxidant defence. These include the scavenging of free radicals, the quenching of ROS or the prevention of their generation, and the termination of radical reactions. Antioxidant defence systems comprise both enzymatic (e.g., the activity of superoxide dismutases (SOD), glutathione peroxidase (GPx), glutathione-reductase (GR), catalase (CAT), and haem oxygenase (HO)) and nonenzymatic mechanisms [ 28 , 33 , 34 ]. The The latest includes the activity of endogenous agents (e.g., glutathione (GSH), the thioredoxin system, melatonin, and coenzyme Q10) and a large group of exogenous antioxidants, which are usually provided by food, such as vitamins, polyphenols, carotenoids, and some minerals [ 19 , 35 , 36 ]. Polyphenols, with their numerous functionall groups, double bonds, and aromatic rings, have an ideal structure to act as effective antioxidants [ 1 , 6 , 37 ]. First of all, polyphenols can scavenge already-formed free radicals, such as a hydroxyl radical ( • OH) or the superoxide anion radical (O 2 −• ), as well as quench reactive oxygens species such as hydrogen peroxide (H 2 O 2 ) or singlet oxygen ( 1 O 2 ) by donating a single electron (SET) or by hydrogen atom transfer (HAT) [ 38 , 39 , 40 , 41 , 42 ]. Thus, they might prevent the initiation and interruption of yet-to-be-initiated radical reactions, such as the peroxidation of lipids, the oxidation of proteins and sugars, and oxidative damage to nucleic acids [ 1 , 43 ]. Moreover, polyphenols are able to chelate the ions of transition metals (e.g., Fe and Cu), thus preventing the formation of free radicals in the Fenton and Haber–Weiss reactions [ 38 , 44 ]. Polyphenols can also function as co-antioxidants and, thus, they are involved in the regeneration of essential vitamins [ 1 ]; they are also involved in the regulation of numerous signalling pathways which are responsible, among others, for energy metabolism, adipogenesis, antioxidant, and anti-inflammatory reactions in cells [ 45 , 46 ]. Therefore, polyphenols, due to their antioxidant properties and the ability to quench free radicals and reactive oxygen species, exert a beneficial effect on human health, and they are believed to slow down the aging process as well as to be useful in the prevention of the development of many diseases [ 5 , 47 , 48 ].

Polyphenols, due to their antioxidant, anti-platelet, and anti-inflammatory properties, can prevent or reduce the symptoms of various metabolic diseases, such as metabolic syndrome (which includes type 2 diabetes mellitus, central and abdominal obesity, systemic hypertension, and atherogenic dyslipidaemia) [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ], as well as cardiovascular diseases (e.g., atherosclerosis, myocardial infarction, heart failure, and stroke) [ 57 , 58 , 59 , 60 , 61 ]. Polyphenols inhibit LDL oxidation and increase HDL, improving endothelial function [ 62 ], reduce blood pressure [ 63 ], and improve the glucose homeostasis [ 64 ]. In vivo studies in rats has shown that animals which were fed on 10% hesperidin had a reduced plasma level of triglyceride as compared to control [ 65 ]. Moreover, although the ingestion of hesperidin did not exert any changes in daily food intake, body weight gain, or food efficiency, the fecal lipid content increased, suggesting inhibition of the pancreatic lipase. A significant decrease in serum lipid and lipid peroxidation was also proved in rats when galangin was administered at the dose of 50 mg/kg for six weeks [ 66 ]. The inhibitory activity of polyphenols against pancreatic lipase can be beneficial, for example, it may help with body mass reduction in obese individuals [ 67 , 68 ]. One of the most dangerous factors linked to deaths caused by cardiovascular diseases is hypertension. Polyphenols both from green and black tea significantly lower blood pressure [ 69 , 70 , 71 ]. Although the exact mechanism is not elicited, it is probable that tea polyphenols play an important role in relaxing smooth muscle contraction, enhancing endothelial nitric oxide synthase activity, reducing vascular inflammation, and inhibiting rennin activity and antivascular oxidative stress. It was proven that a diet rich in polyphenols or supplemented with phenolic compounds also has beneficial effects in systemic and neurodegenerative diseases and amyloid diseases, particularly Alzheimer’s disease and Parkinson’s disease, as well as on cognitive functions [ 52 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. Polyphenols are also important anti-cancer agents [ 79 ]. Tea polyphenol compounds were proven in many animal models to prevent various types of cancers, e.g., ovarian, breast, pancreas, colorectal, oesophagus, liver, lung, and kidney cancers [ 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Moreover, in vitro studies have demonstrated that the anticancer activity of polyphenols relies on their ability to inhibit growth or stimulate apoptosis in various cancer cell lines, such as HL60 human promyelocytic leukaemia cells, A431 epidermoid carcinoma cells, LNCaP and androgen-insensitive PC-3 human prostate carcinoma cells, human prostate cancer LNCaP cells, OVCA 433 human ovarian cancer, HepG2 cells, Caco-2 human colon cancer cells, human pancreatic carcinoma cell line Mia PACA-2, and oestrogen-independent MDA-MB-435 and oestrogen-dependent MCF-7 breast cancer cell lines [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ]. There are also results of in vivo studies that indicate that particular classes of polyphenols, supplied with in an individual’s diet, may reduce the risk of certain cancers, e.g., colorectal [ 99 ], oesophageal [ 100 ], gastric [ 101 ], breast [ 102 ], and prostate [ 103 ], while low intake from food might increase the risk of lung cancer [ 104 ]. Polyphenols are also used to support anti-cancer therapy [ 105 , 106 , 107 ]. Among the mechanisms of anticancer activity of polyphenols are antioxidant/prooxidant activity, inhibition of specific protein kinases and other enzymes and the resulting changes in cellular signalling, inhibition of angiogenesis, estrogenic/antiestrogenic activity, antiproliferation, induction of detoxification enzymes, regulation of the host immune system, and anti-inflammatory activity [ 79 , 108 , 109 , 110 ]. Some polyphenols (e.g., quercetin, kaempferol, curcumin, resveratrol, and EGCG) downregulate the expression of histone deacetylases; this means that these compounds exert anticancer action by restoring epigenetic alterations in cancer cells as well as by DNA methylation and histone modifications which may prevent normal cells from turning into tumours [ 111 ]. It should be underlined that sirtuins (from SIRT1 to SIRT7) are enzymes belonging to class III HDAC (NAD+ −dependent histone deacetylases). They modulate many physiological processes in cells, such as gene expression, cellular survival, DNA repair, metabolism, energy homeostasis, stress resistance, cellular senescence and aging, inflammation-immune function, mitochondrial biogenesis, and many more [ 112 , 113 , 114 ]. It has been proven that some polyphenols, especially resveratrol, but also quercetin, naringenin, curcumin, and others, are able to activate sirtuins [ 115 , 116 , 117 , 118 ]. Therefore, they can regulate various physiological processes or extend the lifespan. A very important role of diet polyphenols is to alleviate undesirable menopausal symptoms. Isoflavones, such as genistein and daidzein, are phytoestrogens which are metabolized by intestinal microbes to bioactive metabolites as O-desmethylangolensin (O-DMA) and S-equol [ 6 ]. These metabolites are oestrogen antagonists—they strongly bind to oestrogen receptors, especially ERβ, and thus exert estrogenic activities [ 119 , 120 ]. Soy isoflavones and their metabolites might also modulate the cytokine-induced natural killer cell function [ 121 ]. Due to their bacteriostatic or bactericidal effect, polyphenols also have a beneficial effect on the functioning of the gastrointestinal tract. On the one hand, they inhibit the growth of various pathogens, e.g., Helicobacter pylori [ 122 , 123 , 124 ], Pseudomonas aeruginosa [ 125 , 126 ], Escherichia coli [ 127 , 128 , 129 , 130 ], Streptococcus mutans [ 131 , 132 ], S. aureus [ 133 , 134 , 135 ], Salmonella enteritidis [ 136 ], Vibrio cholerae [ 137 ], Klebsiella pneumoniae [ 138 ], Yersinia enterocolitica [ 139 ], Listeria monocytogenes [ 140 , 141 ], Candida albicans [ 142 ], Bacteroides fragilis, Clostridium perfringens , and Clostridium difficile [ 143 ]. On the other hand, some polyphenols can stimulate the growth of beneficial bacteria. For example, polyphenols from grape enhanced the growth of Akkermansia muciniphila [ 144 , 145 ], while the growth of Lactobacillus and Bifidobacterium was stimulated by rutin [ 146 ], resveratrol [ 147 , 148 ], cocoa polyphenols [ 149 ], blueberry anthocyanidins [ 150 ], and apple procyanidin B2 and chlorogenic acid [ 151 ]. Considering all of the above, polyphenols seem to be our great ally, helping our bodies to function well. Therefore, diets which are rich in polyphenol compounds, as well as dietary supplements containing them, have become popular. However, it should not be forgotten that the consumption of polyphenolic compounds, especially in large amounts in a purified form (supplements instead of fruits and vegetables), can cause side effects or even have a negative impact on our health. Below is a comprehensive review of the current state of knowledge about the possible adverse effects that polyphenols can have on cells, organs, or entire organisms.

