**2.6 Ginger (***Zingiber officinale* **Roscoe)**

*Phytochemicals in Human Health*

AFB1 to excretable forms [43–46].

the progression of angiogenesis [49].

**2.5 Green vegetables**

Curcumin is a major active component of turmeric. It belongs to curcuminoid group and commonly found in 2–8%. Previous *in vivo* studies investigated the effects of turmeric and curcumin on AFB1-induced toxicity, and results showed that turmeric and curcumin decreased AFB1-adduct formation, biomolecule damage, and hepatotoxicity [43–46], and it also inhibited acute toxicity through disturbing the lysis of erythrocytes [47]. During AFB1 metabolism, free radicals generated by AFB1 could be readily inhibited by turmeric and curcumin via decreasing lipid peroxidation and enhancing glutathione content. Likewise, they could activate several antioxidant enzymes such as glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), GST, and UGT which play a fundamental role in converting

Turmeric is found to be capable of reducing both AFB1-induced toxicity and HCC. Besides, it could also stimulate apoptosis of liver cancer cells through a mitochondria-dependent pathway and accumulation of calcium ions within the cells [48]. Turmeric showed the protective effect against AFB1-induced liver cancer in animal model by inhibition of metastasis and growth factor expression related to

Chlorophyll (chla), a main component of green vegetables, consists of a porphyrin ring structure where magnesium is the central atom of the ring. Chla is important for plants' photosynthesis pathway and used as food additives. One of the characteristics of chla is almost insoluble in water while chlorophyllin (CHL), a derivative of chla, is completely soluble. CHL can be transformed into water-soluble form by saponification, a reaction that magnesium central atom is replaced with copper. *In vivo* and clinical studies in pharmacological researches of both chla and CHL revealed that they provided the therapeutic uses such as wound healing, antiinflammation, anti-oxidation, anti-mutagenesis, and anti-carcinogenesis [50, 51]. Previous studies on the protective effects of chla and CHL on AFB1 toxicity indicated that both compounds could reduce absorption of AFB1 from apical to basolateral sides in Caco-2 cell line [52]. Accordingly, a crossover clinical trial demonstrated that chla and CHL exposure could reduce maximum concentration (Cmax) and area under the curves (AUC) of AFB1 compared to untreated group [53]. These findings suggest that chla and CHL have a strong potential to decrease AFB1 absorption. The effects of chla and CHL co-exposure with AFB1 have also been studied in animal model by emphasizing on antioxidant activities. Both bioactive compounds are capable of reducing AFB1 toxicity through enhancing the expression of glutathione level and several antioxidant enzyme activities such as GPx, SOD,

A recent study investigated the effects of CHL on AFB1-induced hepatotoxicity and incidence of carcinogenesis in animal model. Exposure with CHL reduced hepatotoxicity and incidence of liver cancer [54, 55]. In a clinical study, a randomized controlled trial reported that daily exposure with CHL for 4 months decreased

Several studies were in agreement that chla and CHL reduce AFB1-induced liver cancer through decreasing AFB1 absorption in digestive tract contributing to the decrease of AFB1 bioavailability. Besides, chla and CHL are the powerful antioxidants which effectively lower AFB1-induced oxidative stress. These two compounds not only reduce hepatotoxicity, but also incidence of liver cancer. Thus, the consumption of green vegetables is one of the alternatives to reduce toxicity caused by

AFB1-N7-guanine level in urine compared to placebo group [56].

consuming AFB1-contaminated foods.

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and CAT [54].

Ginger (*Zingiber officinale* Roscoe) contained high content of phenolic compounds in which 6-gingeerol and 6-shogaol are main constitutions [57]. Ginger plays a critical role as hepatoprotective effects through antioxidant mechanism; for example, liver injury by administration of country-made liquor (CML) and ironinduced nonalcoholic fatty liver disease (NAFLD) [58] and liver cirrhosis induced by carbon tetrachloride [59]. It was also reported to show the protective effects against AFB1-induced toxicity.

In in vitro model of AFB1-treated HepG2 cells, ginger extract-pretreated cells exhibited higher percent cell viability and lower intracellular ROS production and DNA strand break when compared to AFB1 treatment alone. In Wistar rats, pretreatment with ginger extract also increased the activities of antioxidant enzymes: GPx, GST, CAT, and SOD, decreased malondialdehyde (MDA) level, and increased reduced glutathione (GSH) content. Co-incubation with ginger extract along with AFB1 also showed a hepatoprotective effect as seen by the lower level of serum enzymes: alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH). Moreover, fat droplets and hepatocyte infiltration with macro-vesicles in liver induced by AFB1 were normalized when pre-treated with ginger extract, clearly showing the effectiveness of ginger on AFB1-induced hepatotoxicity [57].

Mechanism of ginger extract to reduce AFB1-induced hepatotoxicity was demonstrated by *in vivo* study. The expression of nuclear factor-E2-related factor 2 (Nrf2), a redox-responsive transcription factor, was increased when pre-treated with ginger extract. Nrf2 was translocated into the nucleus to regulate the antioxidant response element (ARE) which is the promotor of detoxification and antioxidant genes. Moreover, administration of ginger extract induced the expression of heme oxygenase 1 (HO-1) which is associated with the normalization of redox status [57]. Therefore, ginger extract could reduce AFB1-induced hepatotoxicity in both *in vitro* and *in vivo* through antioxidant activities controlled by the function of Nrf2 and HO-1.
