Role of food-derived antioxidant agents against acetaminophen-induced hepatotoxicity

Abstract

Context Acetaminophen (APAP), also known as paracetamol and N-acetyl p-aminophenol, is one of the most frequently used drugs for analgesic and antipyretic purposes on a worldwide basis. It is safe and effective at recommended doses but has the potential for causing hepatotoxicity and acute liver failure (ALF) with overdose. To solve this problem, different strategies have been developed, including the use of compounds isolated from food, which have been studied to characterize their efficacy as natural dietary antioxidants.

Objective The objective of this study is to show the beneficial effects of a variety of natural compounds and their use against acetaminophen-induced hepatotoxicity.

Methods PubMed database was reviewed to compile data about natural compounds with hepatoprotective effects against APAP toxicity.

Results and conclusion As a result, the health-promoting properties of 13 different food-derived compounds with protective effect against APAP-induced hepatotoxicity were described as well as the mechanisms involved in hepatoprotection.

Keywords:

• Antioxidant capacity
• liver damage
• oxidative stress
• natural compounds

Introduction

Acetaminophen (APAP), also known as paracetamol and N-acetyl-p-aminophenol, is one of the most frequently used drugs for analgesic and antipyretic purposes on a worldwide basis. APAP is a safe and effective drug at recommended doses, but has the potential for causing hepatotoxicity with overdose (Chun et al. 2009; Bunchorntavakul & Reddy 2013; Michaut et al. 2014).

The recommended dose for adults is 325–650 mg every 4–6 h, with a maximum dose of 4 g per day. For children, the recommended dose is 10–15 mg/kg every 4–6 h, with a maximum dose of 50–75 mg per day (Schilling et al. 2010).

When taken at recommended doses, 85–90% of APAP is metabolized by glucuronidation or sulphation and then excreted into the urine, 2% is excreted into the urine unchanged, and <10% is metabolized by the cytochrome P450 into the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). Under normal circumstances, NAPQI is converted to non-toxic metabolites by glutathione (GSH) (Lancaster et al. 2015).

During overdose, APAP is mainly metabolized by cytochrome P450, causing GSH depletion. Consequently, NAPQI reacts with mitochondrial membrane proteins. Mitochondrial protein adducts formation with NAPQI causes ROS production, leading to mitochondrial DNA damage, opening of the mitochondrial permeability transition pore (MPT) and cessation of ATP production. In addition, there is translocation of the membrane protein BAX, which combines with Bak in the outer mitochondrial membrane to form pores and allow the release of intermembrane proteins such as cytochrome c. The release of mitochondrial proteins and cessation of ATP production together lead to cell death (Figure 1) (Jaeschke et al. 2012; Carvalho et al. 2013; Lancaster et al. 2015).

Figure 1. Graphical representation of APAP-induced toxicity. During overdose, APAP is mainly metabolized by cytochrome P450 into the reactive metabolite, NAPQI, which reacts directly with GSH, causing its depletion. As a consequence, NAPQI reacts with mitochondrial membrane proteins. Mitochondrial protein adducts formation with NAPQI causes ROS production in the mitochondria. This leads to mitochondrial deoxyribonucleic acid (DNA) damage, opening of the mitochondrial permeability transition pore (MPT) and cessation of ATP production. In addition, there is translocation of the membrane protein BAX, which combines with Bak within the outer mitochondrial membrane to form pores and allow the release of intermembrane proteins such as cytochrome c. The release of mitochondrial proteins and cessation of ATP production together leads to cell death. ATP, adenosine triphosphate; Ca2+, calcium cation; CI, NADH:ubiquinone oxidoreductase; CII, succinate dehydrogenase; CIII, coenzyme Q: cytochrome c-oxidoreductase; CIV, cytochrome c oxidase; Cyt c, cytochrome c; GSH, glutathione; MPT, permeability transition pore; ROS, reactive oxygen species; Δψm, mitochondrial membrane potential.

APAP-induced hepatotoxicity has been a significant issue for several years. Different strategies to solve this problem have been developed, including the use of natural compounds. The aim of this paper is to provide information about the therapeutic role of food-derived antioxidant agents in APAP-induced hepatotoxicity.

