Article

Protective effects of onion (Allium cepa) extract against doxorubicin-induced hepatotoxicity in rats

Toxicology and Industrial Health 1–7 © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0748233713504807 tih.sagepub.com

Rafet Mete1, Mustafa Oran2, Birol Topcu3, Meltem Oznur4, Erdogan Selcuk Seber5, Asuman Gedikbasi6 and Tarkan Yetisyigit7 Abstract Background/aim: Doxorubicin (DOX) is a widely used and potent chemotherapeutic agent. However, serious dose-limiting toxicity through generation of free oxygen radicals is a commonly encountered clinical problem. The aim of the current study was to assess the protective role of onion (Allium cepa) extract (ACE) against DOXinduced hepatotoxicity in rats. Method: A total of 24 rats were randomly divided into 3 equal experimental groups: (1) DOX; (2) ACE þ DOX; and (3) control groups. ACE was given orally as 1 mL of fresh ACE juice for 14 consecutive days followed by DOX injection. DOX was injected intraperitoneally in a single dose of 30 mg/kg body weight to induce hepatotoxicity, and the rats were killed after 48 h from injection. Control group was given saline only. Results: In the ACE pretreated group (ACE þ DOX), serum aspartate transaminase, alanine transaminase, and tissue malondialdehyde and glutathione levels were significantly lower, while superoxide dismutase and glutathione peroxidase were higher compared with the DOX group. The histopathological examination of liver specimens revealed parenchymal necrosis, proliferation of biliary duct in DOX group; while ACE pretreatment provided marked reduction in these changes. Conclusion: Our study indicates that pretreatment with ACE protects against DOX-induced hepatotoxicity due to the antioxidant properties of ACE. Further studies on efficacy of antioxidant treatment by ACE in DOX-mediated toxicity and underlying mechanisms would provide a better explanation. Keywords Acute toxicity, animal model, liver, hepatic toxicity, anti-inflammatory

Introduction

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Doxorubicin (DOX) is a broad-spectrum anthracycline antibiotic used to treat many neoplasms such as leukemia, lymphoma, and some solid tumors (Minotti et al., 2004). DOX binds to DNA and stabilizes topoisomerase II complex, thereby induces apoptosis via blocking cell cycle primarily in cancerous cells (Skladanowski and Konopa, 1993). However, toxic effects of DOX have restricted its clinical usefulness in cancer treatment (Fadillioglu et al., 2003). It has been suggested that oxidative stress and free radical formation are involved in both antineoplastic and toxic effects of DOX (Yagmurca et al., 2004). Several studies have concluded that semiquinone form of DOX yields free radical formation such as superoxide radicals and hydrogen peroxide (Minotti et al., 1996; Singal et al., 2005). In addition, DOX impairs cellular

Department of Gastroenterology, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey 2 Department of Internal Medicine, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey 3 Department of Biostatistics, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey 4 Department of Pathology, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey 5 Medical Oncology Clinic, Tekirdag State Hospital, Tekirdag, Turkey 6 Biochemistry Department, Sadi Konuk Research and Training Hospital, _Istanbul, Turkey 7 Department of Medical Oncology, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey Corresponding author: Rafet Mete, Department of Gastroenterology, Faculty of Medicine, Namik Kemal University, Namik Kemal Mahallesi Kampus Caddesi No:1, 59100 Tekirdag, Turkey. Email: [email protected]

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Polyphenols Glycosylated polyphenols Quercetin (aglycone or glycosylated)

20–40 60–90 85–98

animals received humane care according to the criteria outlined in the ‘‘Guide for the Care and Use of Laboratory Animals’’ prepared by the National Academy of Sciences and published by the National Institutes of Health of USA. The protocol of this study was approved by the Institutional Animal Ethical Committee of Namik Kemal University, Tekirdag, Turkey.

Quercetin-3,40 -diglucoside Quercetin 3-monoglucoside and quercetin- 40 -monoglucoside Quercetin

5–20 30–70

Preparation of ACE

Table 1. Chemical content analysis of ACE. Molecules

Weight of total flavonols (%)

20–30

ACE: Allium cepa extract.

antioxidant defense systems. Imbalance of reactive oxygen species (ROS) between antioxidants causes oxidative tissue injury. Recently, much attention has been focused on the protective effects of antioxidants and naturally occurring substances against DOXinduced hepatotoxicity (Liu and Thurman, 1992). Onion (Allium cepa), which is also known as the bulb onion or common onion, is a bulbous herb belonging to the Alliaceae family and commercially cultivated worldwide (WHO, 1999). It has been shown that extracts from the outer scales of onions have potent radical scavenging activities in vitro (Nuutila et al., 2003; Suh et al., 1999). In addition, onion oil has been shown to increase the activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione (GSH) peroxidase (GSH-Px) in a variety of tissues (Helen et al., 2000). In this study, the effects of onion extract (ACE) pretreatment on DOX-induced hepatic injury were evaluated in an animal model. To determine the efficacy of ACE, malondialdehyde (MDA) and GSH levels and SOD and GSH-Px activities were measured in liver tissue.