Iron is an essential trace element for human life, and although it is quite abundant in the environment, iron deficiency is a common world-wide disease. A low iron level in the body can be caused both by the low intake of this metal (in some populations), and also by its low bioavailability. According to the World Health Organization (WHO), iron deficiency is responsible for ~50% of anaemia cases, and anaemia affects approximately 25% of the population in both developing and developed countries [ 152 ]. The highest anaemia prevalence has been reported in preschool-age children (47.4%) and pregnant women (41.8%). When geographical regions were analysed, the highest proportion of individuals affected were in Africa (47.5–67.6%). It should be underlined that iron deficiency can occur both when the total body iron stores are low or exhausted (absolute) and when the iron is present at normal concentration but is unavailable for the cells and body (functional) [ 153 ]. Hepcidin, which regulates the release of iron, is responsible for the regulation of iron homeostasis in the body and plays an important role in functional iron deficiency [ 154 , 155 , 156 , 157 ]. The bioavailability of iron from diet depends on its form. Haem iron is derived from hemoglobulin and myoglobulin from animal food sources, while non-haem iron derives from plants and iron-fortified foods, and the latter is characterized by a lower bioavailability due to much-less effective intestinal absorption [ 157 ]. Polyphenols are able to chelate the ions of transition metals (e.g., Fe and Cu), thus inhibiting the formation of free radicals in the Fenton and Haber–Weiss reactions. Both the binding strength and the number of bound ions depend not only on the structure of the polyphenolic compound, but also on the pH or the form of the ion (Fe 2+ vs. Fe 3+ and Cu + vs. Cu 2+ ) [ 44 , 158 ] ( Figure 1 ). It is considered that this activity of polyphenols is beneficial for the body, as it will limit the formation of free radicals. Moreover, the iron-chelating activity of polyphenols is commonly used in the treatment of iron overload, which is a high risk factor for many diseases, especially human chronic diseases [ 159 ]. However, this activity can also have detrimental effects, such as in individuals with iron deficiency. A diet rich in polyphenols or polyphenols supplementation causes these compounds to bind to Fe in the intestine so that it cannot be absorbed, leading to the development of anaemia. They can also interact with the regulation of iron homeostasis. Among potent inhibitors of iron absorption are various teas which are rich in catechins. Hurrel et al. [ 162 ] demonstrated that drinking beverages that contain 20–50 mg total polyphenols per serving caused a reduction in Fe absorption from a bread meal by 50–70% (compared to drinking water), whereas beverages containing 100–400 mg total polyphenols/serving reduced Fe absorption by 60–90%. The most potent inhibitors of Fe absorption were black teas (79–94%), peppermint tea (84%), pennyroyal (73%), and cocoa (71%), and the inhibition was reduced in a dose-dependent fashion depending on the content of total polyphenols. The effect of green tea extract (GTE) supplementation on the body mass, lipid profile, elements and glucose level, and antioxidant status of obese patients was monitored in 46 obese patients in a randomized, double-blind, placebo-controlled study [ 163 ]. Patients received either 379 mg of GTE or a placebo, daily for three months. The treatment with GTE allowed for mass reduction and caused a significant ( p < 0.05) reduction in total cholesterol and triglycerides, low-density lipoprotein, and glucose, as well as in the blood Fe concentration, while the high-density lipoprotein, Zn, and Mg levels increased significantly. Main tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) as well as rich-in-polyphenols grape seed extract (GSE, used within physiological levels, significantly decreased the transepithelial iron transport in Caco-2 intestinal cells [ 164 ]. Interestingly, the cellular level of Fe in cells was increased, although the Fe transfer across the basolateral membrane of the enterocytes was extremely low, and a higher inhibition was reported for EGCG. The authors suggest that the basolateral exit of iron via ferroportin (FPN), a transmembrane protein that transports iron from the inside of a cell to the outside (see Figure 2 ), was impaired by the formation of a non-transportable complex Fe-polyphenol. Similar results were obtained by Ma et al. [ 165 ], who reported that EGCG and GSE decreased the transepithelial transport of haem-derived iron by Caco-2 cells, mainly by the reduction of basolateral iron exit. In another study, the impact of EGCG, GSE, and GTE on haem iron (heme- 55 Fe) absorption by Caco-2 cells was analysed [ 166 ]. The tested polyphenols significantly inhibited heme- 55 Fe absorption in a dose-dependent manner. However, the addition of ascorbic acid was able to balance or even reverse the inhibitory effects of polyphenols when they were used at lower concentrations (≤4.6 mg/L). Coherent results were obtained in a study on rats and Caco-2 cells [ 167 ]. Quercetin (Q), in the form of aglycone or as methylated (M )derivatives 3-MQ, 4′-MQ, and 3,4′-diMQ, were introduced into rat duodenum together with radioactive iron 59 Fe. An increase in the mucosal uptake of 59 Fe was observed (especially for Q and 4′-MQ) in comparison with the untreated control group. On the other hand, the release of 59 Fe from the intestinal mucosa into the blood was significantly diminished in the presence of Q and 4′-MQ in comparison with 3-MQ, 3,4′-diMQ, and the untreated controls. Both the stimulation of Fe uptake and the inhibition of Fe efflux in the presence of Q were also confirmed in Caco-2 cell monolayers. As the methylation of the 3-OH negated both the increase in apical iron uptake and the inhibition of basolateral iron release, the authors postulated that the mechanism is dependent on the iron chelation between 3-hydroxyl and 4-carbonyl groups of quercetin. Probably, the quercetin-iron complex is too large to exit enterocytes via ferroportin (FPN), although some efflux was still possible through the glucose transporters. Moreover, the authors observed that, in the long term, the decrease in iron transport across Caco-2 cells caused by Q was associated with a significant, dose-dependent decrease in FPN protein and FPN mRNA in Caco-2 cells, and it was mediated by the interaction of miRNA with the 3′UTR of FPN mRNA. Quercetin can decrease the intracellular labile iron pool by binding labile iron and transferring it from the cell compartment to the transferrin molecule [ 170 ]. The complexes of quercetin and rutin with iron were proven to permeate cell membranes; however, only free quercetin was able to access to the cytosol and remove iron from cells. The interaction of quercetin and the related flavonoids with iron supplements in an animal model of iron deficiency anaemia (IDA) was assessed by Mazhar et al. [ 171 ]. In the study, female weanling Sprague Dawley rats were kept on a low iron diet for 20 days to induce IDA (manifested by a reduced level of haemoglobin, haematocrit, and serum iron). Then, the animals obtained a dose of 50 mg/kg of ferrous sulphate (FeSO 4 ) supplement combined in an equal ratio with quercetin (Q), quercetagetin (QTG), and patuletin (PAT) for 30 days. The orally-administered doses of a combination of flavonoids and FeSO 4 which were given to the rats significantly improved both the serum levels and spleen tissue availability of iron compared to the IDA model animals. The authors postulated that a complex of iron with quercetin might provide an alternative pathway for iron absorption through the glucose transporter. Moreover, they observed a slightly lower FPN expression in the spleens of rats with the Q-FeSO 4 combination than for FeSO 4 alone; however, QTG-FeSO 4 and PAT-FeSO 4 increased the FPN. The different impacts of polyphenols were probably caused by the differences in the functional group at the C6 position of their molecules. The impact of quercetin was also evaluated in a randomized, double-blind, placebo-controlled study performed in 90 patients with non-alcoholic fatty liver disease. The patients were supplemented with either a quercetin or a placebo capsule twice daily (500 mg) for 12 weeks and their blood parameters were assessed. The results showed that ferritin was significantly ( p = 0.013) decreased, while whole red blood cells (RBC) increased compared to the placebo group [ 172 ]. According to the authors, two mechanisms may be involved. First, quercetin acted as an electron donor in enterocytes and, thus, might facilitate inorganic iron absorption; however—simultaneously—it could reduce the expression of FPN and hephaestin (both responsible for iron transfer from the enterocyte to the blood, see Figure 2 ). Another possibility is that the quercetin–iron complex is retained in the enterocyte cytosol, which results in a functional iron deficiency and implicates a decrease in ferritin. Inconsistent results were obtained in a study by Al-aboud et al. [ 173 ]. They showed that consuming 8 g of raisins ( Vitis vinifera L.) for 20 days resulted in increased haemoglobin and serum iron levels, an increase in ferritin, and a decrease in total iron binding capacity (TIBC) and transferrin. However, the group of volunteers was small (seven women) and raisins, besides various polyphenols, also provide iron and vitamin C. It is known that ascorbic acid enhances the absorption of non-haem iron, mainly due to its ability to reduce Fe 3+ to Fe 2+ , which makes it available for transport by DMT1 ( Figure 2 ). Therefore, the intake of food that is rich in vitamin C should be critical when a given diet is abundant in the inhibitors of iron absorption (polyphenols, phytate, calcium, and proteins) [ 161 ]. To sum up, the influence of polyphenols on the level of iron requires a more thorough analysis, because both its excess (causing, e.g., excessive ROS production) and its deficiency (anaemia) are harmful. The oral iron therapy of IPA often causes gastrointestinal side effects such as constipation, nausea, diarrhoea, abdominal pain, vomiting, heartburn, dark stools, and flatulence [ 174 ]. Moreover, an excess of unabsorbed iron can lead to dysbiosis by modifying the microbiota profile because iron favours the growth of some pathogenic bacteria (e.g., Escherichia coli , Shigella , Campylobacter , Salmonella , Clostridium , and Bacteroides) and also lowers the abundance of beneficial species belonging to Lactobacillus and Bifidobacterium [ 175 ]. Some of pathogenic species of intestinal bacteria can produce genotoxic metabolites which promote inflammation and carcinogenesis. Therefore, further studies are also important from the point of view of the possibility of using polyphenols’ ability to bind iron in cancer therapy [ 176 ]. The ability of flavonoids to chelate iron can be used in the production of more effective drugs or supplements for IDA treatment and prevention [ 174 ].

