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Journal of Dietary Supplements, 10(3):195–209, 2013
C
2013 by Informa Healthcare USA, Inc.
Available online at www.informahealthcare.com/jds
DOI: 10.3109/19390211.2013.822450
Hepatoprotective, Antioxidant, and Ameliorative
Effects of Ginger (Zingiber ofcinale Roscoe)and
Vitamin E in Acetaminophen Treated Rats
Amal S Abdel-Azeem1, Amany M Hegazy1, Khadiga S Ibrahim2,
Abdel-Razik H. Farrag3, & Eman M. El-Sayed1
1Department of Food Science & Nutrition, National Research Centre, Dokki, Cairo,
Egypt, 2Department of Environmental & Occupational Medicine, National Research
Centre, Dokki, Cairo, Egypt, 3Department of Pathology, National Research Centre,
Dokki, Cairo, Egypt
ABSTRACT. Ginger is a remedy known to possess a number of pharmacologi-
cal properties. This study investigated efcacy of ginger pretreatment in alleviating
acetaminophen-induced acute hepatotoxicity in rats. Rats were divided into six groups;
negative control, acetaminophen (APAP) (600 mg/kg single intraperitoneal injection);
vitamin E (75 mg/kg), ginger (100 mg/kg), vitamin E +APAP, and ginger +APAP.
Administration of APAP elicited signicant liver injury that was manifested by remark-
able increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase
(AST), alkaline phosphatase (ALP), arginase activities, and total bilirubin concentra-
tion. Meanwhile, APAP signicantly decreased plasma total proteins and albumin lev-
els. APAP administration resulted in substantial increase in each of plasma triacylglyc-
erols (TAGs), malondialdhyde (MDA) levels, and total antioxidant capacity (TAC).
However, ginger or vitamin E treatment prior to APAP showed signicant hepatopro-
tective effect by lowering the hepatic marker enzymes (AST, ALT, ALP, and arginase)
and total bilirubin in plasma. In addition, they remarkably ameliorated the APAP-
induced oxidative stress by inhibiting lipid peroxidation (MDA). Pretreatment by ginger
or vitamin E signicantly restored TAGs, and total protein levels. Histopathological ex-
amination of APAP treated rats showed alterations in normal hepatic histoarchitecture,
with necrosis and vacuolization of cells. These alterations were substantially decreased
by ginger or vitamin E. Our results demonstrated that ginger can prevent hepatic in-
juries, alleviating oxidative stress in a manner comparable to that of vitamin E. Com-
bination therapy of ginger and APAP is recommended especially in cases with hepatic
disorders or when high doses of APAP are required.
KEYWORDS. acetaminophen, ginger, liver, oxidative stress, proteins, triacylglyc-
erols, vitamin E
Address correspondence to: Khadiga S. Ibrahim, Department of Environmental & Occupational Medicine,
National Research Centre, El-Behoos St. (Tahrir St.Prev.) Dokki, Cairo 12311, Egypt (E-mail khadigasalah@
yahooo).
(Received 29 September 2012; revised 6 March 2013; accepted 3 June 2013)
195
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196 Abdel-Azeem et al.
INTRODUCTION
The liver plays a pivotal role in regulating various physiological processes in the
body such as metabolism, secretion, and storage. It has a great capacity to detox-
icate toxic substances and synthesize useful ones. Drug metabolism and forma-
tion of reactive toxic metabolites by hepatic microsomal enzyme system plays a
role in the hepatotoxic mechanism (Gonzalez, 1992). Xenobiotics are usually me-
tabolized to inert metabolites that are excreted but unfortunately some of which
are metabolized to more reactive compounds that are more toxic than the par-
ent compound. Acetaminophen {N-acetyl-para-aminophenol (APAP)}is an ex-
tensively prescribed analgesic and antipyretic drug. Although safe when used at
therapeutic doses (Hazai, Monostory, Bakos, Zacher, & Vereczkey, 2001), inten-
tional or unintentional overdose of APAP (>4 g/day) has become the most fre-
quent cause of acute liver failure (Jaeschke, McGill, & Ramachundran, 2012). At
normal doses (<4 g/day), APAP is metabolized by cytochrome P450 monooxyge-
nases (CYPs) to form the highly reactive intermediate, N-acetyl-p-benzoquinone
imine (NAPQI). Metabolizing enzyme; glutathione-S-transferase (GST) catalyzes,
the sequestration of this reactive metabolite through conjugation with glutathione
(GSH). High doses of APAP saturate detoxication pathways, leading to excessive
production of NAPQI which causes glutathione depletion. It freely binds to cellu-
lar molecules producing massive cellular damage and tissue necrosis (Hinson, Reif,
McCullough, & James, 2004; Laine, Auriola, Pasanen, & Juvonen, 2009).
