**1.6 Coffee**

*Strawberry - Pre- and Post-Harvest Management Techniques for Higher Fruit Quality*

Green tea Anti-inflammatory More clinical studies are needed

L-carnitine Chelation of transition metal ions More clinical studies are needed

Lycopene Antioxidant More clinical studies are needed

**Antioxidant Main clinical effects Clinical relevance**

Antiarthritic Antimicrobial Antioxidant Neuroprotective Antidiabetic Antiangiogenesis Anticarcinogenic

Antioxidant Cardioprotective Neuroprotective Anti-inflammatory

Anti-inflammatory Chemoprotective Anticarcinogenic

a single dose of benzo(a)pyrene; and at this dose, coadministration of piperine had a much better effect than did curcumin alone showing enhancer activity of piperine. In acute and chronic liver injury, curcumin has been shown to have hepatoprotective effects [25]. In 2007, Reyes-Gordillo et al. [26] showed that curcumin is able to inhibit the release of TNF-α, IL-1B, and IL-6. Additionally, curcumin reduces carbon tetrachloride (CC14)-mediated oxidative stress inactivating the nuclear factor-kB (NF-kB) pathway. Moreover, curcumin's hepatoprotective effect takes place by its interactions with Fe3+ and Cu2+. A study by Jiao et al. [27] suggested that curcumin could serve as an iron chelator since transferrin receptor 1 and iron regulatory proteins, indicators of iron depletion, showed an increase with curcumin administration. Charoensuk et al. [28] have indicated that curcumin increases antioxidant capacity of cells by increasing mRNA and protein levels of factors and enzymes such as nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), glutamate cysteine ligase (GCL), transcription factor-3, peroxiredoxin 3 (Prdx3), and Prdx6. Curcumin also increases the activity of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) activity [29, 30]. Curcumin also interacts with enzymes or genes that are important in liver cirrhosis. Hassan et al. [31] showed that curcumin modulates miRNA 199 and 200 which are associated with liver fibrosis in CC14-induced experimental fibrosis model and that curcumin reduced these miRNAs levels close to their basal levels. Finally, in alcohol-induced liver damage, curcumin inhibits the activity of cytochrome P450 2E1 (Cyp2e1) and also its protein levels [32].

The phytoalexin resveratrol (3,5,4′-trans-trihydroxystilbene) is a polyphenol mostly found in red grapes, red wine, peanuts, and berries [33]. Resveratrol has effects on lipid metabolism, and it also has antioxidant, anti-inflammatory,

**128**

**1.5 Resveratrol**

**Table 1.**

*Nutritional antioxidants.*

Coffee is a mixture of several different molecules such as carbohydrates, vitamins, lipids, nitrogenous molecules, alkaloids, and phenolic compounds [47]. Caffeine, diterpene alcohols (cafestol and kahweol), and chlorogenic acid are the three major compounds found in coffee [48]. Coffee consumption has been linked to the reduction of several chronic diseases [49], probably due to the pharmacological properties that have antinecrotic, antifibrotic, anticholestatic, chemoprotective, and antioxidant functions [50]. Caffeine is the best-known active component of coffee, which is absorbed very rapidly once it has been taken orally (5 min), reaching its peak blood levels after 30 min. When consumed in high amounts, it may produce some side effects. Recommendations from Health Canada in 2013 demanded that the daily caffeine intake for children should not exceed 2.5 mg/kg of the body weight. What is more, tachycardia and arrhythmia typically arise when more than 200 mg of caffeine are ingested [51]. Smith et al. [52] reported in 2002 that the intake of 300 mg of caffeine resulted in a rise in anxiety and tension. Caffeine gets metabolized in the liver. The principal metabolite of caffeine is paraxanthine [53]. An important property of caffeine is that it can easily pass through the blood-brain barrier [54]. Coffee-cirrhosis relationship was shown by Klatsky et al. for the first time [55]. The study showed that the odds ratio for liver cirrhosis tend to decrease from 1.0 for people abstaining from coffee to 0.47, 0.23, 0.21, and 0.16 for 1, 2, 3, or 4 cups of coffee daily, respectively. Although coffee is generally beneficial to the liver, this study failed to show a causative