Flavonoids are able to form complexes with proteins, both through nonspecific forces (e.g., hydrogen bonding and hydrophobic effects) and by covalent bond formation [ 177 ]. As a result of protein binding by polyphenols, they are sequestered into soluble or insoluble complexes, which affects the proteins’ function, structure, solubility, hydrophobicity, thermal stability, and isoelectric point, as well as their susceptibility to digestive enzymes [ 178 , 179 ]. These changes can be crucial for the functioning of the whole organism, as the digestibility and utilization of food proteins can be affected. Moreover, the activity of digestive enzymes (i.e., amylases, proteases, and lipases), which are also proteins, can be affected by binding with polyphenols, and the changes in the enzyme structure implicate an impaired function and disturbances in the course of biochemical reactions or processes that a given enzyme catalyses. Of course, in some diseases, the ability to inhibit certain enzymes may be beneficial, e.g., in the treatment of diabetes or to improve postprandial blood glucose [ 180 , 181 ], as well as in body mass reduction or reducing fat absorption in obese people. However, there are some subpopulations where this generally beneficial effect may have an undesirable effect. Also, in healthy individuals, any disorders in the activity of digestive enzymes are unfavourable, as they cause unpleasant symptoms in the digestive system, as well as the impaired assimilation of some nutrients, which in turn may adversely affect the activity of the organism. The efficient functioning of digestive enzymes, especially glucose-releasing enzymes, is particularly important in people practicing endurance sports, and research has shown that these athletes quite often struggle with gastrointestinal disorders. Along with an increasing intensity of exercise, the blood flow (and its oxygen, nutrients, and ability to clear waste products) naturally changes, and the blood is moved away from the stomach and intestines and directed toward the working muscles to facilitate the movement [ 182 ]. This reduced blood flow in the gut can cause side effects, especially if the athlete, during a very intense exercise-to-exhaustion or long duration/endurance exercise, is feeding with fluids and food while minimal digestion is occurring. As a consequence, the gastrointestinal tract can become more permeable. In such a situation, any additional disturbance in the work of digestive enzymes (e.g., inhibition of enzyme activity caused by the polyphenols) can have harmful effects on the body. Endurance athletes or long-distance runners are known to often experience digestive problems [ 183 ]. Among the known symptoms of digestive enzymes deficiency are food intolerances, poor nutrient absorption, a weaker immune system, weight gain and obesity, skin and digestive problems, etc. Moreover, long-term endurance training for a long duration causes changes in the activity of digestive enzymes (e.g., pancreatic amylase) [ 184 ]. The supplementation of digestive enzymes by athletes is, apart from a method to alleviate unpleasant symptoms, one of the methods of improving sports performance. There are several studies showing that enzyme supplementation can help prevent indigestion and improve nutrient absorption. For example, men who consumed whey protein concentrate (WPC) with patented digestive proteases (Aminogen ® ) had an increased rate of absorption of processed WPC (compared to the controls) [ 185 ]. As well, statistically significant increases in amino acids level were reported, both the total serum amino acid level and the level of individual serum amino acids. Significant decreases in CRP level were also reported. In another study, protease supplementation (two tablets with 325 mg pancreatic enzymes, 75 mg trypsin, 50 mg papain, 50 mg bromelain, 10 mg amylase, 10 mg lipase, 10 mg lysozyme, and 2 mg chymotrypsin) attenuated muscle soreness after downhill running, facilitated muscle healing, and allowed for faster restoration of contractile function after intense exercise [ 186 ]. Therefore, it is worth making athletes aware that simultaneous supplementation with enzymes and preparations rich in purified polyphenols may offset the beneficial effects of these supplements. It was found that dietary polyphenols can decrease glucose uptake, as was confirmed in Caco-2 cells, a cell line which is used as a model of the intestinal epithelial barrier [ 187 ]. The authors investigated the effect of various polyphenols on both the active intestinal transport (sodium-dependent) and facilitated transport (sodium-free) of glucose. The results suggest that aglycones (apigenin, myricetin, phloretin, and quercetin) could inhibit facilitated glucose uptake, whereas glycosides (such as naringin, phloridzin, rutin, and arbutin) inhibited the active transport of glucose. The non-glycosylated dietary polyphenols (such as (+)-catechin, (−)-epicatechin, (−)-epigallocatechin (EGC), (−)-epicatechin gallate (ECG), and (−)-epigallocatechin gallate (EGCG)) appeared to exert their effects via steric hindrance, and EGCG, ECG, and EGC were effective against both transporters. Phenolic acids did not have any effect. Thus, it can be seen that the proper functioning of digestive enzymes is important in healthy people, and any disturbance in their operation may translate into, for example, a worse performance in sports. Another group for which the inhibitory effect of polyphenols on digestive enzymes may be harmful is people with food intolerances resulting from the deficiency or lack of certain enzymes. The most common digestive disorders of this type include gluten intolerance, celiac disease, lactose intolerance or complex carbohydrate intolerance, exocrine pancreatic insufficiency, cystic fibrosis, and pancreas cancer. Some of these diseases are genetic, while others may increase with age [ 188 , 189 ]. It is estimated that adverse reactions to food, including food intolerances and food allergies, may affect up to 20% of the general population [ 190 ], whereas, among patients with irritable bowel syndrome (IBS), the incidence of food intolerance may reach 65% [ 191 ]. Therefore, supplementation with digestive enzymes constitutes an increasingly common method of supporting the body in the digestion of proteins, carbohydrates, and lipids in people suffering from various digestive disorders, from lactose intolerance to celiac disease to cystic fibrosis [ 192 , 193 , 194 , 195 , 196 , 197 ]. In all of these cases, knowledge of food ingredients that may additionally inhibit the already-low activity of specific enzymes is essential for proper diet planning and meal composition in such patients to prevent malnutrition. The last large group affected by a reduced activity of digestive enzymes is elderly people. Some studies conducted in humans showed that individuals above 65 years old had significantly reduced (compared to young controls) bicarbonate and enzyme (lipase, chymotrypsin, and amylase) secretions, due to both a decrease in secreted volume and enzyme concentrations [ 198 , 199 , 200 , 201 , 202 ]. Moreover, the biodiversity and stability of the intestinal microbiota are reduced in the elderly, which significantly correlates with frailty, co-morbidity, nutritional status, and markers of inflammations. An age-related decrease in digestive enzymes and changes in microbiota might lead to a reduced availability and absorption of some nutrients, such as carbohydrates, lipids, amino acids, minerals (calcium and iron), and vitamins (B12, B6, folic acid, and lipid soluble vitamins), which in turn increases the risks for the development of a range of pathologies associated with most systems, in particular the muscoskeletal-, nervous-, cardiovascular-, immune-, and skin systems [ 203 , 204 , 205 ]. Various clinical trials have proven that enzyme supplementation has great potential in the treatment of diseases caused by a deficiency of various enzymes [ 192 , 193 , 206 , 207 ]. However, the right composition of diet is also of crucial significance because various studies have demonstrated that naturally occurring polyphenols, e.g., condensed tannins, can inhibit a number of digestive enzymes, including α-amylase, α-glycosidase, pepsin, trypsin, lipase, and chymotrypsin. Therefore, they influence the digestion process and can further diminish the availability of nutrients. Table 1 summarizes the known and scientifically documented interactions between dietary polyphenols and enzymes that lead to a reduction or inhibition in the activity of digestive enzymes. It should be emphasized, however, that most of the known studies have been conducted in vitro. In vivo studies in humans or animal models are rare and the results are often inconclusive. For example, quercetin was proven to be a promising pancreatic lipase inhibitor by reducing fat absorption in rats in vivo [ 208 ]. Pre-administration with 5 and 10 mg quercetin per kg of body weight significantly reduced fat absorption and, correspondingly, significantly increased fat excretion in rat faeces. The inhibition of quercetin on lipase can last at least 2 h in vivo. As was presented in the Table 1 , there are large differences in the inhibitory activity of various polyphenols. Therefore, some meals containing plant-raw material can exert stronger inhibitory activity than other apparently similar plants. Because of this, the patient, in consultation with a doctor or nutritionist, can choose the right fruits and vegetables or dietary supplements to support their digestive processes, instead of harming them. One example is some soft fruits; strawberry and raspberry can inhibit α-amylase more than blueberry, blackcurrant, or red cabbage, whereas α-glucosidase was more readily inhibited by blueberry and blackcurrant [ 238 ]. Among various berries, strawberry and raspberry, as well as arctic bramble and cloudberry, were proven to have a high potential to inhibit lipase activity, even at low levels, which are achievable in the gut after the intake of a small amount of berries [ 239 ]. On the other hand, extract from rowan berries strongly inhibited α-amylase (IC 50 4.5 µg GAE/mL), while polyphenol-rich extracts from blackcurrants inhibited α-glucosidase activity (IC 50 20 µg GAE/mL). It is worth noting that some polyphenols or polyphenol-rich products delay gastric emptying and lower the postprandial glucose response; therefore, they alter the apparent glycaemic index of food [ 55 , 240 , 241 , 242 , 243 ], which is a rather beneficial influence. However, in particular subpopulations (e.g., people with functional dyspepsia or with eating disorders such as anorexia nervosa), delayed gastric motility would enhance undesired symptoms such as nausea, vomiting, and gastric fullness, and may lead to difficulties during refeeding and weight restoration [ 244 , 245 ].