Reactive oxygen species are causally related to oxidative stress that has been
implicated in a number of disease processes, including heart disease, diabetes, can-
cer, and liver injury (Jaeschke, 2000). The balance between ROS and antioxidants
is, therefore, crucial and could be an important mechanism for preventing damage
caused by oxidative stress. This balance has been suggested to have an important
role in preventing APAP toxicity (Jaeschke, Knight, & Bajt, 2003; Lee et al., 2012).
Herbs and spices are generally considered safe and proved to be effective
against various human ailments. Zingiber ofcinale Roscoe commonly known as
ginger, belongs to the family Zigiberaceae. It is a familiar dietary spice with sev-
eral medicinal properties. It has a long history of use in ailments such as nausea,
respiratory, cardiovascular, and rheumatic disorders (Tapsell et al., 2006). It also
has immunomodulatory properties and is reported to inhibit various inammatory
mediators such as prostaglandins and proinammatory cytokines (Grzanna, Lind-
mark, & Frondoza, 2005). Ginger use has been associated with insignicant side
effects and with no known drug or herb interactions, so it has been considered as
a safe herbal medicine (Ali, Blunden, Tanira, & Nemmar, 2008). The constituents
of ginger are numerous and include volatile oils and pungent phenol compounds
known as gingerols, sesquiterpenoids and shogaols. It also has anthocyanin and
tannin in its root bark (Jolad, Lantz, Chen, Bates, & Timmermann, 2005). Sharma
and Singh (2012) demonstrated that ginger is endowed with strong in vitro and in
vivo antioxidant properties. Ginger has been known for its protective role against
a number of toxic agents such as cisplatin (Ajith, Nivitha, & Usha, 2007) and bro-
mobenzene (El-Sharaky, Newairy, Kamel, & Eweda, 2009).This is attributed to its
antioxidant action. A lot had been reported on the chemical characterization of
phytoconstituents and the ethnopharmacological properties of ginger. However,
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Hepatoprotective Effects of Ginger in Acetaminophen Rats 197
there is still limited information on its potential hepatic protective role against drugs
that induce liver injury when administered at high doses. Hence, the objectives of
the current study were to evaluate the possible hepatoprotective and antioxidant
activities of ginger aqueous suspension against hepatic injury in rats induced by
high dose of acetaminophen. Also, we aimed to determine the effects of ginger ad-
ministration on some nutritional parameters in those rats such as their food intake,
weights and food efciency ratio and to compare the obtained data with those of
vitamin E (Asuku, Atawodi, & Onyike, 2012). Vitamin E has been documented to
protect the liver from several toxins (Ming, Fan, Yang, & Lautt, 2006; Kalender,
Uzun, Ourak, Demir, & Kalender, 2010) by being a standard antioxidant. Thus, it
was used in the current investigation as a reference.
MATERIAL AND METHODS
Drug and Dietary Supplements
Acetaminophen powder was provided by the Arab Drug Company Cairo, Egypt.
Vitamin E was obtained from Pharco Pharmaceuticals, Alexandria, Egypt. Ginger
powder was purchased from MEPACO, Medifood Co. Egypt.
Animals
Adult male Sprague-Dawely rats weighing 120–150 gm were purchased from Ani-
mal House of the National Research Centre, Dokki, Giza, Egypt. They were kept
individually in stainless steel wire bottomed cages at room temperature (25 ±2◦C)
under 12 hr dark-light cycle. Animals were fed standard balanced diet. Rats had
free access to food and water and they were used after acclimatization period of
one week. Animal experiments were conducted according to the guidelines of An-
imal Care and Ethics Committee of the National Research Centre, Egypt.
