Assessment of the Ameliorative Role of Selenium Nanoparticles on the Oxidative Stress of Acetaminophen in Some Tissues of Male Albino Rats

beni-suef university journal of basic and applied sciences 2 (2013) 80e85

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Full Length Article Assessment of the ameliorative role of selenium nanoparticles on the oxidative stress of acetaminophen in some tissues of male albino rats

E.T. Mohammed, G.M. Safwat*

Department of Biochemistry, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, Egypt article info abstract

Article history: Our present study aimed to assess the ameliorative role of selenium nanoparticles (Se- Received 20 November 2012 NPs) with diameters 3e5nmand10e20 nm (Detected by Transmission Electron micro- Accepted 29 January 2013 scopy), as an antioxidant against acetaminophen toxicity in the brain and kidney of male Available online 1 October 2013 albino rats. The experimental rats were divided into four groups, each with eight rats. ThegroupIwereintraperitoneallyinjectedwith saline, the group II were orally admin- Keywords: istrated paracetamol (500 mg/kg b. w.) for two successive days, whereas rats of the Oxidative stress groups III and VI were intraperitoneally injected with 0.5 mg Se-NPs of diameters 3e5nm Paracetamol and 10e20 nm respectively, two days before paracetamol administration and continued Selenium nanoparticles with its administration. The brain and renal oxidative stresses were assessed by Kidney increased tissue malondialdehyde, nitric oxide concentration, DNA fragmented, and Brain significant decrease of glutathione content and total antioxidant capacity. The brain Rat gamma-glutamyltransferase (g-GT) and butyryl cholinesterase (BCHE) were also increased. On the other hand, treatment of rats with selenium nanoparticles with two different diameters 3e5nmand10e20 nm respectively reversed paracetamol-related toxic via more than one mechanism such as the powerful inhibition of malondialdehyde and nitric oxide concentrations in previous tissue. Stimulation of the synthesis of cellular antioxidants represented by significant increase of GSH concentration and significant decrease of the inflammatory response represented by TNF-a concentration. Also DNA fragmentation % significantly decreased in the same tissues. The present results concluded that paracetamol overdose induced oxidative damage in brain and renal tissues were improved by selenium nanoparticles with two different diameters with its antioxidant effects. Copyright 2013, Beni-Suef University. Production and hosting by Elsevier B.V. All rights reserved.

* Corresponding author. E-mail address: [email protected] (G.M. Safwat). Peer review under the responsibility of Beni-Suef University