The negative impact of polyphenols on the functioning of the digestive system could result not only from the inhibition of digestive enzymes, but also from their influencing the intestinal microbiota. In general, the interactions between polyphenolic food ingredients and bacteria residing in the digestive tract are very complex. Firstly, bacterial enzymes are responsible for the release of polyphenols from the food matrix, and thus increase their bioaccessibility and bioavailability. Moreover, bacteria carry out the conversion and degradation of polyphenols, usually through hydrolysis reactions and double bond reduction reactions. The intestinal microbiota are equipped with a huge set of various enzymes that catalyse reactions which are inaccessible to human enzymes, thanks to which all ingredients that are sent to the intestine with food can be modified and used [ 246 , 247 ]. Intestinal bacteria are able to hydrolyse glycosides, glucuronides, ester, sulphates, amides, and lactones through the action of enzymes such as β-glucosidase, α-rhamnosidase, β-glucuronidase, α-galactosidase, esterases, and sulfatases. Moreover, they catalyse the reactions of aromatic rings cleavage, decarboxylation (decarboxylase), demethylation (demethylase), isomerization (isomerase), reductions (reductases and hydrogenases), and dehydroxylation (dehydroxylase) [ 248 , 249 ]. These reactions lead to the degradation of glycosides (glucosides, galactosides, rhamnosides, rutinosides, etc.) or polymeric polyphenols (such as ellagitannins, tannins, and procyanidins) to simpler compounds, i.e., aglycones, and then to phenolic acids and products of their metabolism. The bioactive properties of polyphenol metabolites are completely different from the activity of the parent compounds. Usually, metabolites have weaker antioxidant properties; however, it happens that polyphenol gains its biological activity only after bacterial biotransformation. The best-known cases are transformations of soya isoflavone daidzein to S-equol and O-desmethylangolensin, ellagitannins to urolithin A, and secoisolariciresinol to entererodiol and enterolactone [ 6 , 249 ]. On the other hand, it has been known for many years that polyphenols and foods that are rich in them (such as herbs, spices, fruits, and vegetables) have an inhibitory effect on numerous species of bacteria, both Gram-positive and Gram-negative bacteria [ 6 ]. Unfortunately, this inhibitory effect is not limited to pathogens. Strong antimicrobial activity against Salmonella enterica ser. Typhimurium, E. coli as well as against Lactobacillus rhamnosus and L. rhamnosus GG was reported for extracts of cloudberry, raspberry, and strawberry at higher concentrations [ 250 ]. Strawberry extract was an effective inhibitor against E. faecalis and Bifidobacterium lactis . Myricetin inhibited the growth of all lactic acid bacteria derived from the human gastrointestinal tract flora; however, it had no impact on Salmonella Typhimurium and Lactobacillus plantarum from beer. A bacteriostatic impact of luteolin was reported on some Lactobacillus species, Bifidobacterium lactis and Enterococcus faecalis , while no impact was observed on Gram-negative bacteria. Apigenin, (+)-catechin, kaempferol, isoquercitrin, and rutin had no effect, while phenolic acids inhibited the growth of E. coli and S. enterica . Aqueous extract of Salvadora persica L. inhibited, in a dose-dependent manner, all tested microorganisms, especially Streptococcus mutans , S. faecalis , and S. pyogenes , as well as Staphylococcus aureus , Lactobacillus acidophilus , Pseudomonas aeruginosa , and Candida albicans ; however, methanol extract from the same plant was inactive against L. acidophilus and P. aeruginosa [ 251 ]. Vattem et al. [ 123 ] investigated the impact of 53 constituents of peppermint oil and green tea polyphenols (e.g., (−)-epigallocatechin and (−)-epigallocatechin-3-gallate (EGCG)) on various strains of Escherichia coli. All of the compounds had strong antibacterial activity against non-pathogenic E. coli , while peppermint oil, menthol, menthone, and neomenthol also killed the enterohemorrhagic strain E. coli O157:H7 at concentrations 400 µg/mL within 1 h. GTP inhibited the growth of pathogenic E. coli, although at concentration of 800 µg/mL within 18 h. Other results were obtained by Tzounis et al. [ 252 ], who demonstrated that (+)-catechin caused a significant decrease in the growth of the Clostridium histolyticum group, and a marked increase in the growth of the beneficial bacterial group of C. coccoides–Eubacterium rectale , Lactobacillus spp., and Bifidobacterium spp. Furthermore, (−)-Epicatechin caused a significant increase in the growth of the Eubacterium rectale–C. coccoides . Differences in the effects of polyphenols, depending on their form (aglycones and glycosides), on bacteria that are representative of the physiological intestinal microbiota were investigated by Duda-Chodak [ 146 ]. Quercetin (aglycone) had a strong inhibitory impact (minimal inhibitory concentration, MIC = 20–50 µg/mL) on Ruminococcus gauvreauii, Bacteroides galacturonicus , and Lactobacillus sp. growth, while rutin (glycoside) had no effect. Similarly, naringenin and hesperetin (aglycones) inhibited the growth of almost all analysed bacteria (with MIC value ≥ 250 µg/mL), whereas their glycosides, naringin and hesperidin, had no impact. The concentrations of individual polyphenols used in the above-described in vitro studies are possible to obtain in the human digestive tract when high concentrations of pure polyphenols are taken in the form of dietary supplements. By intaking a balanced diet, even rich in fruits and vegetables, the risk of reaching these unfavourable concentrations of polyphenols is much lower. The inhibition of the growth of lactic acid bacteria/LAB/by 13 phenolic acids (benzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 4-hydroxy-3-methoxybenzoic acid, 3,4-dihydroxybenzoic acid, phenylpropionic acid, 3-hydroxyphenylpropionic acid, 4-hydroxyphenylpropionic acid, 3,4-dihydroxyphenylpropionic acids, phenylacetic acid, 3-hydroxyphenylacetic acid, 4-hydroxyphenylacetic acid, and 3,4-dihydroxyphenylacetic acid) has been reported [ 253 ]. Lactobacillus paraplantarum LCH7 was the most sensitive strain, while Lactobacillus fermentum LPH1 was more resistant. The most active compounds were: 4-hydroxybenzoic acid for L. fermentum CECT 5716, L. fermentum LPH1, L. brevis LCH23, and L. plantarum LCH17; 4-hydroxybenzoic acid and phenylpropionic acid for L. paraplantarum LCH7 and L. coryniformis CECT 5711; 3-hydroxyphenylpropionic acid for L. fermentum CECT 5716. A flavan-3-ol-enriched grape seed extract inhibited the growth of both pathogens and beneficial bacteria ( Streptococcus thermophilus , Bifidobacterium lactis BB12, Lactobacillus fermentum , L. acidophilus , and L. vaginalis ), and simultaneously stimulated the growth of some Lactobacillus plantarum , L. casei , and L. bulgaricus strains, while it had no impact on Bifidobacterium breve 26M2 and B. bifidum HDD541 [ 254 ]. Thirteen tested polyphenols influenced the growth of beneficial bacteria, exerting both stimulatory and inhibitory impacts. Coumaric acid had a strong stimulatory effect on Bifidobacterium bifidum , while vanillic and caffeic acid stimulated Bifidobacterium adolescentis . Hesperidin and quercetin exerted an inhibitory dose-dependent impact on both of the tested bacteria [ 255 ]. In another study, the growth of Lactobacillus ssp. and Bifidobacterium spp. was inhibited by caffeic acid, 3-phenylpropionic acid, and, to a lesser extent, by gallic acid, while Lactobacillus casei Shirota growth was inhibited only by 3-phenylpropionic acid [ 256 ]. On the other hand, there are some studies showing that some polyphenols can stimulate the growth of beneficial bacteria [ 144 , 145 , 147 , 148 , 149 , 150 , 257 , 258 , 259 ]. Usually, a positive influence of polyphenols is observed for plant extracts or natural products (such as berries, cocoa, grape polyphenols, red wine polyphenols, berries extract, tannin-rich products, and pomegranate extract) that are composed of various polyphenols in their more “natural” form (e.g., glycosides), while a negative impact is observed in particular for purified polyphenolic compounds, mainly aglycones [ 249 , 260 ], a form that is rarely found in food but is a common form in dietary supplements. As was mentioned above, the impact of polyphenols as well as the mechanism of this action depends both on the type of polyphenols and bacteria species. Among the mechanisms of antibacterial activity of polyphenols, the most frequently mentioned are: (i) polyphenols’ reactions with proteins; (ii) substrate and metal deprivation; (iii) the inhibition of nucleic acid synthesis by bacterial cells or DNA damage; (iv) interaction with the bacterial cell wall or inhibition of cell wall formation; (v) changes in the function of the cytoplasmic