EXPERIMENTAL DESIGN
Animals were randomly assigned to six groups each of seven rats as follows; neg-
ative control was orally given distilled water, positive control was injected with a
single dose of acetaminophen 600 mg/kg intraperitoneally (I.P.) (after an overnight
fasting (Hwang et al, 2011). Vitamin E group was orally treated with vitamin E
75 mg/kg/day (third group). The fourth group was orally treated with ginger aque-
ous suspension 100 mg/kg/day (Manju & Nalini, 2010), the fth group (APAP +
vitamin E) and the sixth group (APAP +ginger). Rats were weighed three times
per week and their body weights were recorded. In addition, their food intake was
monitored throughout the experimental period for the calculation of food efciency
ratio (body weight variation/total food intake).
Rats were pretreated daily with vitamin E (groups 3, 5) or with ginger (groups
4, 6) for 14 consecutive days. One hour before the nal treatments on day 14, acute
liver injury was induced in APAP groups (positive control, groups 5 and 6 only) by
APAP (I.P.) injection. Rats were starved overnight and then blood samples were
collected on heparin under light ether anesthesia from retroorbital vein. One part
of blood was left for hemoglobin analysis and the other part was centrifuged at
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198 Abdel-Azeem et al.
4,000 rpm for 20 min under cooling and plasma was separated and stored at –80◦C
for subsequent determinations.
Livers were excised, washed quickly with saline and placed immediately in 10%
formalin—Saline buffer for the histopathological examination.
Biochemical Assays
Plasma aspartate and alanine aminotransferases activities were determined accord-
ing to Reitman and Frankel (1957). Alkaline phosphatase activity (ALP) in plasma
was determined according to the principle of Beleld and Goldberg (1971). Plasma
arginase activity was evaluated by using the standard method proposed by March,
Fingerhut, and Miller (1965). Total bilirubin reacted with diazotized sulfanilic acid
in the presence of dimethylsulfoxide to produce azobilirubin which was detected
spectrophotometrically (Walter & Gerard, 1970). Plasma total proteins formed a
blue complex in the presence of copper salt in alkaline solution (Bradford, 1976).
Plasma albumin was quantitatively determined by reacting with bromocresol green
(Doumas, Waston, & Biggs, 1971). Triacylglycerol level (TAGs) was determined en-
zymatically by using the procedure of Fossati and Prencipe (1982). Very low density
lipoprotein concentrations were calculated. Blood hemoglobin was assessed fol-
lowing the standard method proposed by Reuge (1968). Malondialdhyde level, as
a lipid peroxidation end product, was determined by using the thiobarbituric acid
reactive substance (TBARS) assay (Satoh, 1978). Finally, plasma total antioxidant
capacity was assayed calorimetrically (Koracevic, Koracevic, Djordjevic, Andreje-
vic, & Cosic, 2001).
Histopathological Examination
Livers were separated anatomically after anesthetizing the rats by diethylether,
rapidly washed in saline solution to remove the blood. Liver specimens were
removed rapidly from saline, xed in 10% neutral buffered formalin for 24 hr, then
processed up in parafn blocks, sections of 5-mm thick were prepared and stained
with hematoxylin and eosin (Drury & Wallington, 1980) for histopathological
studies.
Statistical Analysis
Data were expressed as mean ±standard error. Statistical differences were assessed
by using F-test, one way of analysis of variance (ANOVA) using SPSS version 14
program. Post-hoc analysis of signicance was made using least-signicant differ-
ence (LSD) test. Differences were considered signicant at p<.05.