Food-derived antioxidant agents

Curcumin

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] (Figure 2) is the main curcuminoid found in Curcuma longa L. (Zingiberaceae), which is used as a spice and food colorant in curry, mustard, cheese, cereals, soups, ice cream and yogurt (Shishodia et al. 2007; Trujillo et al. 2013; Waseem et al. 2014).

Figure 2. Chemical structure of curcumin, α-lipoic acid, sulphoraphane, lupeol, sesamol, resveratrol and apigenin.

Curcumin is classified as a bifunctional antioxidant agent. Curcumin has demonstrated scavenging activity against a variety of ROS, including superoxide anion (O₂^.-), hydroxyl radical (HO^.), peroxyl radical (ROO^.), nitrogen dioxide radical (NO₂^.), 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH^.), 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS^.+) and N,N-dimethyl-p-phenylenediamine dihydrochloride (DMPD^.+) radical (Reddy & Lokesh 1994; Fujisawa et al. 2004; Ak & Gulcin 2008; Trujillo et al. 2013). The antioxidant capacity of curcumin is also related to the inhibition of lipid peroxidation and the induction of nuclear factor E2-related factor 2 (Nrf2) translocation to the nucleus.

Bulku et al. (2012) administered male mice with curcumin (17 mg/kg per day) 12 d before APAP administration (400 mg/kg). The results indicated that curcumin reduced APAP-induced liver injury associated events as serum alanine aminotransferase (80-fold), lipid peroxidation (357%) and DNA fragmentation (469%) to three-fold, 134% and 162%, respectively. The APAP-induced increase in expression of pro-apoptotic genes (Bax, caspase-3) decreased while the expression of anti-apoptotic genes (Bcl-XL) increased in curcumin pre-exposed mouse livers, and these changes were mirrored in the pattern of apoptotic and necrotic cell deaths.

In 2013, male mice were fed a single dose of APAP (400 mg/kg) with a single dose of curcumin (200 or 600 mg/kg). The results showed that curcumin supplementation significantly decreased serum transaminase, hepatic malondialdehyde (MDA) and inflammatory cytokines compared with the APAP group. Supplementation of mice with curcumin significantly increased the GSH level compared with the APAP group. In the APAP-treated group, the liver showed extensive hemorrhagic hepatic necrosis at all zones. Curcumin supplementation caused the liver histopathology to improve (Somanawat et al. 2013).

Girish et al. (2009) treated mice of either sex with curcumin (50 or 100 mg/kg) 7 d before APAP administration (500 mg/kg). Pretreatment of mice with curcumin reversed APAP-induced increase in the activities of marker enzymes (alanine transaminase, aspartate transaminase and alkaline phosphatase) in serum and MDA level in liver. Curcumin pretreatment significantly increased GSH and catalase levels compared with the APAP group. In addition, the normalization of phenobarbitone induced sleeping time suggests the restoration of liver cytochrome P450 enzymes.

In summary, curcumin prevents APAP-induced liver damage through the improvement of liver histopathology by reducing liver inflammation, restoring GSH, preventing the lipid peroxidation and augmenting the antioxidant defence system or regeneration of hepatocytes.

Honey

Honey is a highly healthy material, it is considered to be a balanced food source (El-Kholy et al. 2010). Its chemical composition is very complex, honey contains about 180 compounds. The main constituents include enzymes, vitamins, amino acids and minerals (Bariliak et al. 1996).

Cumulative data showed that honey possesses a considerable anti-inflammatory, antioxidative and antitumour activity. In addition, several studies demonstrated that honey is capable of scavenging hydroxyl and superoxide radicals (Inoue et al. 2005; Henriques et al. 2006; Kucuk et al. 2007; Krishna-Kishorea et al. 2011; Alvarez-Suarez et al. 2012). Moreover, it prevents the depletion of the antioxidant enzymes. Furthermore, it has been shown to provide an effective protection against chemically induced lipid peroxidation in rat liver, brain and kidney homogenates (Perez et al. 2006; Alvarez-Suarez et al. 2012).

Its antioxidant capacity varies depending on the honey floral source, possibly due to the differences in the content of plant secondary metabolites as polyphenolics and enzyme activities (Meda et al. 2005; Vela et al. 2007; Ferreira et al. 2009; Alvarez-Suarez et al. 2010a,b, 2012). It has been found that several constituents of honey play a significant role in antioxidant capacity as glucose oxidase, catalase, ascorbic acid, organic acids, Maillard reaction products, amino acids, proteins, phenolic acids and flavonoids (Alvarez-Suarez et al. 2013).