membrane (e.g., modifications of the membrane permeability or fluidity, cytoplasmic membrane damage, and—as a result—the membrane’s disruption); (vi) inhibition of energy metabolism; (vii) changes in cell attachment as well as inhibition of biofilm formation [ 6 ]. Polyphenols modulate the profile of microbiota, both by stimulating some species and by inhibiting others, which results in a changed ratio between the most important groups of bacteria—the condition called dysbiosis. Dysbiosis involves the loss of beneficial bacteria and/or an expansion of pathogenic microbes (pathobionts), which leads to an imbalance between the number of particular bacteria or to reduced microbial diversity. It has been shown that dysbiosis promotes inflammation and immunological dysregulation, and is associated with various diseases such as irritable bowel syndrome (IBS), functional dyspepsia, metabolic disorders (diabetes, obesity, and non-alcoholic fatty liver disease), colorectal cancer, inflammatory bowel diseases (Crohn’s disease and ulcerative colitis), cardiovascular diseases, and small intestinal bacterial overgrowth (SIBO) [ 261 , 262 , 263 , 264 , 265 , 266 ]. Instability of the gut microbiome can be caused by many factors, including infection, exercise, sleep pattern, exposure to antibiotics, various co-morbidities, and—as proven above—by diet. This, of course, does not mean that polyphenols are responsible for the mentioned diseases; however, it is possible that they can interfere with the severity of symptoms or the treatment. Recently, there is growing interest in the other serious consequences of gut microbiota imbalance. Gut dysbiosis impairs the function of the gut–brain axis, which is associated with the development of various neurological and psychiatric disorders such as anxiety, stress, major depressive disorder, schizophrenia, bipolar disorder, autism spectrum disorder, and attention-deficit hyperactivity disorder, as well as Parkinson’s disease, Alzheimer’s disease, dementia, multiple sclerosis, and epilepsy [ 267 , 268 , 269 , 270 , 271 ]. In conclusion, the inhibition of intestinal microbiota by polyphenols implicates changes in their physiological role, e.g., in the amount of all bacterial metabolites that are important for human health, such as vitamins, amino acids, SCFA, antimicrobial peptides, and neurotransmitters [ 265 , 272 ]. Moreover, the participation of microbiota in detoxication is also disturbed, as these microorganisms are responsible for the degradation not only of food ingredients, but also of a number of xenobiotics (such as drugs), in particular, compounds with branched chains or aromatic rings [ 272 , 273 , 274 ].

Polyphenols, due to numerous active functional groups, interact not only with reactive oxygen species or free radicals, but also with other chemical compounds that they “encounter” in their environment. Among such interactions, it is worth mentioning some that can have a very negative impact on human health. The most important are the interactions of polyphenols with the components of various drugs (e.g., with iron-containing preparations used to treat anaemia) and the influence of polyphenols on drug metabolism, as well as pharmacokinetics, which may result both in increasing and diminishing their therapeutic effect. In general, consumers are often aware of such interactions, and, for example, they know that medicines should not be taken with grapefruit juice or herbal infusions. However, they are not fully aware of what lies at the basis of such recommendations. The basic mechanism relies on the impact of polyphenols on the activity of drug-metabolizing enzymes, such as phase I and phase II enzymes, e.g., cytochrome P450, glutathione S-transferase, UDP-glucuronosyltransferase, sulfotransferase, N-acetyltransferase, methyltransferase, epoxide hydrolase, and NAD(P)H:quinone oxidoreductase [ 109 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 ]. The cytochrome P450 (P450 or CYP) is a group of haem-containing isoenzymes that are responsible for the metabolism of a wide range of endogenous compounds (steroid hormones, lipids, and bile acids), as well as various xenobiotics, mainly those of hydrophobic nature, including drugs, carcinogens, environmental pollutants, and dietary products [ 283 , 284 ]. It is also the final element of the electron transport chain, in which electrons are transferred to an oxygen atom in the O 2 molecule, reducing it to the H 2 O molecule [ 285 ]. The basic P450 reactions catalysed by P450 include C- and N-hydroxylation; N-, O-, and S-dealkylation; N- and S-oxidation; epoxidation; dehalogenation; ring contraction and formation; dehydration; C-C bond cleavage; isomerization; reduction; oxidative deamination [ 280 , 284 ]. Various isoenzymes occur widely in almost all tissues; however, they show the greatest activity in the liver and gut [ 280 ]. In the human genome, there are above one hundred different genes (with names that begin with CYP) that code for different cytochromes P450 and the number following the letters “CYP” indicates the gene family, while subfamilies are represented by a letter that is followed by yet another number to indicate the specific gene (e.g., for the enzyme CYP3A4, “3” stands for the gene family, “A” for the subfamily, and “4” defines the gene that encodes a specific polypeptide) [ 286 ]. Cytochromes that belong to families 1, 2, and 3 are the principal xenobiotic metabolizers, while the others are involved in the biotransformation and elimination of various endogenous biomolecules such as fatty acids and hormones. The most significant CYP isoenzymes and the most abundant in humans are CYP3A4 and CYP2D6, which are present mainly in the liver and the gut wall [ 280 , 285 , 287 ]. Polyphenols, as well as polyphenol-rich food (e.g., herbs, spices, and fruit), can alter drug absorption, distribution, and metabolism, the latter both by the inhibition of P450 activity (the basic types of enzyme inhibition are competitive, non-competitive, and uncompetitive), and the reduction of P450 activity, which of course directly influences the clinical effects of drugs [ 110 , 281 , 282 , 288 , 289 , 290 , 291 , 292 , 293 ]. When the metabolism of a drug is limited, its concentration in the blood or tissues increases, causing various effects which are sometimes very dangerous. On the other hand, the induction of P450 activity diminishes the duration of action of a drug by increasing its metabolic elimination, which is also an undesirable effect and may pose a serious risk [ 109 ]. In addition, polyphenols can also affect drug transport through their interaction with the drug transporters, e.g., P-glycoprotein belonging to ABC transporters [ 294 ], organic anion transporting polypeptides (OATPs), and organic cation transporters (OCTs) [ 293 , 295 ]. This means that there is a considerable risk for an adverse impact of the drug–polyphenol interactions, especially for drugs with a narrow therapeutic index such as warfarin, cyclosporine A, and digoxin. To avoid these side effects, both the patient and the doctor should be aware of the known interactions between the most commonly used drug and various kinds of food or herbal preparations. Known interactions are summarized and presented in Table 2 . Summarizing the available literature, the most important polyphenols that exert inhibitory activity against drug-metabolizing enzymes include quercetin and its derivatives [ 331 , 332 ], resveratrol [ 282 ], chrysin [ 333 ], anthocyanins, naringenin [ 334 , 335 ], apigenin [ 336 ], coumarins [ 337 ], kaempferol [ 332 ], acacetin [ 338 ], luteolin, diosmetin [ 339 ], caffeic acid [ 340 ], and gallic acid [ 109 , 341 ]. There are also some “dangerous” plants that, if consumed along with medications that are permanently taken, should be carefully controlled, and the concomitant consumption should be under the supervision of a physician. These include, among others, grapefruit, orange, grape, apple, goji berries, raspberry, cranberry, mulberry, mango, tangerine, ginger, green tea, St. John’s Wort, avocado, spinach, and tomato juice [ 295 , 342 ]. Therefore, both physicians and other health care providers, including pharmacists in community pharmacies, should draw the attention of patients to the fact that “natural” is not always “safe.” It is necessary that patients that permanently take medicines and want to use herbal supplements should purchase them from a pharmacy only after pharmacist counselling. There is a strong need for proper communication about possible side effects of the concomitant use of many natural products with drugs. This means that the physician, when prescribing a drug from the group susceptible to interactions (especially, but not only, those listed in Table 2 ), should inform the patient in detail about potential interactions with food ingredients and explain the resulting health and even life risks [ 343 ].