RESULTS
APAP single administration resulted in acute liver injury manifested by the signi-
cant increases of plasma AST, ALT, ALP, and arginase activities and total bilirubin
level (p<.01) (Table 1). Pretreatment with ginger signicantly reduced plasma
levels of ALP, ALT, AST, and arginase by 34.9%, 22.2%, 20%, 17.5%, and 42.3%,
respectively, as compared to APAP group (positive control). The recovery from
APAP-induced toxicity by ginger pretreatment was nearly similar to that seen with
vitamin E. As the percentages of reduction produced by vitamin E were 18.6%,
22.2%, 26.7%, 13.1%, and 39.4% respectively. No signicant differences were
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Hepatoprotective Effects of Ginger in Acetaminophen Rats 199
TABLE 1. Changes in Plasma Hepatic Enzyme Activities and Total Bilirubin of
Concentration Various Experimental Groups
Groups
Negative Positive Vitamin Vitamin Ginger +
Control Control E Ginger E +APAP APAP
Parameters
ALP (U/L) 138 ±8.25 241a∗∗ ±17.1 133 ±5.67 148 ±5.17 196b∗∗ ±1.87 157b∗∗ ±9.43
ALT (u/ml) 23.0 ±2.98 43.7a∗∗ ±3.82 26.7 ±2.03 22.7 ±1.42 34b∗±3.06 34.0b∗±1.23
AST (u/ml) 48.9 ±3.94 92.9a∗∗ ±3.21 50 ±3.50 54.9 =4.22 68.1b∗∗ ±3.36 74.3b∗∗ ±3.26
Arginase (u/L) 110 ±1.67 137a∗∗ ±1.37 105 ±4.51 116 ±3.92 119b∗∗ ±5.14 113b∗∗ ±1.98
Total bilirubin
(mg/dl)
0.70 ±0.08 1.70a∗∗ ±0.14 0.96 ±0.15 0.71 ±0.04 1.03b∗∗ ±0.15 0.98b∗∗ ±0.16
Values are expressed as mean ±S.E.
avalues significantly differ from normal control.
bvalues significantly differ from APAP.
∗p<.05; ∗∗p<.01.
observed in enzyme activities or total bilirubin level of healthy rats treated by gin-
ger or vitamin E when compared with those of normal rats.
APAP-administration induced marked oxidative stress (Table 2). Where, it sig-
nicantly increased MDA, a marker for lipid peroxidation. The MDA content in
APAP group was ≈3 fold that of the negative control. Pretreatment by ginger
signicantly reduced MDA level (p<.05) as compared to that of APAP group
(positive control). Meanwhile, TAC was signicantly higher than that of normal
rats. However, ginger treatment prior to APAP administration showed non signi-
cant changes in TAC. Blood hemoglobin (considered as antioxidant through tran-
sitional iron compartmentalization mechanism) showed nonsignicant change in
positive control as compared to negative control. Overall, ginger administration
produced comparable results as those of vitamin E when their effects were com-
pared to APAP inuences. No signicant differences were observed in MDA or
TAC of normal rats treated by either ginger or vitamin E.
The changes in plasma proteins and lipids of different groups are illustrated in
Table 3. APAP treatment markedly reduced both total proteins and albumin
TABLE 2. Plasma Malondialdehyde Level, Total Antioxidant Capacity and Blood
Hemoglobin Level of Various Experimental Groups
Groups
Negative Positive Vitamin Vitamin Ginger +
Control Control E Ginger E +APAP APAP
Parameters
Malondialdehyde
(nmol/ml)
2.38 ±0.21 7.28a∗∗ ±0.59 3.13 ±0.15 2.61 ±0.48 4.49b∗∗ ±0.42 6.09b∗±0.07
Total antioxidant
capacity (mol/L)
1.2 6 ±0.12 1.82a∗∗ ±0.027 1.36 ±0.07 1.42 ±0.09 1.86 ±0.02 1.88 ±0.02
Hemoglobin gm/L 15.5 ±0.22 15.0 ±0.25 13.9a∗∗ ±0.22 14.7 ±0.23 14.5 ±0.65 14.3 ±0.29
Values are expressed as mean ±S.E.
avalues significantly differ from normal control.
bvalues significantly differ from APAP.
∗p<.05; ∗∗p<.01.
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200 Abdel-Azeem et al.