Galal et al. (2012) administered male rats with honey (5, 10 or 20 g/kg) for 7 d. APAP (2 g/kg) was administered 1 h after the last honey dose. APAP caused marked liver damage as noted by significant increase in the activities of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as well as the level of Il-1β. APAP also resulted in a significant decrease in liver GSH content and GPx activity which paralleled an increase in Il-1β and MDA levels. Pretreatment with honey prior to the administration of APAP significantly prevented the increase in the serum levels of hepatic enzyme markers, and reduced both oxidative stress and inflammatory cytokines. Histopathological evaluation of the livers also revealed that honey reduced the incidence of APAP-induced liver lesions.

Silymarin

Silybum marianum (L.) Gaerthner (Asteraceae) is a Mediterranean region native plant. It is characterized by thorny branches, milky sap and oval leaves that reach up to 30 cm; its flowers are bright pink and can measure up to 8 cm in diameter (Madrigal-Santillan et al. 2013). Milk thistle grows in its wild form in southern Europe, North Africa and in the Middle East, but it is cultivated in Hungary, China and in South American countries, such as Argentina, Venezuela and Ecuador. In Mexico, it has been consumed as a food supplement for many years (Morazzoni & Bombardelli 1995).

Silymarin is a natural compound present in Silybum marianum. It has been used worldwide for many years as a complementary alternative medicine because of the beneficial effects associated with the treatment of hepatic diseases (Vargas-Mendoza et al. 2014).

Its protective capacity is related to different mechanisms, such as suppressing toxin penetration into hepatic cells, increasing SOD activity, increasing the GSH tissue level, inhibiting lipid peroxidation and enhancing hepatocyte protein synthesis. The hepatoprotective activity of silymarin can be explained based on its antioxidant properties due to the phenolic nature of its flavonolignans. Furthermore, it stimulates liver cell regeneration and cell membrane stabilization to prevent hepatotoxic agents from entering hepatocytes (Abou Zid 2012; Madrigal-Santillan et al. 2013).

Bektur et al. (2013) administered female mice with silymarin (100 mg/kg) 1 h after APAP administration (500 mg/kg) for 7 d. Treatment of mice with overdose of APAP resulted in the elevation of AST, ALT, blood urea nitrogen (BUN) and serum creatinine levels in serum and liver, and significant histological changes including decreased body weight, swelling of hepatocytes, cell infiltration, dilatation and congestion, necrosis and apoptosis. Post-treatment with silymarin significantly normalized the body weight, histological damage and serum ALT, AST, BUN and serum creatinine levels.

In a further study, male rats were administered APAP (500 mg/kg) from days 1 to 3 and silymarin (25 mg/kg) from days 4 to 14. APAP administration resulted in significant elevation of serum triglycerides, total cholesterol, BUN, serum creatinine and AST activity. Post-treatment with silymarin significantly reversed the alterations of above said markers (Gopi et al. 2010).

α-Lipoic acid

α-Lipoic acid (ALA) or 1,2-dithiolane-3-pentanoic acid (Figure 2) is a dithiol compound found in dietary sources such as vegetables (spinach, broccoli and tomato) and meat, mainly viscera. ALA can be also synthesized through enzymatic reactions in plants and animals’ mitochondria from octanoic acid and cysteine (as a sulphur donor) (Padmalayam et al. 2009; Szeląg et al. 2012).

It is believed that ALA or its reduced form, dihydrolipoic acid (DHLA) have many biochemical functions acting as biological antioxidants, as metal chelators, reducing the oxidized forms of other antioxidant agents such as vitamin C and E and GSH, and modulating the signalling transduction of several pathways, like insulin and nuclear factor kappa B (NFκB) (Golbidi et al. 2011).

Moreover, ALA has been described as a detoxification agent and an anti-diabetes medicine. In addition, it has been used to improve age-associated cardiovascular, cognitive and neuromuscular deficits (Devasagayam et al. 1993; Scott et al. 1994; Han et al. 1997; Anuradha & Varalakshmi 1999; Liu et al. 2002; Smith et al. 2004).