Among polyphenols are isoflavones, which have gained popularity as an alternative treatment for menopausal symptoms for women who cannot take hormones. Isoflavones are structurally similar to oestrogens in that, in various tissues, they can exert both estrogenic and antiestrogenic properties [ 344 ]. It is very important to remember that the biological activity of isoflavonoids depends on the gut microflora composition, because only enzymes of particular bacteria can conduct the conversion of isoflavonoids, i.e., daidzein can be converted into its biologically active metabolites S-equol or O-desmethylangolensin, while genistein can be converted to p-ethyl phenol. Although isoflavones seem to have a positive impact on post-menopausal women, their impact on women at the reproductive age might be less beneficial. Chandrareddy [ 345 ] described the case of three women with endometrial pathology whose abnormal uterine bleeding was related to a high intake of soy products. The first of the patients had postmenopausal bleeding with uterine polyp, proliferative endometrium, and a growing leiomyoma, the second had severe dysmenorrhea, abnormal uterine bleeding, endometriosis, and uterine leiomyoma not responding to treatment, and the last woman—severe dysmenorrhea, abnormal uterine bleeding, endometriosis, and uterine leiomyomata presented with secondary infertility. In all of these cases, the problems were reduced or disappeared when soybean and soybean products were excluded from the diet. The side effect of soy isoflavones was also reported in a placebo-controlled crossover trial conducted by Hutchins et al. [ 55 ]. The only participant, upon entry into the study, was a healthy, well-nourished, and normotensive postmenopausal woman (51 years old). She consumed the first of four randomly assigned treatments (500 mg vitamin C plus 5 mg/kg body weight soy isoflavones) and, during this treatment, her systolic blood pressure spiked to a recorded 226/117 mmHg, which required a medical intervention and discontinuation of study participation. A possible mechanism for this reaction can involve the inhibition of monoamine oxidase by the isoflavones or their metabolites (S-equol) [ 346 , 347 ] as well as an imbalance in the renin-angiotensin system, an important regulator of blood pressure. Angiotensinogen production by the liver can be modulated by oestrogens [ 348 ]; therefore, an increase in serum isoflavone concentrations, due to the high isoflavone intake, might stimulate an oestrogenic response, thereby increasing hepatic angiotensinogen production and its release into the plasma. This means that, regardless of the mechanism, patients who are consuming soy isoflavone supplements should be informed that elevated blood pressure may be a potential side-effect to consider and it should be monitored. There is also evidence that, while in women the estrogenic activity of isoflavones is harmless or even beneficial, in the case of men it can lead to troubles with sexual activities. It was proven that the plasma testosterone and androstenedione levels were significantly lower in adult Sprague–Dawley rats that were fed a phytoestrogen-rich diet (containing approximately 600 µg/g isoflavones) compared with animals fed a phytoestrogen-free diet [ 349 ]. After five weeks of consuming these diets, plasma phytoestrogen levels were 35 times higher, while body and prostate weights were significantly decreased in animals fed the phytoestrogen-rich diet vs. the phytoestrogen-free fed animals. There is also a known case of a 60-year-old man with bilateral gynecomastia of six months’ duration, who also reported erectile dysfunction and decreased libido [ 350 ]. In his medical history, no changes in testicular size, no testicular trauma, no sexually transmitted diseases, no headaches, no visual changes, and no change in muscular mass or strength were reported, and testicular ultrasonography was normal. However, a laboratory assessment showed that his estrone and oestradiol concentrations were increased four-fold above the upper limit of the reference range. After another detailed interview, it was revealed that the patient drank three quarts of soy milk daily. After he discontinued drinking soy milk, his breast tenderness resolved, and his oestradiol concentration slowly returned to normal. With the exception of the case which was just described, findings from various human studies and meta-analyses show that neither isoflavone supplements nor soy products affect male reproductive hormones, and serum testosterone or oestrogen levels in men are not altered [ 351 ]. In other words, isoflavones do not exert feminizing effects on men when consumed at levels equal to and even considerably higher than are typical for males [ 352 ]. Therefore, can isoflavones actually cause hormonal imbalances? Generally, it seems that, in healthy people, isoflavones do not pose a threat; however, in the case of people with complete deficiencies or diseases, the situation may be different. Several studies have found that soy isoflavones can inhibit the thyroid hormones in people with iodine deficiency. Genistein has been shown to reduce thyroid peroxidase (TPO) (in vivo studies with rats) by up to 80% in a dose-dependent manner [ 353 ]. In another study, genistein and daidzein were proven to induce microfollicular changes in the thyroid tissue in rats and reduced the level of thyroid hormones in Orx middle-aged male rats (a model of andropause). This reduction consequently led to a feedback stimulation of pituitary TSH cells, and the stimulatory effect was higher in the daidzein-treated rats [ 354 ]. Some in vitro and in vivo studies have shown that various polyphenols can act as potent inhibitors of TPO, a key enzyme in thyroid hormone synthesis. For example, flavonoids such as fisetin, kaempferol, naringenin, and quercetin inhibited TPO with IC 50 values ranging from 0.6 to 41 µM, while the IC 50 values for inhibition of TPO-catalysed reactions by genistein and daidzein were ~1–10 µM [ 355 , 356 ]. In subjects with subclinical hypothyroidism, diet supplementation with 16 mg soy phytoestrogens caused a three-fold increased risk of developing overt hypothyroidism; a soy phytoestrogen supplementation significantly reduced the insulin resistance, hsCRP, and both systolic and diastolic blood pressure in these patients [ 357 ]. On the other hand, a randomized controlled trial among Chinese postmenopausal women that were “equol-producers” demonstrated that the consumption of both soy and purified daidzein are safe and have no detrimental effect on thyroid function [ 358 ]. Similarly, when 14 trials (thyroid function was not the primary health outcome in them) were analysed for the effects of soy products or isoflavones on thyroid function, either no effects or only very modest changes were noted [ 359 ]. Thus, the findings provide little evidence that, in euthyroid or iodine-replete individuals, soy products or isoflavones adversely affected thyroid function. This is contrary to the hypothyroid patients, in which soy foods, by inhibiting absorption, could increase the dose of thyroid hormones. Genistein, glycitein, and daidzein were proven to compete with thyroxine in the attachment to transthyretin [ 360 ], which is the main transport protein for thyroid hormones. Therefore, isoflavones might change the concentration of free thyroid hormones, resulting in impaired tissue availability and metabolism, followed by a disturbance in the feedback regulation of hormonal networks, including the pituitary–thyroid–periphery axis during development and in adult organisms. Research conducted by Ariyani et al. [ 361 ] has shown a novel mode of action of soybean isoflavones on thyroid hormone receptors (TR) function. They proved that genistein and daidzein augmented T3-liganded TR-mediated transcription in a concentration-dependent manner and augmented the recruitment of steroid receptor coactivator-1 and nuclear corepressor to liganded or unliganded TRs. These findings indicate that the augmentation of the TR-mediated transcription by genistein and daidzein is due to their direct binding to the TR-ligand-binding domain to induce the recruitment of steroid receptor coactivators. In another study, the correlation was analysed between feeding children with soy-containing formulas and the development of autoimmune thyroid disease [ 362 ]. The authors reported that the frequency of feedings with soy-based milk formulas in early life was significantly higher in children with autoimmune thyroid disease as compared to their siblings (prevalence 31% vs. 12%, respectively) as well as to healthy nonrelated control children (prevalence 13%). Therefore, the association of soy formula feedings in infancy with autoimmune thyroid disease was proved. In conclusion, the available results of various studies are ambiguous and often even contradictory. Further research is needed to clearly show whether the use of isoflavones is safe, or in which subpopulations these compounds will have side effects or could pose a threat.