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1. Introduction selenium nanoparticles (Se-NPs) of diameter 3e5 nm and 10e20 nm were obtained from Pharmaceutical department, Paracetamol is a common analgesic and antipyretic drug that faculty of Pharmacy, Beni-Suef University. Sizes of Se- is safe at therapeutic dosages 10e15 mg/kg, but at high doses it nanoparticles were detected by Transmission Electron Mi- produces hepatic necrosis and renal failure in humans and croscopy. Butyryl cholinesterase (BCHE), Gamma-glutamyl- the experimental animals (Kelley et al., 1992; Bond et al., 2003). transferase (g-GT), nitric oxide (NO), total antioxidant capacity Paracetamol is predominantly metabolized in the liver by (TAC) and glutathione kits were purchased from Biodiagnostic conjugation with sulphate (around 30%) and glucuronide Company, Egypt. Rat TNF-a immunoassay kit (Catalog Num- (60%). A smaller amount, of its un-metabolised form, is elim- ber RTAOO-SRTAOO-PRTAOO) was purchased from Quanti- inated outside the body via urine. However, approximately kine R&D Systems, Inc. USA. Other non-mentioned chemicals 5e10% of paracetamol is metabolized to N-acetyl-P-benzo- used in the present experiment were purchased from Sigma, quinoneimine (NAPQI), a toxic metabolite via CYP450- USA. dependent pathways (Dahlin et al., 1984). NAPQI is then detoxified by glutathione and is eliminated in urine or bile. 2.2. Animals The previous reports indicate that reactive oxygen species (ROS) are generated after treatment with high doses of para- Adult male albino rats, weighing 120e150 g, were used as an cetamol (Arnaiz et al., 1995), and a variety of endogenous experimental model. Rats were maintained in cages (8 rats per antioxidants begin to remove these free radicals from the cage), and were fed a maintenance ration and water ad libitum. circulation and tissues to protect the body against acetamin- They were obtained from Animal House Colony of the Na- ophen toxicity (Amimoto et al., 1995; Schnellmann et al., tional Research Centre, Doki and Giza, Egypt. The rats were 1999). kept under observation for one week before the onset of Selenium (Se) is fundamental and necessary to the experiment to be acclimatized. They were maintained at a mammalian health. This metal, in the form of selenocysteine, room temperature of 25 Æ 1 C under 12-h light dark cycle. All function as a redox center of an array of selenoproteins experimental procedures were conducted in accordance with (Copeland, 2003; Driscoll and Copeland, 2003), some of which the guide for the care and use of laboratory animals and in have important enzymatic functions for homoeostasis, such accordance with the local Animal Care and Use Committee. as glutathione peroxidase (GPx) (De Haan et al., 2003; Miyamoto et al., 2003), phospholipid hydroperoxide gluta- 2.3. Experimental design thione peroxidase (PHGPx) (Imai and Nakagawa, 2003; Nakagawa and Imai, 2000) and thioredoxinreductase (Arner Thirty two rats were divided into four groups, each with 8 rats. and Holmgren, 2000; Becker et al., 2000). Group I (normal rats) were intraperitoneally injected with 0.9% The efficacy of Se in inducing Se-containing enzymes in vivo saline, group II (paracetamol group) were orally administrated depends on its chemical form (Brigelius-Flohe´ et al., 1996; 500 mg of paracetamol/Kg body weight for two successive Ortuno et al.1996). It is known that particles of elemental Se days by using of stomach tube (Kim et al., 2009). Rats of group (Se0) formed from some bacterial strains and the redox system III and VI were intraperitoneally injected with 0.5 g/Kg body of glutathione or ascorbate and selenite has a very low weight of Se-NPs with a diameter <5 nm and <20 nm for two bioavailability (Combs et al., 1996; Garbisu et al., 1996; Schlekat successive days, then after 24 h, re-injected with the same et al., 2000). Presence of protein in the redox system can control dose and sizes of Se-NPs in combination with 500 mg/Kg body the aggregation of elemental Se atoms to form elemental Se weight of paracetamol, respectively (Peng et al., 2007). All rats nanoparticles (Nano-Se). Various sizes of Nano-Se can be ob- were sacrificed 24 h after the last Se-nanoparticles and para- tained by changing the concentration of bovine serum albumin cetamol doses. (BSA). Generally; the higher BSA concentration the resulting the smaller Nano-Se particle size (Zhang et al., 2004). The size of nanoparticles plays an important role in their biological activ- 2.4. Sampling and preparation ity. Generally, the smaller sized nanoparticles are more active than those of larger size (Oberdorster et al., 2005). All groups of rats were decapitated in the 5th day after the The purpose of the present study was, to evaluate the role begging of the Se-nanoparticles administration either alone of selenium nanoparticles sizes (Se-NPs), to ameliorate the or with paracetamol. The brain and kidney were excised. A oxidative stresses, induced by paracetamol overdose, in the suitable weight, of the fresh brain and renal tissues (0.5 g), kidney and brain of male albino rats. was homogenized in (5 ml) of ice cold phosphate buffer saline (pH 7), and then the homogenate was centrifuged at 20,000 Â g for 10 min at 4 C. The supernatant was collected for estimation of the concentrations of malondialdehyde 2. Materials and methods (MDA), nitric oxide (NO), GSH, total antioxidant capacity (TAC), pro-inflammatory cytokines (TNF-a) and deoxy- 2.1. Drugs and chemicals ribonucleic acid (DNA) fragmentation in the brain and kidney, whereas the activities of gamma glutamyltransferase (g-GT) Ò Paracetamol (Novaldol 1000 mg) was obtained from Savo and butyryl cholinesterase (BCHE) activity were determined Aventis Company, Cairo, Egypt. Red dispersed solution of in the brain only. 82 beni-suef university journal of basic and applied sciences 2 (2013) 80e85

Table 1 e Concentrations of glutathione (GSH, nmol/100 mg) and total antioxidant capacity (TAC, mM/100 mg), in the brain and kidney of rats of group I, II, III and VI. Each value is a mean of eight rats ± SE. Parameters GSH (nmol/100 mg) TAC (mM/100 mg)

Groups Brain Kidney Brain Kidney

Group I 490.7 Æ 51.60a 800.7 Æ 47.47a 0.76 Æ 0.049a 0.665 Æ 0.026a Group II 257.2 Æ 27.02b 409.0 Æ 29.04c 0.67 Æ 0.037a 0.548 Æ 0.034a Group III 398.9 Æ 44.35ab 627.8 Æ 39.55b 0.75 Æ 0.055a 0.648 Æ 0.041a Group VI 354.3 Æ 36.47ab 530.6 Æ 40.53bc 0.75 Æ 0.063a 0.618 Æ 0.057a

Means which have the same superscript letter(s) are similar, i.e. insigniﬁcant difference (P > 0.05).