ALA and DHLA are natural antioxidant agents, able to scavenge many ROS. Both may scavenge hydroxyl radicals and hypochlorous acid, while ALA also terminates singlet oxygen (Kaiser et al. 1989; Devasagayam et al. 1991; Haenen & Bast 1991; Suzuki et al. 1991; Devasagayam et al. 1993).

Furthermore, ALA/DHLA is an activator/inducer of translocation of Nrf2 to the nucleus for regulation of antioxidant gene expression (Koriyama et al. 2013).

Elshazly et al. (2014) treated male rats with α-lipoic acid (20 or 100 mg/kg) simultaneously with APAP (1.5 g/kg) or 1.5 h after its administration. Administration of APAP resulted in elevation of serum ALT and hepatic MDA content, as well as decrease in hepatic GSH content. In addition, elevation in hepatic haemeoxygenase-1 (HO-1) and NADPH oxidase expression was observed accompanied with a significant reduction in glutathione synthase and cystathionine-β-synthase (CβS) expression. Furthermore, nuclear factor kappa-B (NF-κB) activity was enhanced in APAP-treated rats. Administration of α-LA (20 mg/kg), simultaneously or 1.5 h after APAP, ameliorated APAP-induced alterations in liver function, oxidant and inflammatory markers. Importantly, simultaneous administration of α-LA (20 mg/kg) was more protective than their later administration. However, the beneficial effect of α-LA was lost at higher dose level (100 mg/kg).

Sulphoraphane

Sulphoraphane [1-isothiocyanate-(4R)-(methylsulphinyl)butane; SFN] (Figure 2) is a naturally occurring isothiocyanate synthesized by the enzymatic action of the myrosinase on glucopharanin, a glucosinolate found in cruciferous vegetables of the genus Brassica such as broccoli, brussel sprouts and cabbage (Guerrero-Beltran et al. 2012).

Recently, SFN has attracted much attention as an inductor of phase II enzymes. It has been proposed that the induction of the nuclear translocation of Nrf2 and its binding to the antioxidant response element (ARE), whereby the cytoprotective genes transcription is activated, may occur either by disruption of interactions between Nrf2 and Kelch-like ECH-associated protein 1 (Keap 1) or by mitogen-activated protein kinases (MAPK) pathways activation (Vasanthi et al. 2009; Dinkova-Kostova & Kostov 2012; Guerrero-Beltran et al. 2012). Therefore, SFN is classified as an indirect antioxidant which scavenging ability for several ROS is very low or negligible (Gaona-Gaona et al. 2011).

Noh et al. (2015) treated male mice with APAP (300 mg/kg) 30 min after SFN administration (5 mg/kg). APAP alone caused severe liver injuries as characterized by increased plasma AST and ALT levels, GSH depletion, apoptosis and 4-hydroxynonenal (4-HNE) formations. This APAP-induced liver damage was significantly attenuated by pretreatment with SFN. Furthermore, while hepatic ROS levels were increased by APAP exposure, pretreatment with SFN completely blocked ROS formation.

Zingiber officinale Rosc

Zingiber officinale Rosc. (Zingiberaceae) is a well-known and widely used herb, especially in Asia. It contains several bioactive constituents and possesses health-promoting properties (Ghasemzadeh et al. 2010). The spice is extensively grown in the tropics, with the main exporting countries being India, Nigeria, Australia, China and Jamaica. Ginger is used throughout the world as a spice and food additive because of its characteristic pleasant fresh aroma and pungency (Kubra & Rao 2012).

Ginger has been used for over 2000 years by Polynesians for treating diabetes, high blood pressure, cancer, fitness and many other illnesses (Tepe et al. 2006).

It contains a number of antioxidants such as beta-carotene, ascorbic acid, terpenoids, alkaloids and polyphenols such as flavonoids, flavones glycosides and rutin (Aruoma et al. 1997).

The in vitro antioxidant activity of gingerol and other constituents of ginger (Kikuzaki & Nakatani 1993) had been reported. Dehydrogingerone showed mild inhibition of lipid peroxidation by acting as a free radical scavenger (Rajkumar & Rao 1993). Gingerol, the pungent factor in ginger oleoresin, inhibited phospholipids peroxidation induced by the FeCl₃ ascorbate system (Aeschbach et al. 1994). Inhibition of xanthine oxidase activity responsible for the generation of ROS, such as superoxide anion, was documented with gingerol (Chang et al. 1994). Sekiwa et al. (2000) reported that glucosides related to gingerdiol from ginger has antioxidative activity using the linoleic acid model system and by their DPPH radical scavenging ability.