Although polyphenols are strong antioxidants, in certain circumstances (high level of metals, alkali pH, and O 2 presence) they can also act as prooxidants. Their prooxidant activity is catalysed mainly by transition metals (copper and iron) and results from the generation of a redox complex with a transition metal ion or a phenoxyl radical [ 363 ]. Phenoxyl radicals can then react with oxygen and various reactive oxygen species (ROS) (such as O 2 −• and H 2 O 2 ) are formed. These molecules are highly reactive and induce DNA damage or lipid peroxidation, or initiate the oxidation of other important molecules. It has been proven that some polyphenols, especially those with small molecules such as dihydroxycinnamic acids, are easily oxidized and cause DNA incision or lipid peroxidation as a result of the activity of radicals produced in the presence of Cu and oxygen [ 364 , 365 ]. Zeng et al. [ 366 ] indicated that the compounds bearing a dihydroxyl group in the ortho - conformation (e.g., caffeic acid and chlorogenic acid) or bearing a 4-hydroxy-3-methoxyl group (e.g., sinapic acid and ferulic acid) induced significantly higher DNA damage than the ones bearing no such functionalities, and that ROS and Cu ions were involved in the damage. In addition to copper, the metals and metalloids that can catalyse such reactions also include Al, Zn, Ca, Cr, Mn, Co, Ni, Mg, As, and Cd [ 363 ]. Taking into account that copper is a rate-limiting nutrient for the growth and proliferation of cancer cells, they are often characterized by higher level of intercellular copper than in normal cells [ 367 ]. Therefore, the prooxidant activity of some polyphenols in the presence of copper can be used against cancer cells because they would exert a pro-apoptotic effect in various types of tumour cells, avoiding normal cells [ 368 , 369 ]. There have been many studies demonstrating the prooxidant activity and the associated destructive potential of various polyphenolic compounds, including resveratrol [ 370 ], kaempferol [ 371 ], curcumin [ 372 , 373 ], caffeic acid [ 374 , 375 ], p -coumaric acid [ 376 ], ferulic acid [ 377 ], gallic acid [ 378 ], salicylic, syringic, vanillic, p -, m - and o -coumaric acids, p - and m -hydroxybenzoic acids [ 379 ], catechin [ 380 ], epicatechin and epigallocatechin [ 381 ], ellagic acid, phloroglucinol, pelargonidin, pelargonidin-3- O -rutinoside [ 382 ], quercetin [ 383 , 384 ], and metal complexes of quercetin such as quercetin copper(II) complex [ 385 ], quercetin nickel(II) complex [ 386 ], quercetin zinc(II) complex [ 387 ], and quercetin manganese(II) complexes [ 388 ]. Moreover, it is not only pure polyphenols which can act as prooxidants. A prooxidant activity was observed for polyphenolic extracts prepared from Syrah and Chardonnay grape pomaces [ 389 ] or wines [ 390 ]. The extracts made from red raspberry ( Rubus idaeus L.) stem could exert prooxidant activity when adequate conditions of pH and temperature are provided [ 391 ]. In the study by Tsukada et al. [ 392 ], an aqueous extract of grape pomace obtained from winemaking upon photo-irradiation generated hydroxyl radicals and, thus, exerted prooxidant activity. While the prooxidative properties of polyphenols are intended and are a means of destroying cancer cells, polyphenols can be considered beneficial molecules. However, if polyphenols begin to induce the oxidation of normal cell components, including DNA damage, which may eventually lead to mutagenesis, the effects may be undesirable. Therefore, further research should be conducted to explain under what conditions an antioxidant changes its face and begins to be a prooxidant.

In some cases, polyphenols can have a negative impact on cells, stimulating mutagenesis or exerting cancerogenic and genotoxic effects. There are several studies which show that some flavonoids can mediate DNA cleavage not only by prooxidant activity, but also due to their interaction with topoisomerase IIα and IIβ. The results showed that genistein enhanced DNA cleavage mediated by human topoisomerase IIα and Iiβ, and the scission could be reversed when EDTA was added to reaction mixtures before cleavage complexes were trapped by SDS [ 393 ]. In other studies, (−)-epigallocatechin gallate (EGCG) [ 394 ] was proven to be a redox-dependent topoisomerase II poison that acts by covalently adducting to the enzyme. Similar studies have revealed that various polyphenols can inhibit topoisomerase due to different mechanisms. EGCG and (−)-epigallocatechin (EGC) were redox-dependent topoisomerase II poisons, kaempferol and quercetin were traditional poisons, myricetin utilized both mechanisms, and (−)-epicatechin gallate(ECG) and (−)-epicatechin/EC/had no significant activity [ 395 ]. According to the authors, the C4′–OH was critical for the polyphenols to act as a traditional poison, while the addition of –OH groups at C3′ and C5′ increased the redox activity of the B ring and allowed the compound to act as a redox-dependent poison. This means that other polyphenols with similar structure can also be potential topoisomerase poisons. The abovementioned studies were conducted with human cells, and flavonoids were proven to be poisons of human topoisomerase IIα and IIβ. However, there are some data suggesting that flavonoids, such as coumarins, quercetin, EGCG, ECG, EGC, and apigenin, can also act as inhibitors of the bacterial enzymes DNA gyrase and topoisomerase IV [ 396 , 397 , 398 , 399 , 400 ]. Both belong to the type II bacterial topoisomerases; the first is involved in supporting nascent chain elongation during replication of the bacterial chromosome, whereas the second separates the topologically linked daughter chromosomes during the terminal stage of DNA replication [ 401 ]. This inhibitory impact on bacterial topoisomerases may result in the dysbiosis of intestinal microbiota, with its all consequences. Some polyphenolic compounds can exert mutagenic activity. In the study by Spada et al. [ 402 ], 23 samples of frozen fruit were tested for their mutagenic and antimutagenic activity. The obtained results showed that acai, cashew apple, kiwi fruit, and strawberry pulps exhibited mutagenic activity in all loci ( Lys -revertant, His -revertant, and Hom -revertant) that were assayed when investigated in a haploid XV 185-14C strain of Saccharomyces cerevisiae cells. The impact was observed for high concentrations (5–15% [wt/vol]) and was dose-dependent. Carcinogenic effects of polyphenols can be also a result of their intercalating into DNA or their ability to induce chromosome damage [ 386 , 403 , 404 , 405 ]. Some studies suggest that quercetin induces H 2 O 2 -mediated DNA damage, which results in apoptosis or mutations and may be related to the carcinogenic effects of quercetin, whereas luteolin induces apoptosis via DNA cleavage mediated by topoisomerase II [ 406 ]. Other data demonstrate that some bioflavonoids can cause chromosomal translocations through either topoisomerase II-dependent (myricetin, genistein, and quercetin) or topoisomerase II-independent (luteolin and kaempferol) mechanisms [ 405 ]. Among several dozen naturally occurring flavonoids, the flavones C-glycosides vitexin and orientin showed moderate sister chromatid exchange (SCE)-inducing activity, while other compounds showed only weak activity or were inactive [ 407 ]. Procyanidins consisting of three or four flavanol units, and—to a lesser extent—flavone, flavonol, and anthocyanidin aglycones, induced polyploidy. Aglycones, as well as C- and O-glycosides, spiraeoside, and luteolin-7-glucoside, were more or less active in inducing micronuclei in lymphocytes. In turn, no genotoxic effects were caused by flavonol O-glycosides (rutin and hyperoside) as well as monomeric and dimeric flavanols. In vitro experiments on calf thymus DNA treated with quercetin for various time periods have shown that the initial interaction of quercetin with DNA may have a stabilizing effect on the DNA secondary structure; however, the prolonged treatment with quercetin led to an extensive disruption of the double helix [ 408 ]. When the ability of various flavonoids (morin, apigenin, and naringin) to bind to DNA was investigated, both intercalation and external binding to the DNA duplex were observed [ 409 ]. Structural analysis demonstrated that quercetin, kaempferol, and delphinidin can bind weakly to adenine, guanine (major groove), and thymine (minor groove) bases, as well as to the backbone phosphate group; the stability of adduct formation was in the order of quercetin > kaempferol > delphinidin [ 410 ]. In further studies, quercetin, kaempferol, and delphinidin were proven to intercalate tRNA duplex, whereas flavonoid-DNA adducts showed both intercalation and external bindings [ 411 ]. Low flavonoid concentration induced the stabilization of the double helix, whereas high content caused helix opening. In other studies, myricetin [ 412 ] and kaempferol [ 413 ] were proven to induce a significant concentration-dependent nuclear DNA degradation concurrent with lipid peroxidation, both enhanced by the presence of iron (III) or copper (II). As lipid peroxidation induced by myricetin could be inhibited by SOD in the presence of copper (II), whereas it was enhanced by catalase in the presence of iron (III), similarly for kaempferol, the results suggest prooxidant properties of the studied polyphenols and their dual role in mutagenesis and carcinogenesis. The UV spectroscopic and fluorescence quenching proved that quercetin can bind to bovine serum albumin (the tryptophan residues are involved) and that the complex may lead to fragmentation of the protein when Cu(II) is present [ 414 ]. In vitro studies demonstrated that the exposure of primary human CD34+ hematopoietic cells to biologically relevant concentrations of flavonoids (quercetin, genistein, and kaempferol) caused a dose-dependent double-strand break (DSB) [ 415 ]. An incorrect repair of these DSBs resulted in chromosomal translocations and correlated with infant leukaemias. These results were then confirmed in in vivo studies on an animal model, in which heterozygous Atm-ΔSRI mice (DNA repair-deficient mice) obtained a flavonoid-poor (normal) chow or the same chow supplemented with genistein (270 mg/kg) or quercetin (302 mg/kg) throughout pregnancy [ 416 ]. The results revealed that prenatal exposure to both quercetin and genistein supplements was associated with higher frequencies of Mll rearrangements and a slight increase in the incidence of malignancies, especially in the presence of compromised DNA repair. One of the most common loci