role of coffee in prevention of liver injury. Therefore, additional basic research and controlled prospective studies are needed in order to show exact effect of coffee on liver tissue. Arauz et al. [50] demonstrated that coffee has a protective effect upon liver injury caused by chronic administration of thioacetamide (TAA). Coffee ameliorated cholestasis and necrosis and this was seen by the measurement of γ-glutamyl transpeptidase (γ-GTP), alkaline phosphatase, and ALT levels. Arauz et al. [50] demonstrated in murine models that coffee prevents experimental liver cirrhosis. In these studies, coffee reduced the expression of the profibrogenic cytokine TGF-β. Cavin et al. [56] reported coffee to be an inductor of GST, aldo-keto reductase, GSH, HO-1, GST-P1, which are enzymes involved in the detoxification process. Also, they suggested that a possible mechanism of chemoprotection of coffee by stimulating the Nrf2 pathway. In another study, coffee was able to elevate mRNA levels of NQO1 and glutathione-S transferase Al in the liver and the small intestine [57].

#### **1.7 Quercetin**

Quercetin, 3,3,4,5,7-penta-hydroxyflavone, is a flavonol especially found in apples and onions [58]. Quercetin chelates heavy metals and has anticarcinogenic, cardioprotective, bacteriostatic, anti-inflammatory, and antioxidant properties [59]; it also functions as a hepatoprotective agent [60]. The normal daily intake of quercetin is less than 5–40 mg. However, if the peels of the foods that contain high amount of quercetin are also consumed, daily intake of quercetin increases to 200–500 mg [59]. In 2004, high-purity quercetin used in foods was grass that serves 10–125 mg of quercetin [59]. The functional groups responsible for quercetin's antioxidant activity were described by Bors et al. [61] in 1990, and they found that orthodihydroxy or catechol groups in the B-ring, a 2,3-double bond of the C-ring, and OH substitution on positions 3 and 5 of the C-ring and A-ring, respectively, are important players in antioxidant action of quercetin [61]. It can interact with both FR and metal ions like Fe3+ and Cu2+ for chelation. In a study by Mira et al. [62], it was reported that reduction of Fe3+ and Cu2+ takes place by quercetin's 2,3-double bond and the presence of catechol group in the B-ring. Following ingestion, quercetin is rapidly absorbed and its levels in blood peak at approximately in 30 min [63] before it is metabolized by glucuronidation and sulfation by the UGT and ST, respectively.

In experimental fibrosis model in rats, quercetin showed hepatoprotective properties under CCl4 treatment that lasted 8 weeks. The hepatoprotective effect of quercetin was found to be mediated by its ability to suppress the expression of profibrogenic expressions of TGF-β, CTGF, and collagen-lα (Col-1α). On the other hand, quercetin also activated enzymes such as metalloproteinases 2 and 9 (MMP2 and MMP9); it also improved the activity of SOD and CAT [64]. Pavanato et al. [65] extended CCl4 treatment for 16 weeks and also observed that quercetin improved the hepatic liver enzymes AST, ALT, and inducible NOS (INOS) expressions; it also decreased collagen amount and reduced lipid peroxidation in liver. Granado-Serrano et al. [66] showed that quercetin modulated Nrf2 and p38 in HepG2 cells. Quercetin has also been shown to suppress the activity of Cyp2e1 in hepatocytes in the presence of ethanol [67]. In line with this finding, in a nonalcoholic steatohepatitis (NASH) model, quercetin was able to reduce Cyp2el activity [68].