Materials and methods Experimental animals A total of 24 fertile, inbred, healthy, male Sprague– Dawley rats, weighing 200–250 g and aged 16 weeks, were utilized in this study. The animals were obtained from Trakya University Animal Care and Research Unit. The rats were housed at a temperature of 23 + 1 C with 12-h/12-h light/dark cycles, respectively, and 45 + 5% humidity. Filtrated tap water and standard laboratory rat feed were provided ad libitum. Animals were quarantined for 1 week before being randomized into experimental groups of eight animals per cage. All

ACE was prepared according to the method described by Nelson et al. (2007). Briefly, fresh onion bulbs were rinsed thoroughly in clean, sterile, distilled water and air-dried for 1 h. Then, 200 g of onion were blended after the outer coverings were manually peeled off. The resulting paste was allowed to stand for 24 h in a clean glass container. Juice was then filtrated and squeezed out of it. The extract was stored below 4 C. Chemical content analysis of ACE. An ACE weight gain control composition includes 20 to 40% by weight of polyphenols belonging to the flavonol family.The composition of ACE, which is expressed in weight based on the dry extract total weight, used in the experiment were as follows: from 60 to 90% of the total flavonols in the extract comprises glycosylated polyphenols; from 85 to 98% comprises quercetin in free form (aglycone) or in glycosylated form; from 5 to 20% comprises quercetin-3,40 -diglucoside; from 30 to 70% comprises quercetin-3-monoglucoside and quercetin-40 -monoglucoside; and from 20 to 30% comprises quercetin (Table 1).

Treatment model The rats were randomly divided into three equal experimental groups: DOX, ACE þ DOX, and control; each group consisted of eight animals. The rats in the ACEpretreated group were given 1 mL of freshly prepared ACE via an intragastric tube. The control group was given the same volume of saline. This application continued daily for a total of 14 days before DOX injection. DOX (Carlo Erba, Milan, Italy; 30 mg/kg body weight) was injected intraperitoneally in a single dose to induce hepatotoxicity in DOX and ACE þ DOX groups. The rats were killed 48 h after DOX injection.

Sample collection and storage At the end of the day 14, all animals were killed. Their livers were removed immediately, divided into two pieces and one piece was stored at 80 C for

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biochemical analysis (lipid peroxidation products and antioxidant enzymes). The other piece was blocked for histopathological examination. Blood samples were also collected from animals at the time of death, through cardiac puncture after opening the thoracic region. Five milliliter of blood per animal was kept at room temperature for approximately 30 min and then centrifuged at 4000 r/min for 10 min. The serum samples were stored at 80 C until used for the measurement of serum aspartate transaminase (AST) and serum alanine transaminase (ALT).

Tissue homogenization Liver tissues were homogenized in ice-cold 0.15 M potassium chloride (10%, w/v). MDA and GSH levels were determined in tissue homogenates. For the measurement of antioxidant enzyme (SOD and GSH-Px) activities, homogenate was centrifuged at 600g for 10 min at 4 C to remove crude fractions; then, the supernatant was centrifuged at 10,000g for 20 min to obtain the postmitochondrial fraction.

Biochemical analyses Lipid peroxidation product measurement. MDA, as an endpoint of lipid peroxidation, was measured by detecting absorbance of thiobarbituric acid reactive substances at 532 nm (Buage and Aust, 1978). MDA levels were expressed in nanomoles of MDA per milligram protein. The breakdown product of 1,1,3,3tetraethoxypropane was used as the standard. GSH measurement. GSH levels were determined using Elman’s reagent (Beutler et al., 1963), and the results were expressed in nanomoles of GSH per milligram protein. Tissue antioxidant enzymes assay. GSH-Px activity was measured using the method described by Lawrence and Burk (1976) and SOD activity measurement based on the method followed by Segura-Aguilar (1993). The results were expressed in nanomole nicotinamide adenine dinucleotide phosphate per milligram protein per minute and international units per milligram protein, respectively. Protein measurement. The bicinchoninic acid method was used for determination of the amount of protein in samples (Smith et al., 1985).