TABLE 3. Plasma total Proteins, Albumin, Triacylglycerols and Very low Density
Lipoproteins of Different Experimental Groups
Groups
Negative Positive Vitamin Vitamin Ginger +
Control Control E Ginger E +APAP APAP
Parameters
Total proteins
(gm/dl)
6.13 ±0.10 5.74a∗∗ ±0.06 6.75 ±0.16 7.07 ±0.25 6.50b∗±0.23 6.50b∗∗ ±0.16
Albumin (gm/dl) 4.07 ±0.11 3.89a∗∗ ±0.22 3.73 ±0.17 3.18a∗∗ ±0.05 3.76 ±0.11 3.87 ±0.15
Triacylglycerols
(mg/dl)
45.1 ±3.61 93.7a∗∗ ±5.66 47.2 ±2.49 52.1 ±1.94 78.3b∗±4.15 59.7b∗±5.13
VLDL (mg/dl) 9.02 ±0.72 18.7a∗∗ ±1.13 9.26 ±0.52 10.4 ±0.38 15.6b∗∗ ±0.811 11.9b∗±1.02
Values are expressed as mean ±S.E.
avalues significantly differ from normal control.
bvalues significantly differ from APAP.
∗p<.05; ∗∗p<.01.
concentrations (p<.01) as compared to those of normal rats. APAP treatment
signicantly (p<.01) increased TAGs and VLDL levels as compared to the cor-
responding values of the negative control. Total proteins, TAGs and VLDL levels
were extremely ameliorated by ginger, where total proteins were signicantly in-
creased, TAGs and VLDL levels were signicantly decreased as compared to pos-
itive control. Ginger effects were similar to those of vitamin E.
No signicant differences were observed in nutritional parameters between
APAP treated and normal rats, Also, food efciency ratio showed insignicant al-
terations throughout various experimental groups (Figure 1).
Histopathological examinations of liver sections from control, rats treated with
vitamin E, and rats treated with ginger showed normal lobular architecture and
normal hepatic cells with a well preserved cytoplasm and well dened nucleus
and nucleoli (Figures 2 A–C). Liver from paracetamol treated animals showed
vacuolization of hepatocytes, sinusoidal dilation, inltration Kupper cells and fatty
degeneration (Figures 2 D–E). The liver of rats treated with vitamin E or ginger
and APAP showed comparatively normal architecture of the liver, having restored
to a large extent, the hepatic lesions produced by the toxins, almost comparable to
the normal (Figures 2 F–I).
FIGURE 1. Food efficiency ratio in various expermintal groups.
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Hepatoprotective Effects of Ginger in Acetaminophen Rats 201
FIGURE 2. Section of liver of rats (A: negative control, B: vitamin E and C: ginger). Sections
of liver of rats treated with paracetamol (D, E). Sections of liver of rats treated with parac-
etamol and vitamin E (F, G). Sections of liver of rats treated with paracetamol and ginger
(H, I).
DISCUSSION
Acetaminophen is a well-known nonsteroidal antipyretic and analgesic agent,
which is safe in therapeutic doses. However, overdoses of APAP can produce
fatal hepatic necrosis and apoptosis in experimental animals and humans (Amar
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202 Abdel-Azeem et al.
& Schiff, 2007). The ability of humans to metabolize and clear xenobiotics such
as drugs is a natural process carried out by enzymes called drug metabolizing en-
zymes. APAP subjected to oxidation by CYP2E1 then conjugated by sulfotrans-
ferases (SULT), UDP-glucuronosyltransferases (UGT), and GST (Gonzalez &
Tukey, 2006). The activity of these metabolizing systems is affected by nutrients
(Hwang et al., 2011). Among followed strategies to attenuate APAP toxicity are
dose optimization and the use of combined therapy with antioxidants. Cornas ofc-
inalis fruit extract was reported to protect against APAP hepatic injury (Lee et al.,
2012).
Our data demonstrated that rats treated with APAP developed signicant hep-
atic damage which was observed by a substantial increase in the activities of plasma
enzymes; AST, ALT, ALP, and arginase. Also, plasma total bilirubin level exhibited
a signicant increase. Our results coincided with those of Murayama et al. (2008),
Yassin et al. (2010), Hwang et al. (2011), Sabina et al. (2011), and Lee et al. (2012).
The superiority of arginase to ALT and AST has been demonstrated in toxicant-
induced acute and chronic hepatotoxicity in rats (Murayama, Ikemoto, Fukuda,
Tsunckawa, & Nagata, 2006; Murayama et al., 2008).