In 2013, rats were pretreated daily with ginger aqueous suspension (100 mg/kg) for 14 consecutive days. One hour before the final treatments on day 14, acute liver injury was induced by APAP (600 mg/kg) i.p. injection. Administration of APAP caused significant liver injury that was manifested by remarkable increase in plasma ALT, AST, alkaline phosphatase (ALP) and arginase activities, and total bilirubin concentration. Meanwhile, APAP significantly decreased plasma total proteins and albumin levels. APAP administration resulted in substantial increase in each of plasma triacylglycerols (TAGs), MDA levels and total antioxidant capacity. However, ginger treatment prior to APAP showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, ALP and arginase) and total bilirubin in plasma. In addition, it remarkably ameliorated the APAP-induced oxidative stress by inhibiting lipid peroxidation (MDA). Pretreatment by ginger significantly restored TAGs and total protein levels. Histopathological examination of APAP-treated rats showed alterations in normal hepatic histoarchitecture, with necrosis and vacuolization of cells. These alterations were substantially decreased by ginger (Abdel-Azeem et al. 2013).

Hibiscus sabdariffa L. extract

Hibiscus sabdariffa L. (HS) (Malvaceae), commonly known in English as roselle or red sorrel, is widely grown in Central and West Africa, South East Asia and elsewhere. The calyces of the flower are consumed worldwide as a cold beverage and as a hot drink (sour tea). These extracts are also used in folk medicine against many complaints that include high blood pressure, liver diseases and fever (Dalziel 1937; Wang et al. 2000; Ross 2003; Bako et al. 2009). The red anthocyanin pigments in the calyces are used as food colouring agents (Esselen & Sammy 1975).

Its flowers contain polyphenolic acid, flavonoids and anthocyanins (Chen et al. 2003) with a considerable antioxidant activity (Tseng et al. 1997; Wang et al. 2000; Odigie et al. 2003). There are numerous studies regarding HS components (Samy 1980; Rao 1996; Tsai et al. 2002; Blazovics et al. 2003) and their health-promoting properties.

In 2012, male mice were treated with Hibiscus sabdariffa L. polyphenol extract (HPE) (100, 200 or 300 mg/kg) for 2 weeks prior to APAP administration (1000 mg/kg). The results show that pretreating with HPE increased the level of GSH, decreased the level of lipid peroxidation and increased catalase activity in the liver. A histopathological evaluation shows that HPE could decrease APAP-induced liver sterosis accompanied by a decreased expression of AIF, Bax, Bid and p-JNK in the liver. Moreover, an in vitro assay revealed that HPE could reduce APAP-induced death of BABL/c normal liver cells (BNLs), reverse the lost mitochondrial potency and improve the antioxidative status, similarly to the results of the in vivo assay (Lee et al. 2012).

HPE protect the liver from APAP-caused injury, maybe by decreasing oxidative stress and attenuating the mitochondrial dysfunction.

Lupeol

Lupeol (Figure 2) is a triterpene present in diverse species of the plant kingdom. It is found in edible vegetables and fruits such as white cabbage, pepper, cucumber, tomato, carrot, pea, bitter root, soy bean, ivy gourd, black tea, figs, strawberries, red grapes, mulberries, date palm and guava. Lupeol is also found in abundance in medicinal plants such as Shea butter plant, licorice, Tamarindus indica, Celastrus paniculatus, Zanthoxylum riedelianum, Allanblackia monticola, Himatanthus sucuuba, Leptadenia hastata, Crataeva nurvala, Bombax ceiba, Sebastiania adenophora, Aegle marmelos and Emblica officinalis (Erazo et al. 2008; Saleem 2009).

Lupeol is reported to exhibit pharmacological activities against various disease conditions including inflammation, arthritis, diabetes, cardiovascular ailments, renal disorder, hepatic toxicity, microbial infections and cancer (Al-Rehaily et al. 2001; Fernández et al. 2001a,b; Chaturvedi et al. 2008; Sudhahar et al. 2008a,b).