Liver function tests. In the present study, the liver function was evaluated by serum levels of ALT and AST. The assay for ALT and AST was carried out according to the methods described in the Abbott Laboratories commercial kits (Abbott Park, Illinois, USA). The results for both enzymes were expressed in units per liter.

Histopathological analysis For the histopathological examination under light microscope, fresh liver samples were fixed in Bouin’s fluid. Following two days of fixation, the specimens were washed and dehydrated through a graded series of ethanol. Then, they were embedded in paraffin wax. Blocks were made and sectioned at 4 mm thickness using a rotary microtome. Sections were rehydrated in distilled water and stained with hematoxylin–eosin and then examined under a light microscope.

Statistical analysis All statistical analyses were performed using Statistical Package for Social Sciences software (SPSS PASW statistics 18.0, Chicago, Illinois, USA). Data were presented as mean + SD. Dual comparisons between groups exhibiting significant values were analyzed with Mann–Whitney U test. Differences were considered significant when p < 0.05.

Results Biochemical results The results are summarized in Figures 1 and 2. It was observed that ALT and AST levels of DOX group were significantly higher when compared with that of the control group (p < 0.001) and significantly lower in ACE þ DOX group in comparison with both DOX and control groups (p < 0.05 for each). Tissue MDA levels were significantly higher, and GSH level and SOD and GSH-Px activities were significantly lower in DOX- and ACE þ DOX-treated rats than that of the control group (for MDA, GSH, and GSH-Px, p < 0.001 and p < 0.05, respectively; for SOD, p < 0.01 and p < 0.05, respectively). On the other hand, ACE pretreatment significantly prevented the elevation induced by DOX in tissue MDA levels and reducuced SOD and GSH-Px enzyme activities and GSH level in the liver tissue (for MDA and GSH, p < 0.01; for SOD and GSH-Px, p < 0.05).

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Figure 1. ALT and AST levels in control, DOX, and ACE þ DOX groups. ap < 0.001: DOX versus control; bp < 0.05: DOX versus ACE þ DOX; cp < 0.05: ACE þ DOX versus control. ACE: Allium cepa (onion) extract; DOX: doxorubicin.

Figure 2. Tissue MDA and GSH levels, SOD and GSH-Px enzyme activities in control, DOX and ACE þ DOX groups. a p < 0.001, p < 0.01: for MDA, GSH, and GSH-Px and SOD and DOX versus control, respectively. bp < 0.01, p < 0.05: MDA and GSH and SOD, GSH-Px, and DOX versus ACE þ DOX, respectively. cp < 0.05 for MDA and GSH and b p < 0.05 for SOD, GSH-Px, and control versus ACE þ DOX. ACE: Allium cepa (onion) extract; DOX: doxorubicin; GSH: glutathione; GSH-Px: glutathione peroxidase, SOD: superoxide dismutase; MDA: malondialdehyde.

Histopathological results The histological findings are presented in Figures 3 to 5. Control animals revealed clear cut hepatic lobules separated by interlobular septa and traversed by portal veins. Within the lobule, hexagonal array of hepatic plates, radiating toward periphery from a central vein were visible. The hepatocytes were

polyhedral. The nuclei were round-shaped, and the size was roughly the same (Figure 3). Animals treated with DOX only indicated marked alterations of hepatic pathology. Intraperitoneal injection of 30 mg/kg body weight of DOX caused histological changes in the rat liver consisting of congestion and thrombosis of central vein, degeneration and

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Figure 3. Photomicrograph of histological liver section from control animal showing a hepatic lobule with the uniform pattern of the hepatocyte radiating from the CV toward the periphery. Sections were stained by hematoxylin–eosin. Original magnification was 200. CV: central vein.

pleomorphism in hepatocytes, cytoplasmic eosinophilia, parenchymal necrosis, proliferation of biliary duct, focal necrosis, and inflammation in portal space (Figure 4). However, all histopathological changes were prevented by ACE pretreatment in ACE þ DOX group in comparison with DOX administration only (Figure 5).