Evaluation of the mechanisms of drug induced liver injury and release of solu-
ble products including AST, ALT, arginase, and ALP indicates that mitochondria
are critical targets for drug toxicity, either directly or indirectly through the for-
mation of reactive metabolites such as NAPQI. The consequence of these modi-
cations is generally a mitochondrial oxidant stress and peroxynitrite formation,
which leads to structural alterations of proteins and mitochondrial DNA. In ad-
dition, the release of intermembrane proteins, such as apoptosis-inducing factor
and endonuclease G, and their translocation to the nucleus, leads to nuclear DNA
fragmentation. Together, these events trigger necrotic cell death. Alternatively, the
release of cytochrome C and other proapoptotic factors from mitochondria can pro-
mote caspase activation and apoptotic cell death. Drug toxicity can also induce an
inammatory response with the formation of reactive oxygen species by Kupffer
cells and neutrophils. If not properly detoxied, these extracellularly generated ox-
idants can diffuse into hepatocytes and trigger mitochondrial dysfunction and oxi-
dant stress, which then induces necrotic cell death (Jaeschke et al., 2012). Moreover,
APAP treatment has been shown to elevate mRNA level of CYP2E1 (Ito, Abril,
Bethea, McCuskey, & McCuskey, 2006; Yamaura, Shimada, Nakayama, & Ueno,
2011) with concomitant generation of the highly reactive intermediate NAPQI and
apoptosis in HepG2 cells (Cederbaum, 1998). Free radicals resulted from NAPOI
and CYP2E1 production; induce peroxidation of polyunsaturated fatty acids in the
hepatocytes membranes.
Malondialdhyde is a good indicator of lipid peroxidation. In the current study,
remarkable increase in MDA level was observed in APAP-treated rats as com-
pared to controls. This nding is consistent with Gamal El-din et al. (2003) and
Sabina et al. (2011). Increased lipid peroxidation is generally believed to be an im-
portant underlying cause of the initiation of oxidative stress related various tissues
injuries, cell death, and the progression of acute and chronic diseases (Halliwell,
1997). An interesting nding of this study was the elevation of total antioxidant ca-
pacity by APAP administration. This may be explained as a body defense mecha-
nism against APAP-induced oxidative stress. HO-1 has been shown tobe protective
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Hepatoprotective Effects of Ginger in Acetaminophen Rats 203
in several hepatic injuries. It has been reported that expression of HO-1 is rapidly
up regulated in the liver and macrophages following administration of high doses
of acetaminophen (Noriega, Ossola, Tomaro, & Batlle, 2000; Chiu, Brittinghum,
& Laskin, 2002; Lee et al., 2012). Thus, HO-1 induction by APAP may be, at least
in part, the reason for the increase of total antioxidant capacity. Hemoglobin was
considered as antioxidant through transitional iron compartmentalization mecha-
nism (Heffner & Repine, 1989). However, the emerged data showed nonsignicant
changes in hemoglobin levels in various groups. Ginger treatment extremely de-
creased lipid peroxidation but signicantly increased total antioxidant capacity as
compared to those of rats given APAP only. These ndings are consistent with those
obtained by (Onwuka, Erhabor, Eteng, & Umoh, 2011; Sharma & Singh, 2012).
APAP treatment signicantly reduced albumin and protein concentrations com-
pared to normal. These results are in consistence with Parameshappa et al., (2012).
Impairment of the hepatic synthetic function by APAP may be the cause of de-
creased protein level and the hypoalbuminemia. Also, the excessive reactive elec-
trophiles and free radicals originated from cytochrome P450 mediated oxidation of
APAP, attack the macromolecules causing oxidation to proteins (Sun, Suqivama,
Masuda, Och, & Takeuchi, 2011). Moreover, APAP enhanced protein catabolism
as indicated from increased level of blood urea nitrogen after APAP treatment
(Gopi, Reddy, Jyothi, & Kumar, 2010). Regarding the effects of APAP adminis-
tration on triacylglycerols; our results showed signicant increase in TAGs level.
This nding was in agreement with the results of Chen et al. (2009), Gopi et al.