2.5. Biochemical assays corresponding rats of group I, whereas GSH contents of brain of group III and VI were insignificantly increased, in compar- Kidney and brain tissue homogenates were used for spectro- ison with group II, but still similar to rats of group I (Table 1). photometric estimation of the following parameters by using There was no significant variation in TAC of the same organs. of Biodiagnostic commercial kits. Malondialdehyde (MDA) Se-nanoparticles at a size (3e5 nm) (group III) caused a sig- level as an index of lipid peroxidation was measured colori- nificant increase in renal GSH content in comparison to group metrically according to the method of Albro et al. (1986). The II. Also there was no significant variation between group III total antioxidant capacity (TAC) was measured in the previous and group VI. tissues according to the method described by Koracevic et al. Our results, in (Table 2), revealed that overdose of para- (2001). Also the concentrations GSH and NO were measured cetamol alone induced significant (P < 0.05) increase in MDA according to Beutler et al. (1963) and Montgomery and Dymock and NO levels in the brain and kidney, in comparison to rats of (1961), respectively. The activities of butyryl cholinesterase group I. On the contrary, Se-nanoparticles significantly (BCHE) and Gamma-glutamyltransferase (g-GT) were esti- decreased MDA level in the same organs, in comparison those mated in the brain by kinetic colorimetric method according of group II. Administration of Se- nanoparticles significantly to Knedel and Bo¨ ttger (1967) and Szasz (1969) respectively. The decreased the NO concentration in brain tissue only in com- brain and kidney DNA fragmentation was measured as parison to group II. described by Jafari and Rabbani (2000) depending on colori- Results in (Table 3) showed that paracetamol overdose metrical quantitation upon staining with diphenylamine alone induced a significant (p < 0.05) increase in TNF-alpha (DPA). The renal and brain pro-inflammatory cytokines TNF-a level and nuclear DNA fragmentation % in rat brain and kid- levels were measured by aid of ELIZA according to Perlstein ney tissues. Se-nanoparticles significantly decreased TNF- and Chan (1987). alpha levels in the same organs in comparison to paracetamol group (group II). Se-nanoparticles treatment at a size of 2.6. Statistical analysis (3e5 nm) significantly decreased DNA fragmentation % in renal tissue only. Statistical analysis was carried out using student’s t-test. The activities of BCHE and g-GT enzymes in brain tissue in The values are expressed as mean Æ standard error (SE). P rats of group II, were significantly increased in comparison values less than 0.05 were considered statistically significant with those of group I (Table 4). Se-nanoparticles significantly (P < 0.05). decrease g-GT enzyme in the same organ in comparison to paracetamol group. Also se-nanoparticles significantly decrease BCHE enzyme in brain tissue in comparison to group 3. Results II, while its level was still significantly higher than that of group I. In the present results, the brain and renal GSH contents of It was obvious that there was no significant variation be- group II were decreased significantly, in comparison with the tween the two different diameters of se- nanoparticles.

Table 2 e Concentrations of MDA (nmol/100 mg) and NO (mmol/100 mg), in the brain and kidney of groups I, II, III and VI. Each value is a mean of eight rats ± SE. Parameters MDA (nmol/100 mg) NO (umol/100 mg)

Groups Brain Kidney Brain Kidney

Group I 31.11 Æ 2.03a 26.26 Æ 1.81a 45.64 Æ 0.60a 42.33 Æ 3.33a Group II 51.48 Æ 4.003b 47.25 Æ 4.27b 58.32 Æ 3.53b 59.70 Æ 5.20b Group III 31.07 Æ 4.12a 35.01 Æ 1.74a 46.46 Æ 3.47a 47.70 Æ 3.93ab Group VI 34.38 Æ 4.91a 34.26 Æ 3.40a 50.13 Æ 2.90ab 45.83 Æ 1.68ab

Means which have the same superscript letter(s) are similar, i.e. insigniﬁcant difference (P > 0.05). beni-suef university journal of basic and applied sciences 2 (2013) 80e85 83

Table 3 e Concentrations of TNF-a (pg/ml) and DNA fragmentation %, in the brain and kidney of groups I, II, III and VI. Each value is a mean of eight rats ± SE. Parameters TNF-a (pg/ml) DNA fragmentation %

Groups Brain Kidney Brain Kidney

Group I 234.1 Æ 22.58a 136.6 Æ 13.93a 39.76 Æ 2.15a 44.38 Æ 1.94a Group II 400.2 Æ 8.42b 321.6 Æ 18.64b 51.02 Æ 1.70b 55.77 Æ 3.02b Group III 289.3 Æ 6.69a 194.5 Æ 6.28a 46.39 Æ 0.76b 46.76 Æ 0.89a Group VI 295.1 Æ 15.27a 182.7 Æ 9.19a 46.02 Æ 1.63ab 48.25 Æ 1.24ab

Means which have the same superscript letter(s) are similar, i.e. insigniﬁcant difference (P > 0.05).