Lupeol has been investigated for its hepatoprotective potential. In 2012, Kumari and Kakkar studied rats given a prophylactic treatment of lupeol (150 mg/kg, for 30 consecutive days) with a co-administration of APAP (1 g/kg). Lupeol significantly prevented hepatic damage as evident from the histopathological studies and significant decline in serum transaminases. In addition, co-administration of lupeol significantly decreased the level MDA and protein carbonyl content. It also prevented ROS generation and mitochondrial depolarization. Furthermore, lupeol enhanced the mitochondrial antioxidant and redox status and inhibited DNA damage and cell death by preventing the downregulation of Bcl-2, upregulation of Bax, release of cytochrome c and the activation of caspase 9/3.

Sesamol

Sesamol (3,4-methylenedioxyphenol; SM) (Figure 2) is one of the non-fat antioxidants present in sesame oil (Fukuda 1990). It is reported to have antioxidant, neuroprotective (Kumar et al. 2009), anti-inflammatory (Chu et al. 2010) and hepatoprotective (Hsu et al. 2006) activities.

Furthermore, SM protects against oxidative stress as well as liver and kidney injuries in iron-intoxicated mice (Hsu et al. 2007, 2008). In addition, SM decreases hydroxyl radical generation by inhibiting the Haber–Weiss and Fenton reactions to protect against lipid peroxidation in iron-induced hepatic injury (Hsu et al. 2007).

In 2009, male rats were given APAP (1000 mg/kg) and then, immediately afterward, were injected with SM (10 mg/kg, i.p.), to assess its prophylactic effects. In the APAP group, APAP significantly increased the levels of serum AST and ALT, centrilobular necrosis, ferrous ions, hydrogen peroxide, hydroxyl radicals, and lipid peroxidation, and decreased mitochondrial aconitase activity in rat liver tissue 24 h later. In the APAP + SM group, SM prevented these alterations (Chandrasekaran et al. 2009).

Resveratrol

Resveratrol (3,4,5-trihydroxystilbene; RSV) (Figure 2) is a polyphenol compound found in various berries, nuts, grapes and other plants sources, including traditional Asian medicines. It has been shown to protect against liver damage caused by hepatic ischemia-reperfusion (Plin et al. 2005; Hassan-Khabbar et al. 2008, 2010), ethanol toxicity (Ajmo et al. 2008; Min et al. 2008), high-fat diet (Ahn et al. 2008) and hepatotoxic agents such as APAP (Sener et al. 2006; Masubuchi et al. 2009) and carbon tetrachloride (Rivera et al. 2008). The mechanisms that may explain this protection include antioxidant effects, up-regulation of phase II enzymes, modulation of inflammatory responses and induction of mitochondrial biogenesis (Baur et al. 2006; Sener et al. 2006; Lagouge et al. 2006; Masubuchi et al. 2009; Bishayee et al. 2010).

Du et al. (2015) administered male mice with APAP (300 mg/kg) and 1.5 h later with RSV (50 mg/kg). RSV reduced liver injury after APAP overdose in mice. Importantly, RSV did not inhibit reactive metabolite formation and protein bindings, or did it reduce activation of JNK. However, RSV decreased protein nitration after APAP treatment, possibly through direct scavenging of peroxynitrite. Interestingly, RSV also inhibited release of apoptosis-inducing factor and endonuclease G from mitochondria independent of Bax pore formation and prevented the downstream nuclear DNA fragmentation.

RSV protects against APAP hepatotoxicity both through antioxidant effects and by preventing mitochondrial release of endonucleases and nuclear DNA damage.

Aloe barbadensis Miller

Aloe barbadensis Miller (Asphodelaceae) is originated in the dry areas of Africa, Asia and Southern Europe, especially in the Mediterranean regions. These plants possess extensive water storage tissue in their leaves, the part of the plant, which is used for its therapeutic properties (Rodriguez Rodriguez et al. 2010).

It has been used in folk medicine for over 2000 years and remained an important component in the traditional medicine of many contemporary cultures, such as China, India, the West Indies and Japan (Grindlay & Reynolds 1986).

Aloe vera possesses many health-promoting properties, including anti-inflammatory (Saito 1993; Vazquez et al. 1996; Shimpo et al. 2002), immunostimulant (Imanishi 1993; Qiu et al. 2000), wound healing (Heggers et al. 1995; Chitra et al. 1998; Rajendran et al. 2007), antiulcer (Koo 1994), antidiabetic (Ghannam et al. 1986; Ajabnoor 1990; Beppu et al. 1993; Okyar et al. 2001; Rajesekaran et al. 2004) and antitumour (Corsi et al. 1998; Pecere et al. 2000) in which the mediation of ROS levels could be involved.