(2010), and Oyagbemi and Odetola (2010). APAP induces disruption of free fatty
acid β-oxidation. It is known that mitochondrial proteins are the main targets
of APAP-elicited covalent binding (Qiu, Benet, & Burlingame, 1998). Therefore,
inhibition of fatty acid β-oxidation might be a consequence of APAP-elicited
structural damage to the mitochondria or a direct effect of inhibiting enzymes and
transporters involving in β-oxidation pathway by the reactive metabolites and ROS,
generated by CYP2E1-mediated reactions. Moreover, this oxidative stress stim-
ulates over production of epinephrine (Rosano & Whitley, 1999) which in turn
markedly suppresses insulin secretion with concomitant increase in glucagon, such
hormonal changes induce hormone sensitive lipase activity which greatly enhances
lipolysis in adipose tissue and liver increasing the concentration of free fatty acids in
circulation. Consequently, the conversion of free fatty acids to TAGs was associated
with concomitant increase in VLDL levels (Ghebremeskel et al., 2002).
Previous studies investigated the hepatoprotective effects of ginger against liver
injury induced by ethanol, carbon tetrachloride, and bromobenzene (Yemitan &
Izegbu, 2006; Mallikarjuna, Sahitya, Sathyavelu, & Rajendra, 2008; El-Sharaky
et al., 2009).
Polyphenolic compounds, avonoids and vitamin C present in ginger contribute
to ginger antioxidant activity (Oboh, Akinyemi, & Ademiluyi, 2012). Ginger, pre-
vents the production of free radicals, neutralizes, and scavenges free radicals pro-
duced in the body and chelats prooxidant transition metals as iron. Gingerols and
shogaols are the major bioactive avonoids present in ginger, they suppress the ac-
cumulation of reactive oxygen and/or nitrogen species in the cells (Dugasani et al.,
2010). Moreover, ginger enhances the activities of antioxidant enzymes; superoxide
dismutase, and glutathione peroxidase and increases GSH level (El-Sharaky et al.,
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204 Abdel-Azeem et al.
2009). Gingerol treatment upregulated mRNA and protein expression of antiox-
idant enzymes such as γ-glutamyl-cysteine ligase the rate-limiting enzyme in the
glutathione biosynthesis (Lee, Park, Kim, & Jang, 2011).
APAP overdose was reported to increase inammatory cytokines such as
interleukin-6 (IL-6) and several proinammatory factors including tumor necrosis
factor α(TNF-α), and interferon-gamma (IFN-gamma) (Bourdi et al., 2007). The
6-gingerol treatment regulate the overexpression of TNF-αand IL6 in arsenic in-
toxicated mice (Chakraborty et al., 2012). Both gingerols and shagaols inhibit pro-
duction of inammatory mediators such as nitrite and prostaglandin E signicantly
and dose dependently (Dugasani et al., 2010). Ginger was found to inhibit the in-
duction of several genes involved in the inammatory response, and some of these
genes encode cytokines, chemokines, and COX-2 (Grzanna, Phan, Polotsky, Lind-
mark, & Frondoza, 2004). It also suppresses leukotriene biosynthesis by inhibiting
5-lipoxygenase (Nurtjahja-Tjendraputra, Ammit, Roufogalis, Tran, & Duke, 2003).
Constitutive androstane receptor (CAR), xenobiotic receptor, is a key regula-
tor of APAP metabolism and hepatotoxicity (Zhang, Huang, Chua, Wei, & Moore,
2002). Ginger may reduce the cellular uptake of APAP possibly due to steric mod-
ication of CAR. Besides, Ginger enhances APAP catabolism by inducing the
drug metabolizing enzymes (Nakamura, Murakami, Ohigashi, Osawa, & Uchide,
2004; El-Sharaky et al., 2009; Jackie, Haleagrahara, & Chakravarthi, 2011). Also 6-
gingerol pretreatment protects against amyloid-induced cytotoxicity and apoptotic
cell death (Lee et al., 2011).
Our emerged data demonstrated that pretreatment of ginger aqueous suspension
prior to APAP-treated rats signicantly increased total protein which is in agree-
ment with Al-Amin, Thomson, Al-Qattan, Peltonen-Shalaby, & Ali, (2006). Mean-
while, it markedly decreased plasma TAGs concentrations; that is consistent with
Fuhrman et al. (2000), Goyal and Kadnur (20 06), and Chakraborty et al. (2012). Al-
Amin et al. (2006) demonstrated that ginger treatment to diabetic rats signicantly
declined urine protein levels indicating decreased protein catabolism by ginger. On
the other hand, the decrease in TAGs may be attributed to the signicant improve-
ment of insulin sensitivity in ginger treated rats (Chakraborty et al., 2012), which
results in increased clearance of VLDL-Ch, consequently, TAGs level was dropped.