involved in chromosomal translocations is the break point cluster region of the mixed-lineage leukaemia (MLL) gene. This gene is involved in normal haematopoiesis and chromosomal translocations involving the MLL gene are often in various leukaemias. Lu et al. [ 417 ] have demonstrated that EGCG can induce death and DNA damage in human lung and skin normal cells. The results of their study showed direct evidence of reductive DNA damage in the cells; EGCG at concentrations below 100 µM slightly increased the lung cancer cell viability. Moreover, EGCG induced DNA double-strand breaks and apoptosis in normal cells, and enhanced the mutation frequency. The mutagenic activity of phenolic-rich extracts made from Ficus adhatodifolia and F. obtusiuscula (plants used in traditional medicine mainly for the treatment of worms) was demonstrated by the Salmonella typhimurium reverse mutation test (four strains) [ 418 ]. Mutagenic activity of the TA97 strain without metabolic activation was observed for both tested extracts; in the case of the TA102 strain, both extracts were mutagenic with metabolic activation, while the extract of F. adhatodifolia was shown to be mutagenic to the TA102 strain without metabolic activation. The mutagenic properties of the ethanolic extract (EE) from flowers of Combretum leprosum (a traditionally used Brazilian medicinal plant) were proven in experiments performed using the XV185-14c haploid strain of S. cerevisiae , while its toxicity was proven in Chinese hamster lung fibroblast (V79) cells [ 419 ]. Destructive effects of polyphenols on cells can also be the result of their interactions with cell membranes. Ollila et al. [ 420 ] reported that acacetin, rhamnetin, apigenin, and morin caused destabilization of the membrane structure (by the disorientation of the membrane lipids), which resulted in induced leakage from the model vesicle. Similarly, naringenin and hesperidin significantly increased the fluidity of model lipid membranes composed of dimyristoylphosphatidylcholine [ 421 ]. Both of the flavonoids induced alterations in the arrangement of polar heads of lipids; hesperidin caused weakly disorder in hydrophobic region, while naringin has an ordering effect in this region. Naringin was also more effective than hesperidin in terms of inducing changes in the membrane organization. Considering that polyphenols can disrupt the membrane functioning, there is a high risk of their toxic effect on cells. The prooxidative activity of some polyphenols combined with their ability to affect membranes may cause the mitochondrial toxicity due to collapsing the mitochondrial membrane potential and directing the cell into apoptotic pathway [ 275 ]. The impaired function of the mitochondria is involved in various human disorders, such as neurodegenerative diseases, diabetes, obesity, and cancer, while disorders in the control of apoptosis may result in carcinogenesis. On the other hand, quercetin, which can interact with DNA, is able to arrest cell cycles and, hence, cause tumour regression by activating the mitochondrial pathway of apoptosis [ 422 ]. Although the results of in vitro studies or animal models are not always confirmed by in vivo studies on humans, people or companies marketing polyphenol-containing supplements and foods fortified with these compounds should be aware of the dangers associated with polyphenols and their potential negative impact on human health.

Polyphenols are quite important secondary metabolites of plants. Up until now there are about 8000 polyphenolic structures which have been found in plants and described [ 1 ]. Among the primary functions they perform in plants are giving colour to flowers and fruits, mainly by anthocyanins. Thanks to this, insects necessary for pollination or animals that contribute to the distribution of fruits and seeds contained in them are attracted. By giving fruits and vegetables a tart taste (astringent) polyphenols cause an unpleasant sensory perception [ 2 ]), polyphenols protect plant tissues to some extent against herbivores and—thanks to their antimicrobial activity—limit the spread of pathogens in plants [ 3 ]. Some polyphenols, such as flavonoids, are also involved in energy transfer, sex determination, regulation of growth factors, photosynthesis, and morphogenesis. They also protect plants against other abiotic stressors, such as UV radiation, cold, heat, and salinity [ 4 ]. Polyphenols are a large group of compounds that comprise phenolic acids, flavonoids (these include flavonols, flavanones, flavan-3-ols, flavones, anthocyanins, and isoflavones), lignans, stilbenes, and—according to some classifications—tannins and coumarins [ 5 , 6 ]. In a human diet, they are provided mainly by plant food. Among the richest food sources of polyphenols are seasonings and dried herbs (e.g., cloves, peppermint, anise, oregano, and rosemary), green tea, cocoa, dark-coloured berries, some seeds and nuts (e.g., flaxseed, soybean, chestnut, and hazelnut), and some vegetables (e.g., black olives, globe artichoke heads, and red chicory) [ 7 , 8 ]. However, various fresh, frozen, and dried fruits should also be taken into account (e.g., pomegranate and tropical fruits) [ 9 , 10 , 11 ]. In addition, many people take polyphenols in the form of dietary supplements that contain either purified polyphenols (e.g., quercetin [ 12 ] and resveratrol [ 13 ]) or extracts from raw materials which are rich in these ingredients (such as extracts from tea, red wine, grapes, blueberries, pomegranate, etc.) [ 11 , 14 , 15 , 16 ]. Unfortunately, even when phenolic compounds occur in the human diet in large quantities, they do not always show high biological activity immediately after consumption [ 5 ]. Their activity depends on both their bioaccessibility (the amount of an ingested nutrient that is available for absorption in the gut after digestion) and their bioavailability (the fraction of an ingested nutrient that reaches the systemic circulation and the specific sites where it can exert its biological action). The main factors which affect the bioavailability/bioaccessibility of polyphenols are food matrix, food processing, and digestive enzymes [ 17 , 18 ]. Moreover, some polyphenolic compounds can exert their biological activity only after the biotransformation by intestinal microbiota [ 6 ].

Analysing the examples cited in this work, it can be seen that many studies have been conducted in vitro, and the doses of polyphenols that exerted a specific effect are often very high and difficult to achieve with the consumption of “normal” food. Unfortunately, in the minds of consumers, there are often only abbreviated versions of the results, such as “improves the condition of the circulatory system,” “reduces cholesterol,” “increases immunity,” “reduces the risk of cancer,” “slimming effect,” etc. Wanting to achieve the intended effect as soon as possible, many reach for a simpler way, i.e., they choose supplements. Thus, the problem of possible negative impacts of polyphenols becomes real, because the consumption of supplements is not controlled in any way, and polyphenol supplements contain huge doses of pure polyphenols. What is more, they are easily available and very cheap. Why are they so dangerous? A few examples to better illustrate the phenomenon are: there are many supplements that contain 2000 mg of pure resveratrol in one pill or capsule; moreover, the recommended serving dose is sometimes more than one piece. Among food, the richest in resveratrol is red wine prepared from muscadine grapes, containing about 30 mg of resveratrol per litre. This means that, to achieve 2 g of resveratrol with wine, one would be required to drink almost 100 L. This is, of course, impossible; however, in the form of supplements, it can be done with ease! Just swallow one capsule. The same situation exists for quercetin. According to the Phenol explorer base ( http://phenol-explorer.eu/ , accessed on 2 March 2023), the highest concentration in food sources was found in dried oregano, up to 42 mg per 100 g fresh weight. If someone wants to provide their body with 1 g of quercetin, they can either swallow one supplement capsule or consume 2.4 kg of this seasoning. Commercially available supplements (EGCG Green Tea Standardized Extract) contain 1800 mg of green tea extract, in which 45% of the extract constitutes pure EGCG. Infusions of green tea made at home contain about 270 mg EGCG per litre. Again, one can take one capsule, providing the body with about 800 mg of EGCG, or drink approximately 3 L of tea infusion. It should be clearly emphasized that, in general, polyphenols are safe for healthy individuals when consumed as a part of a balanced and varied diet. They are valuable natural compounds which help to prevent and treat many diseases or defend against various kinds of stress. Therefore, polyphenols should be introduced into our diet, especially as components of natural, low- or non-processed food such as fruit, vegetables, nuts, herbs, spices, tea, or juices. However, the risk of possible negative side effects increases when polyphenols are consumed in large amounts without medical supervision in the form of dietary supplements or as various plant extracts. Such products usually contain huge doses of polyphenols which are often in the form of chemically purified aglycones (instead of glycosides which are present in “natural” food) that are impossible to achieve by normal food consumption. The negative effects of polyphenols are also more likely to occur when a polyphenol-rich diet or supplements are taken by people being treated for various chronic illnesses who are required to take prescribed medications each day. Therefore, the authors of the review claim that it is very important to raise public awareness about the possible side effects of flavonoid supplementation, especially in the case of various vulnerable subpopulations. Further research is needed to explain in detail which cell types and under what kind of conditions polyphenols can exert prooxidant, mutagenic, or genotoxic effects, and thus promote the development of cancer. It should also be clarified whether the polyphenols may have a beneficial effect due to their damaging impact on the cancer cells only. We claim that, in the near future, all polyphenol supplements, as well as some types of novel food or enriched food, should be provided with detailed characteristics of their ingredients, describing both the positive, desirable influences of their intake on the human body and possible negative impacts, with vulnerable groups being enumerated.