generation of ROS appears as an early sign which precedes 4. Discussion intracellular GSH depletion and cell damage (Manov et al., 2002). In the present study, overdose treatment of paracetamol In our experiments, we observed that paracetamol-induced (500 mg/kg b. w.) caused a significant reduction of the con- fragmentation of genomic DNA, suggesting that paracetamol- centrations of glutathione (GSH) in the kidney and brain, in induced kidney and brain cell damage occurs through comparison with the corresponding rats of group I. These necrotic pathway. The genotoxic potential of acetaminophen might be attributed to the metabolic activation of paracetamol has also been observed by Dybing et al. (1984) and Hongslo et al. to the reactive metabolite N-acetyl-p-benzoquinone imine (1994). They reported that DNA strand breaks in rat hepatoma (Hart et al., 1994), which is considered a major mechanism of cells induced by the reactive acetaminophen metabolite N- its toxicity. As this metabolite can directly react with gluta- acetyl-p-benzoquinone imine (NABQI). NAPQI binding to thione and, at overdose of paracetamol, depletes its cellular mitochondrial proteins enhances the conversion of the mo- content, leading to two possible adverse consequences: (1)- it lecular oxygen (O2) to reactive oxygen radical, leading to the reduces the inactivation of the reactive metabolite and tends mitochondrial oxidative damage. This causes the mitochon- to increase its covalent binding to a number of intracellular drial membrane lost its integration and became hyper- target proteins (Bessems and Vermeulen, 2001), (2)- it may permeable with more transition pore opening (Masubuchi have several deleterious effects on cell homeostasis and may et al. 2005), matrix swelling, outer membrane lysis that poten- therefore aggravate the toxic effects of reactive metabolite. tiate the release of apoptosis-inducing factor and endonuclease Several mechanisms were suggested as probable pathways G from the mitochondria. The released endonucleases pass to for paracetamol-mediated nephrotoxicity. These included the the nuclei, and enhance the fragmentation of the nuclear DNA r oxidative metabolism to NAPQI then de-acetylation to - (Bajt et al., 2006). aminophenol and further oxidation to an aminophenoxy Tumor necrosis factor alpha (TNF-a) is a pleiotropic cyto- radical and benzoquinone imine (Mugfordand Tarloff, 1997; kine produced by a variety of cell types including macro- Harmon et al., 2005). phages, T-cells, mast cells, and keratinocytes. Leukocyte The elevation in MDA level, in both kidney and brain in rats infiltration, a hallmark of inflammation, is observed in most overdosed with paracetamol, is an indicator of lipid peroxi- liver injuries caused by various types of chemical substances dation, which has been suggested to be closely related to including paracetamol (Luster, 2001). Paracetamol overdose is paracetamol-induced tissue oxidative damage (Sener et al., known to be associated with inflammation that associated 2003). It has been proven that hydrogen peroxide and super- with a marked increase in the inflammatory cytokines; TNF- oxide anion are generated during biotransformation of para- alpha (Jamesetal., 2003). Our results confirmed that as the cetamol in the CYP450 system (Dai and Cederbaum, 1995) and level of TNF-alpha in the kidney and brain significantly from mitochondria during paracetamol intoxication (Knight increased. et al., 2001). It has been further suggested that the In addition, the overdose of paracetamol in rats increased the production of nitric oxide in kidney and brain tissues. These results are in favoring of the possibility that over- Table 4 e Activities of g-GT (U\L) and BCHE (U\L) enzymes production of NO plays an important role in the pathogenesis in the brain and kidney of groups I, II, III and VI. Each of paracetamol induced renal and brain damage (Zhang et al., value is a mean of eight rats ± SE. 2000; Abdel-Zaher et al., 2007). As infiltrated macrophages Parameters g-GT (U\L) BCHE (U\L) release reactive oxygen species and large quantities of nitric Groups Brain Brain oxide (NO), via inducible NO synthase (iNOS)-dependent mechanism, in response to inflammatory stimuli (Harstad Group I 9.77 Æ 0.88a 32.21 Æ 3.15a and Klaassen, 2002; Knotek et al., 2001). Group II 14.40 Æ 1.52b 132.7 Æ 11.32b Group III 9.51 Æ 0.46a 65.79 Æ 4.77c Our experiments show that paracetamol, a drug that is Group VI 8.03 Æ 0.68a 89.07 Æ 7.61c widely used as a mild pain reliever and anti-thermic has neurotoxic effects on rat brain when administrated in over- Means which have the same superscript letter(s) are similar, i.e. dose (more than 100 mg/kg B.W), (Posadas et al., 2010). In the insignificant difference (P > 0.05). present data, the levels of butyryl cholinesterase and gamma 84 beni-suef university journal of basic and applied sciences 2 (2013) 80e85

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