Moreover, insulin stimulates lipogenesis in adipose tissue and induces lipoprotein
lipase both virtually decreased TAGs. Sahebkar (2011) proved that ginger could
activate peroxisome receptor Y that induces adiponectin and downregulates pro-
inammatory cyt/okines, changing the balance between adiponectin and TNF-αin
favor of adiponectin promoting considerable antioxidant effects, antidysplipidemic
properties, and reducing hepatic TAGs.
The effect of ginger was comparable to that of standard antioxidant vitamin E.
The potential therapeutic benets of oral vitamin E supplementation have been
evaluated in several liver diseases including viral autoimmune hepatitis, alcoholic
liver diseases, nonalcoholic steatohepatitis, and cholestatic liver diseases (Medina
and Moreno-Otero, 2005). Besides, vitamin E had a remarkable protective effect
against toxins-induced hepatotoxicity (Awodele, Akintonwa, Osunkalu, & Coker,
2010; Uzunhisarcikli & Kalender, 2011; Asuku et al. 2012). Our data are in ac-
cordance with the above mentioned authors as vitamin E supplementation to our
rats prior to APAP showed noticeable hepatoprotection manifested by reduction
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Hepatoprotective Effects of Ginger in Acetaminophen Rats 205
of hepatic enzyme activities and total bilirubin level. In parallel, it signicantly de-
creased MDA level. Treatment with vitamin E could efciently downregulate in-
ammatory pathways important in liver injury. Furthermore, vitamin E is a potent
agonist of the nuclear hormone receptor, pregnane x, which regulates the transcrip-
tion of cytochrome P450s and other enzymes involved in xenobiotic metabolism
(Kim and Lee, 2006; Park, Kim, & Lee, 2009). Thus, vitamin E could enhance the
detoxication of APAP and reduce hepatic injury in this fashion.
Vitamin E dual actions; enhancement of liver status and its antioxidant activity
shared the amelioration of total proteins after APAP treatment. This nding is con-
sistent with Kalender et al. (2010). It was notable that plasma TAGs concentration
was signicantly reduced by vitamin E treatment prior to APAP administration that
is in agreement with Augusti et al. (2005). The hypolipidemic effect of vitamin E
may be attributed to the increased insulin sensitivity by vitamin E via increasing
the release of hepatic insulin-sensitizing substance (Ming et al., 2006).
In conclusion, our data have shown that, ginger can improve the likelihood of
subsequent hepatic changes following administration of high dose of APAP. It can
ameliorate both histological and biochemical hepatic alterations. Ginger hepatic
protection, in major part, caused by decreasing oxidative stress and by increasing
total antioxidant capacity. The therapeutic efcacy of ginger was comparable to that
of vitamin E. From this point of view, combination regimens containing suitable
doses of ginger and acetaminophen could be advantageous, particularly in treating
patients who are susceptible to liver function disorders or when high doses of APAP
are needed. However, further detailed clinical studies are required to establish its
application.
Declaration of interest: The authors report no conicts of interest. The authors
alone are responsible for the content and writing of the article.
ABOUT THE AUTHORS
Amal S Abdel-Azeem, is a Researcher of Nutrition, Department of Food Science
& Nutrition, National Research Centre, Dokki, Cairo, Egypt. Amany M Hegazy,
is a Researcher of Nutrition, Department of Food Science & Nutrition, National
Research Centre, Dokki, Cairo, Egypt. Khadiga S Ibrahim, is a Professor of Bio-
chemistry, Department of Environmental & Occupational Medicine, National Re-
search Centre, El-Behoos St. (Tahrir St.Prev.), Dokki, Cairo 12311, Egypt. Abdel-
Razik H. Farrag, is a Professor of pathology, Department of Pathology, National
Research Centre, Dokki, Cairo, Egypt. Eman M. El-Sayed, is a Professor of Bio-
chemistry Nutrition, Department of Food Science & Nutrition, National Research
Centre, Dokki, Cairo, Egypt.
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