#### **1.8 Silymarin**

Silymarin, milk thistle or Saint Mary's thistle, is a natural substance obtained from *Silybum marianum* [7]. Silymarin has not been associated with any side effects at acute consumption and the dose range used in literature ranges between 280 and 800 mg/kg of body weight per day. After oral administration, the silymarin peak

**131**

**Figure 3.**

*Dietary Antioxidants in Experimental Models of Liver Diseases*

plasma concentration is achieved at approximately 6–8 h. The metabolites of silymarin get conjugated in the liver by UGT and ST (phase II reactions) [69]. This substance has many hepatoprotective effects (**Figure 3**). In fact, silybin, a major constituent of silymarin, has found to have iron chelating properties [71]. In a study performed by Najafzadeh et al. [72], hepatoprotective effect of silymarin in iron-overload-induced hepatotoxicity was attributed to its iron-chelator activity; however, no studies have proved the chelating properties per se of silymarin in liver diseases. Silymarin acts as hepatoprotector against several hepatotoxins including D-galactosamine [73]. Silymarin's ameliorating effects on oxidative stress, fibrosis, cirrhosis, and lipid peroxidation are modulated by its phosphatidylethanolamine amount [74]. This hepatoprotective effect is seen with the improvement of liver enzyme activities and levels of cholesterol/phospholipids and also sphingomyelin/phosphatidylcholine ratios in the membrane [75, 76]. Kim et al. [77] showed that silymarin increases nuclear translocation of Nrf2 in activated HSC. Also, silymarin increases the activity of antioxidant enzymes such as SOD, GPX [78], and CAT [79]. A clinical trial examining silymarin in a complex with phosphatidylcholine found reduced levels of the liver enzymes, ALT and γ-GGT, and serum bilirubin levels in a dose-dependent manner in patients suffering from hepatitis due to virus infection or alcohol abuse [80] (**Figure 3**).

Naringenin is also recognized as 5,7,4′-thihydroxyflavanone, and it is a flavanone

*A schematic notation of the main pharmacological effects of silymarin in accordance with its hepatoprotective features: The effects of Sm upon cell membranes (upper left) and intracellular cascades are shown here. The metabolic paths are indicated by interrupted lines, while its signal effects are shown in full lines. LTB4, leukotriene B4; GSH, glutathione; NF-kΒ, nuclear factor kappa B; PG's, prostaglandins; Sm, silymarin; SOD,* 

*superoxide dismutase; ROS, reactive oxygen types=; TNFa, tumor necrosis factor α [70].*

found in citrus fruits and tomatoes [81]. In a recent study, Yang et al. [82] have

*DOI: http://dx.doi.org/10.5772/intechopen.83485*

**1.9 Naringenin**

#### *Dietary Antioxidants in Experimental Models of Liver Diseases DOI: http://dx.doi.org/10.5772/intechopen.83485*

plasma concentration is achieved at approximately 6–8 h. The metabolites of silymarin get conjugated in the liver by UGT and ST (phase II reactions) [69]. This substance has many hepatoprotective effects (**Figure 3**). In fact, silybin, a major constituent of silymarin, has found to have iron chelating properties [71]. In a study performed by Najafzadeh et al. [72], hepatoprotective effect of silymarin in iron-overload-induced hepatotoxicity was attributed to its iron-chelator activity; however, no studies have proved the chelating properties per se of silymarin in liver diseases. Silymarin acts as hepatoprotector against several hepatotoxins including D-galactosamine [73]. Silymarin's ameliorating effects on oxidative stress, fibrosis, cirrhosis, and lipid peroxidation are modulated by its phosphatidylethanolamine amount [74]. This hepatoprotective effect is seen with the improvement of liver enzyme activities and levels of cholesterol/phospholipids and also sphingomyelin/phosphatidylcholine ratios in the membrane [75, 76]. Kim et al. [77] showed that silymarin increases nuclear translocation of Nrf2 in activated HSC. Also, silymarin increases the activity of antioxidant enzymes such as SOD, GPX [78], and CAT [79]. A clinical trial examining silymarin in a complex with phosphatidylcholine found reduced levels of the liver enzymes, ALT and γ-GGT, and serum bilirubin levels in a dose-dependent manner in patients suffering from hepatitis due to virus infection or alcohol abuse [80] (**Figure 3**).
