Hepatoprotective role and antioxidant capacity of selenium on arsenic-induced liver injury in rats

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Abstract

The present study was undertaken to evaluate the protective effect of selenium against arsenic-induced oxidative damage in experimental rats. Males were randomly divided into four groups where the first was served as a control, whereas the remaining groups were respectively treated with sodium selenite (3 mg/kg b.w.), sodium arsenite (5.55 mg/kg b.w.) and a combination of sodium arsenite and sodium selenite. Changes in liver enzyme activities, thiobarbituric acid reactive substances (TBARS) level, antioxidants and reduced glutathione (GSH) contents were determined after 3 weeks experimental period.

Exposure of rats to As caused a significant increase in liver TBARS compared to control, but the co-administration of Se was effective in reducing its level. The activities of glutathione peroxidase (GPx) and glutathione-S-transferase (GST) of As-treated group were found lower compared to the control and the Se-treated group. The co-administration of Se had an additive protective effect on liver enzyme activities compared to As-treated animals. On the other hand, a significant increase in plasmatic activities of AST, ALT and ALP was observed in As-treated group. The latter was also exhibited a decrease in body weight and an increase in liver weight compared to the control. The co-administration of Se has decreased the activities of AST, AST and ALP and improved the antioxidant status as well. Liver histological studies have confirmed the changes observed in biochemical parameters and proved the beneficial role of Se. To conclude, results suggest that As exposure enhanced an oxidative stress by disturbing the tissue antioxidant defense system, but the Se co-administration protected liver tissues against As intoxication probably owing to its antioxidant properties.

Introduction

Arsenic is a naturally occurring element that is ubiquitously present in the environment in both organic and inorganic forms. Millions of people worldwide are at risk of many diseases (National Research Council, 2001, Kenneth and Gilbert, 2002). Human exposures to the generally more toxic inorganic arsenic compounds occur in occupational or environmental settings, as well as through the medicinal use of arsenicals (Aposhian, 1989). Drinking water and industrial pollution are major sources of exposure to inorganic arsenic for humans.

Once ingested, soluble forms of arsenic are readily absorbed from the gastrointestinal tract to blood stream and then distributed to organs and tissues after first passing through the liver. Generally, As interferes with a number of organ and body functions such as the central nervous system (Vahidnia et al., 2008) and liver and kidneys (Smith et al., 1998, Kannan et al., 2001). However, As induced skin lesions are characterized by symptoms like hyper pigmentation and keratosis. Other clinical manifestations include Blackfoot disease (Tseng, 1989), diabetes mellitus (Lia et al., 1994, Tseng, 2004), hypertension (Chen et al., 1995), atherosclerosis (Simeonova and Luster, 2004), and cancers of the skin, lung, bladder and liver (Chen et al., 1992).

The acute and chronic toxicity largely depend on the chemical form and physical state of the compound involved (Garcia-Vargas and Cebrian, 1996). Inorganic trivalent arsenic is generally regarded as being more toxic than pentavalent arsenic, which in turn is more toxic than methylated form. Trivalent arsenic toxicity could be mediated by its direct binding with –SH groups, or indirectly through generation of reactive oxygen species (ROS) (Jonnalagadda and Prasada Rao, 1993, Chen et al., 1998, Nandi et al., 2006). The toxicity of inorganic arsenic appears to be mediated through its ability to substitute phosphate groups, affecting enzymes that depend on this group for their activity (e.g., interfering in the synthesis of ATP and DNA). However, As generates ROS and free radicals like hydrogen peroxide (H2O2) (Barchowsky et al., 1996, Wang et al., 1996, Chen et al., 1998), hydroxyl radicals species (HOradical dot), nitric oxide (NOradical dot) (Gurr et al., 1998), superoxide anion (O2radical dot) (Lynn et al., 2000), dimethyl arsenic peroxyl radical ([CH3)2 AsOO]) and dimethyl arsenic radical [(CH3)2Asradical dot] (Yamanaka et al., 1997, Csanaky and Gregus, 2002, Gailer, 2007). There is a proposal that all of these reactive species generated by arsenic are responsible for the oxidative stress responses (Flora, 1999, Allen and Rana, 2003, Garcia-Shavez et al., 2006).

