**1.9 Naringenin**

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transferase Al in the liver and the small intestine [57].

glucuronidation and sulfation by the UGT and ST, respectively.

titis (NASH) model, quercetin was able to reduce Cyp2el activity [68].

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

**1.7 Quercetin**

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

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

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 steatohepa-

**130**

**1.8 Silymarin**

Naringenin is also recognized as 5,7,4′-thihydroxyflavanone, and it is a flavanone found in citrus fruits and tomatoes [81]. In a recent study, Yang et al. [82] have

#### **Figure 3.**

*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].*

reported that naringenin did not cause any harmful effects in beagle dogs, the maximum time of exposure being 180 days and with doses varying of 20, 100, or 500 mg/kg body weight per day. Naringenin has many pharmacological properties. It acts as a hypolipidemic, antihypertensive, anti-inflammatory, antioxidant, and antifibrotic agent [81]. The metabolism of naringenin takes place in small intestine where glycoside form of naringenin gets cleaved, resulting in sulfate and glucuronide metabolites in the small intestine wall; then, it gets absorbed [77]. Mira et al. [62] showed that naringenin can reduce Fe3+ and Cu2+ ions but it is less potent than quercetin. Chtourou et al. [83] found that naringenin averts depletion of SOD, CAT, GPx, and GSH. On the other hand, naringenin also prevents an increase in lipid peroxidation, and it also prevents increase of enzymes ALT and AST [78]. Yen et al. [84] also obtained similar results on liver enzymes and prevention of lipid peroxidation when they used naringenin alone and also naringenin-loaded nanoparticle system (NARN). In both treatments, naringenin exhibited antioxidant and hepatoprotective activities. In these experiments, treatment with naringenin also inhibited the activation of caspases 3 and 8. However, NARN was found to have better hepatoprotective and antioxidant effects than free naringenin, and it was also shown to inhibit caspase 9 during CC14-induced hepatotoxicity in rats. Han et al. [64] reported that a pretreatment with naringenin-7-O-glucoside increases NQO1 and ERK phosphorylation and translocation of Nrf2 to the nucleus in H9c2 cardiomyocytes. It also upregulated the mRNA expression of GCLC and GCL modifier [64]. Similar findings have been reported by Esmaeili et al. [85] who showed that naringenin attenuates CC14 induced liver injury by downregulating TNF-α, INOS, and cyclooxigenase-2 and also by increasing Nfr2 and HO-1 expressions. Motawi et al. [86] showed that naringenin inhibits Cyp2e1 in liver microsomal assay done on rats [86].