Discussion DOX is a widely used anticancer drug in the treatment of solid tumors and leukemia. However, valuable anticancer therapy with DOX and other quinone anthracyclines is severely limited by severe toxicities (Jamieson and Boddy, 2011). DOX toxicity is attributed to its prooxidant action. Free radical formation was suggested to be involved in DOX-induced hepatotoxicity (Llesuy and Arnaiz, 1990). Treatment with DOX has been shown to cause hepatotoxicity in various animal species (Kwiecien´ et al., 2006; Yagmurca et al., 2007). Focal damage in hepatocytes, significant steatosis, and vascular damage were shown in the liver tissue after administration of DOX (Pedrycz et al., 2004). In the present study, DOX-induced hepatotoxicity has been confirmed by histopathological changes in the liver tissue similar to those reported in other studies (El-Sayyad et al., 2009). Histopathological changes identified in the present study were degeneration and pleomorphism in hepatocytes, proliferation in bile duct, cytoplasmic eosinophilia, parenchymal necrosis, congestion and thrombosis in central vein, and inflammation in portal space in liver tissue of a single dose of DOX-administered rats.

These findings were demonstrated to be markedly prevented by ACE pretreatment, thereby highlighting its protective role in countering the oxidative cytotoxic injury inflicted by DOX. It was shown that DOX injection (20 mg/kg) increased serum ALT level twice normal in mice (Miranda et al., 2003). Similarly, in the present study, there are significant changes in both liver-specific enzymes (ALT and AST) after administration of DOX alone and preceded by ACE. DOX-induced increases in serum activities of ALT and AST in the present study have been also confirmed by other studies (Mohamad et al., 2009). The increase in ALT and AST activities following DOX administration was significantly prevented by ACE treatment. MDA is known to be a major oxidation product of peroxidized polyunsatured fatty acids, and increased MDA is an important indicator of lipid peroxidation (Marnett, 2002). In the present study, MDA level significantly increased in DOX-treated rats; while ACE þ DOX-administered rats showed a significantly lower MDA levels in comparison with the DOX-administered rats similar to previous reports (Yagmurca et al., 2007). Therefore, it may be suggested that increase in MDA level can be an indicator of DOX injury, and pretreatment with ACE significantly reduced lipid peroxidation. Helen et al. (1999) demonstrated the preventive role of onion against lipid peroxidation. Various studies have shown that even a single dose of DOX administration can impair hepatic antioxidant system and damage the liver (Marchand and Renton, 1981). DOX not only increases free radical production in the tissue but also decreases its ability to detoxify ROS. Liver tissue is especially susceptible to free radical injury because low levels of GSH and free radical detoxifying enzymes like SOD and GSH-Px were seen after DOX administration (Abd El-Aziz et al., 2001). These changes observed in the antioxidant defense capacity were believed to be results of DOX-induced hepatotoxicity. The findings of the present study confirm the reports of Deepa and Varalakshmi (2003) that demonstrate deteriorating antioxidant status in the DOX group. Similarly, in the present study DOX caused a decrease in the activities of SOD, GSH-Px and GSH levels; while ACE pretreatment provided an increase in these enzymes when compared with DOX only group. This may be associated with onion’s widely reported antioxidant properties (Griffiths et al., 2002). Vazquez-Prieto and Miatello (2010) have shown that the antioxidant property of onion was

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Figure 4. Photomicrographs of histological liver section from a DOX-treated animal demonstrating (a) congestion and thrombosis of central vein, eosinophilia (arrows) and necrosis in cytoplasm of hepatocytes (stars); (b) proliferation of biliary duct (arrow), degeneration of cells (triangle), and focal necrosis (stars); and (c) focal necrosis (stars), pleomorphism (triangles) and degeneration (arrows) of hepatocytes. Sections were stained by hematoxylin–eosin. Original magnification was 200. DOX: doxorubicin.

Figure 5. Photomicrographs of histological liver section from an ACE þ DOX-treated animal demonstrating decreased focal necrosis, pleomorphism, and degeneration of hepatocytes. Sections were stained by hematoxylin–eosin. Original magnification was 200. ACE: Allium cepa (onion) extract; DOX: doxorubicin; CVL: central vein.

mainly due to the high organosulfur content as well as flavonoids. Onion leaves were demonstrated to have the highest total flavonoid content in comparison to other common vegetables (Miean and Mohamed, 2001). The phenolic hydroxyl groups in the structure of flavonoids have been recognized to function as electron or hydrogen donors, conferring a free radical scavenging effect (Shahidi et al., 1992). In conclusion, the present study indicates that pretreatment with ACE protects against DOX-induced hepatotoxicity in rats, and this is a result of the antioxidant properties of ACE. Further studies on efficacy of antioxidant treatment by ACE in DOX-mediated toxicity and underlying mechanisms would provide a better explanation. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Protective effects of onion (Allium cepa) extract against doxorubicin-induced hepatotoxicity in rats.

Doxorubicin (DOX) is a widely used and potent chemotherapeutic agent. However, serious dose-limiting toxicity through generation of free oxygen radica...
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