In the event that oxidative stress can be partially implicated in arsenic toxicity, a therapeutic strategy to increase the antioxidant capacity of cells against arsenic poisoning. This may be accomplished by either reducing the possibility of metal interacting with critical biomolecules and inducing oxidative damage, or by boosting the cells antioxidant defenses through endogenous supplementation of antioxidant molecules (Parola et al., 1992, Nandi et al., 2005, Gupta et al., 2007).

Although many investigators have confirmed that arsenic induces the oxidative stress, the usefulness of antioxidants has recently been considered as a better treatment. Therefore, supplementation of antioxidants such as vitamin C, vitamin E (Ramnathan et al., 2002, Kannan and Flora, 2004), n-acetylcysteine (Flora, 1999, Modi et al., 2006) and some micronutrients like zinc and selenium (Modi et al., 2004, Modi et al., 2005) have been found to be more effective when given during the course of chelation therapy compared to the treatment with chelating agents alone as they have been known to displace toxic metals and have roles in many biochemical functions.

Selenium is an essential dietary trace element, which plays an antioxidant role. Selenium is an integral part of many proteins with catalytic and structural functions. Its nutritional deficiency leads to muscular dystrophy, endemic fatal cardio myopathy (Keshan disease), and chronic degenerative diseases in humans that could be prevented by selenium supplementation when used alone or in combination (Rayman, 2002). The most important metabolic roles of selenium in mammalian cell is due to its function in the active site of many antioxidant enzymes, e.g., thioredoxin reductase and glutathione peroxidase (GPx) (Hopenhayn-Rich et al., 1996, Flora et al., 2002). The GPx enzyme was the first established selenoenzyme that can prevent oxidative damage of cell membranes. Moreover, GPx does not only protect cells against damages by free radicals, but also protects membrane lipids against such oxidation generated by peroxides and permits regeneration of membrane lipid molecules through reacylation (Esterbauer et al., 1992, McPherson, 1994, Hsu et al., 1997). Thus, GPx may prevent the harmful effects of free radicals and may also reduce the formation of the reactive metabolites induced by arsenic. The present study, therefore, has been undertaken to evaluate the protective capacity of selenium on arsenic-induced liver injury in male rats. Accordingly, the antioxidant status of liver was determined by measuring the activity of glutathione-S-transferase (GST), glutathione peroxidase (GPx), reduced glutathione (GSH) and TBARS level. In addition, plasma transaminases, and alkaline phosphatase activities were also estimated to assess the possible cytoplasmic enzyme leakage from injured cells.

Section snippets

Chemicals

Sodium arsenite (NaAsO2) and sodium selenite (Na2SeO3) were purchased from Sigma Chemical Co (St Louis, France) and all other chemicals used in the experiment were of analytical grade.

Animals and experimental design

Twenty-eight male Wistar rats (aged 9 weeks; weighing 270–290 g) were obtained from the Pasteur Institute (Algiers, Algeria). Animals were acclimated for 2 weeks under the same laboratory conditions of photoperiod (12 h light:12 h dark) with a minimum relative humidity of 40% and room temperature of 23 ± 2 °C. Food

Effects of treatments on body, absolute and relative liver weights

The variations in body and relative liver weights of animals subjected to different treatments were shown in Table 1. During the course of present investigations, it was observed that the control body weight and Se-treated group have increased progressively throughout the study. Contrary, in As-treated rats, results revealed significant decrease in body weight gain by −13% as compared to the control. Besides, a significant increase of As-treated group in absolute and relative liver weights was

Discussion

Reduction in body weight is used as an indicator for the deterioration of rat general health status. It has been reported that As could induce toxicological effects and biochemical dysfunctions representing serious health hazards (Yousef et al., 2008). The findings from the present study indicate that excessive As exposure has changed body weight, absolute and relative liver weights, leading however to significant decrease in animal growth and production performances. Hence, these findings were

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