Werawatganon et al. (2014) administered male mice with APAP (400 mg/kg) and Aloe vera (150 mg/kg). In the APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive-stained cells were significantly increased, whereas hepatic GSH was significantly decreased when compared with the control group. The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive-stained cells, and hepatic GSH in the Aloe vera-treated group were improved as compared with the APAP group. Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in the Aloe vera-treated group, the liver architecture was improved histopathology.

Apigenin

Apigenin (4′,5,7-trihydroxy flavone) (Figure 2) is a natural plant flavone present in numerous vegetables and fruits, such as parsley, onions, oranges, tea and chamomile. It possesses health-promoting properties including antioxidant, anti-inflammatory and anticarcinogenic (Rice-Evans 2001; Patel et al. 2007; Shukla & Gupta 2010; Lefort & Blay 2013).

In 2013, male mice were given apigenin (100 or 200 mg/kg) for 7 d. After the apigenin treatment, mice were intraperitoneally injected with APAP (350 mg/kg). In mice treated with apigenin, the levels of serum ALT and AST, and the severity of liver injury decreased. Significant changes in liver necrosis were observed in the apigenin 200 mg/kg group. Apigenin increased the hepatic glutathione reductase (GR) activity and GSH content, and decreased the hepatic MDA content (Yang et al. 2013).

Apigenin protects against APAP-induced acute liver injury in mice and the mechanisms involved may be associated with enhancing hepatic GSH content via increment of GR activity.

Artichoke leaf extract

Artichoke [Cynara scolymus L. (Asteraceae)] has multiple pharmacological actions. It was shown to have antitoxic activity (Heidarian & Rafieian-Kopaei 2013) and glycaemia-lowering effect (Fantini et al. 2011). Moreover, it was protective against hepatocellular carcinoma (Metwally et al. 2011) and human breast cancer (Mileo et al. 2012). In addition, it has shown hepatoprotective effect in different models of liver injury in vitro and in vivo (Adzet et al. 1987; Gebhardt 1997; Mehmetcik et al. 2008; Metwally et al. 2011).

El Morsy and Kamel (2015) administered male rats with artichoke leaf extract (ALE) (1.5 mg/kg), suspended in 10% Tween 80 solution, for 14 d. One hour after the last dose, rats received APAP (2 g/kg) suspended in 10% Tween 80 solution. APAP increased serum aminotransferases activities as well as hepatic MDA and NO levels. GSH content, GR, GST and SOD activities were decreased significantly. Comet assay parameters (tail length, percentage of tailed cells, percentage of migrated DNA and tail moment) were increased, indicating apoptosis. Histopathological examination showed necrotic areas. ALE pretreatment replenished hepatic GSH, reversed oxidative stress parameters, DNA damage and APAP-induced necrosis.

Concluding remarks and future directions

APAP-induced hepatotoxicity has been a significant issue for several years because APAP is used widespread and is responsible for more emergency room visits than any other drug on the market.

Food-derived compounds have been shown to possess hepatoprotective properties against APAP-induced hepatotoxicity (Table 1). The study of physical and chemical properties of these compounds as well as the mechanisms involved in hepatoprotection has led to the development of therapies which are viable because of the easy access to these compounds.

Table 1. Protective effect of food-derived antioxidant agents against APAP-induced hepatotoxicity.

Food-derived antioxidant	Food sources	Protective effect against APAP-induced hepatotoxicity	References
Curcumin	Curcuma longa (cheese, mustard, cereals, soups, ice cream and yogurt)	Curcumin prevented APAP-induced liver damage through the improvement of liver histopathology by reducing liver inflammation, restoring GSH, preventing the lipid peroxidation and augmenting the antioxidant defense system or regeneration of hepatocytes	Bulku et al. (2012), Somanawat et al. (2013), Girish et al. (2009)
Honey	Honey	Pretreatment with honey prior to the administration of APAP significantly prevented the increase in the serum levels of hepatic enzyme markers, and reduced both oxidative stress and inflammatory cytokines. Histopathological evaluation of the livers also revealed that honey reduced the incidence of APAP-induced liver lesions	Galal et al. (2012)
Silymarin	Milk thistle	Post-treatment with silymarin significantly normalized the body weight, histological damage, serum ALT, AST, BUN and creatinine levels. Moreover, it reversed elevation of serum triglycerides and total cholesterol	Bektur et al. (2013) and Gopi et al. (2010)
alpha-Lipoic acid	Spinach, broccoli, tomato and meat	Administration of APAP resulted in elevation of serum ALT and hepatic MDA content, as well as decrease in hepatic GSH content. In addition, elevation in hepatic hemeoxygenase-1 (HO-1) and NADPH oxidase expression was observed accompanied with a significant reduction in glutathione synthase and cystathionine-beta-synthase (CβS) expression. ALA ameliorated APAP-induced alterations in liver function, oxidant and inflammatory markers	Elshazly et al. (2014)
Sulphoraphane	Broccoli, brussel sprouts, and cabbage	APAP caused increase in plasma AST and ALT levels, GSH depletion, apoptosis, and 4-hydroxynonenal (4-HNE) formations. Pretreatment with SFN attenuated these alterations. Furthermore, it completely blocked ROS formation	Noh et al. (2015)
Zingiber officinale Roscoe	Ginger	Ginger treatment prior to APAP lowered the hepatic marker enzymes (AST, ALT, ALP and arginase) and total bilirubin in plasma. In addition, it remarkably ameliorated the APAP induced oxidative stress by inhibiting lipid peroxidation (MDA). Pretreatment by ginger significantly restored TAGs, and total protein levels	Abdel-Azeem et al. (2013)
Extract of Hibiscus sabdariffa L.	Roselle or red sorrel	Pretreatment with HPE increased the level of GSH, decreased the level of lipid peroxidation, and increased catalase activity in the liver. A histopathological evaluation shows that HPE could decrease APAP-induced liver sterosis accompanied by a decreased expression of AIF, Bax, Bid and p-JNK in the liver Moreover, HPE could reduce APAP-induced death of BABL/c normal liver cells (BNLs), reverse the lost mitochondrial potency and improve the antioxidative status	Lee et al. (2012)
Lupeol	Cabbage, pepper, cucumber, tomato, carrot, pea, bitter root, soy bean, ivy gourd, black tea, figs, strawberries, red grapes, mulberries, date palm and guava	Lupeol significantly prevented increase in serum transaminases. In addition, it decreased the level MDA and protein carbonyl content. It also prevented ROS generation and mitochondrial depolarization. Furthermore, lupeol enhanced the mitochondrial antioxidant and redox status and inhibited DNA damage and cell death by preventing the downregulation of Bcl-2, upregulation of Bax, release of cytochrome c and the activation of caspase 9/3	Kumari and Kakkar (2012)
Sesamol	Sesame oil	In the APAP group, APAP increased the levels of serum AST and ALT, centrilobular necrosis, ferrous ions, hydrogen peroxide, hydroxyl radicals, and lipid peroxidation, and decreased mitochondrial aconitase activity in liver tissue. SM prevented these alterations	Chandrasekaran et al. (2009)
Resveratrol	Berries, nuts, grapes	RSV decreased protein nitration after APAP treatment, possibly through direct scavenging of peroxynitrite. RSV also inhibited release of apoptosis-inducing factor and endonuclease G from mitochondria independent of Bax pore formation and prevented the downstream nuclear DNA fragmentation	Du et al. (2015)
Aloe vera	Aloe vera	The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive-stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group. Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology	Werawatganon et al. (2014)
Apigenin	Parsley, onions, oranges, tea, and chamomile	Apigenin decreased the levels of serum ALT and AST, and the severity of liver injury. Significant changes in liver necrosis were observed in the apigenin 200 mg/kg group. Apigenin increased the hepatic GR activity and GSH content, and decreased the hepatic MDA content	Yang et al. (2013)

The aim of future investigations may be to assess direct and indirect antioxidant capacity of the compounds which have not been identified as direct or indirect antioxidant agents. Furthermore, attenuation of APAP-induced mitochondrial alterations might be examined in the compounds where has not been determined.

A better understanding of the mechanisms involved in hepatoprotection will be a key in the improvement of therapies.

Funding information

This work was supported by CONACYT Grants 220046 and 252008 and PAPIIT IN210713.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.