Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 43, Num. 4, 2011, pp. 429-432

Indian Journal of Pharmacology, Vol. 43, No. 4, July-August, 2011, pp. 429-432

Research Article

Comparison of the effect of vanadium and deferoxamine on acetaminophen toxicity in rats

H Najafzadeh¹, A Rezaie¹, AM Masoodi¹, S Mehrzadi²

¹ Faculty of Veterinary Medicine, Shahid Chmran University, Ahvaz, Iran
² Tehran University; Young Researcher Club Ahvaz Branch, Ahvaz, Iran

Correspondence Address: H Najafzadeh Faculty of Veterinary Medicine, Shahid Chmran University, Ahvaz Iran najafzadeh@scu.ac.ir

Date of Submission: 09-Sep-2010
Date of Decision: 15-Apr-2011
Date of Acceptance: 25-Apr-2011

Code Number: ph11114

DOI: 10.4103/0253-7613.83115

Abstract

Keywords: Acetaminophen, deferoxamine, hepatotoxicity, rat, vanadium

Introduction

Acetaminophen (APAP) is one of the most common ingredients in most household medicines. Intake of a large dose of APAP may result in severe hepatic necrosis. Oxidative stress mediated by oxidative capacities of the APAP metabolite (N-acetyl-p-benzoquinoneimine), is considered as the main cause of hepatotoxicity of APAP. ^[1] Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principle separate pathways: conjugation with glucuronide, conjugation with sulfate and oxidation via the cytochrome P ₄₅₀ dependent, mixed-function oxidative enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further, metabolized to form cysteine and mercapturic acid conjugates. ^[2] When glutathione is depleted, the reactive metabolite causes necrosis of the liver and other tissues. Treatment of APAP toxicity involves supplying alternate sulfhydryl donors or inhibiting oxidative formation of the reactive metabolite. ^[2]

Clinically, deferoxamine (desferal) is the most current drug for decreasing concentration of iron in patients. ^[3] Deferoxamine has an antioxidative effect along with the iron chelatory property. ^[4]

The vanadium compounds exert insulinomimetic effects on the cardiovascular system. These effects are exerted at the level of glucose transporter type 4 (GLUT-4) translocation and glucose transport, as well as at the level of smooth muscle contractility. ^[5] Also, Tas et al, reported that vanadium sulfate has an antioxidative action in dibetic rats. ^[6]

In the present study, based on probable antioxidant effect of deferoxamine and vanadium, the effect of vanadium was compared with deferoxamine on hepatotoxicity and also on kidney function alteration during APAP administration in rats.

Materials and Methods

Materials

Vanadium (sodium monovanadate) was purchased from Merk Co., (Germany). Desferal was purchased from Novartis Co., Switzerland. Commercial kits for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) measurement were purchased from Pars Azmon Co., Iran.

Animals

Adult, male Wistar rats, weighing 180-220 g were obtained from the animal center of University of Jondishapour. The animals were kept under standard conditions and had access to a standard diet and clean drinking water.

Methods

The animals were divided randomly into 5 groups of 5 animals each. The rats received the drugs as a single dose. The first group, group I, received saline intraperitoneally (i.p.), this group served as a control. The second group, group II, received APAP 500 mg/kg, p.o. The third group, group III, received APAP 500 mg/kg, p.o. with defroxamine at a dose of 50 mg/kg, i.p. The fourth group, group IV, received APAP 500 mg/kg, p.o. with vanadium 10 mg/kg, i.p.. The fifth group, group V, received only vanadium 10 mg/kg, i.p.

After 48 hours, the animals were anesthetized with ketamine (100mg/kg, i.p.), and blood samples were obtained. The serum samples were separated for the measurement of ALT and AST levels that were estimated according to the method of commercial kits. These enzymes are related to the liver injury; especially AST is more specific for the liver of rats.

Sections from the liver of each animal were fixed in phosphate-buffered formaldehyde, embedded in paraffin by Histokinnet apparatus, and 5 μm thick sections were prepared. The sections were stained with hematoxylin and eosin for the evaluation of liver tissue.

Data were expressed as mean ± SEM. Group variance was analyzed by one-way analysis of variation (ANOVA) and Fisher least significant difference test (LSD) was tested for significant differences between the groups. P≤0.05 was considered statistically significant.

Results

Administration of APAP (500 mg/kg, single dose) resulted in a significant increase serum ALT and AST concentration. The mean of ALT concentration in group II (98 IU/L) was significantly greater than group I (48 IU/L) (P < 0.05). This elevation of ALT was lowered in group III (received APAP and deferoxamine) with comparison to group II. The mean was significantly different in group IV (which received APAP and vanadium) and V (received vanadium) with comparison to group II [Figure - 1]. The mean of serum activity of AST in group II (187 IU/L) was significantly greater than group I (141 IU/L) (P < 0.05). Also, the mean serum activity was significantly (P < 0.05) decreased in other groups in comparison with group II [Figure - 2].

The change of factors, which related to the kidney function, i.e., BUN, creatinine, sodium, and potassium was not significant [Figure - 3].

Histopathological evaluation of livers is shown in [Figure - 4] and was as follows:

Group I: The liver was normal at light microscopic examination.

Group II: Rats which received APAP showed sever hydropic degeneration with irregular spaces in hepatocytes and sinusoids were occluded which is due to hepatocyte swelling.

Group III: The liver examination showed congestion and moderate cell swelling. There were a few foci of lymphocyte accumulation in the portal area.

Group IV: Moderate cell swelling was observed.

Group V: Mild cell swelling was observed.

Discussion

Administration of APAP was toxic for rats in the present study. However, various dosages were used in other studies. ^[7],[8],[9] The result of the present study shows that the selected dose can induce hepatotoxicity in biochemical and histopathological aspects. We did not see considerable changes of biomedical factors which were related to the kidney function with present regime. However, APAP- induced nephrotoxicity was reported by Laster et al and Younes et al. ^[9],[10] The difference in our result may be related to the dosage and route of APAP administration.

The prophylactic effect of administration of deferoxamine in the present study was similar to other studies. ^{[10],[11],[12]} These concluded that the protective effect of deferoxamine against APAP-induced liver injury may be attributable to the chelation of iron, which can catalyze the generation of active oxygen species, in hepatocytes. ^[11]

In our previous study, we demonstrated the preventive effect of deferoxamine on iron-induced hepatotoxicity in rats. ^[13] The role of oxidative stress in APAP-induced hepatotoxicity and preventive and therapeutic effect of natural antioxidant was evaluated in some studies. ^[14],[15] For example, the hepato protective effect of aqueous ethanol extract of Zingiber officinale against APAP-induced acute toxicity is mediated either by preventing the decline of hepatic antioxidant status or due to its direct radical scavenging capacity. ^[16] The ethanolic extract of Cuscuta chinensis can prevent hepatic injuries of APAP-induced hepatotoxicity in rats and this is likely to be mediated through its antioxidant activities. ^[17] Similar results were seen in the Phyllanthus niruri administration in mice. ^[18]

The co-administration of vanadium had preventive effect on APAP-induced hepatotoxicity in the present study. The mechanism of this effect is not clear and the present study is first of its kind in evaluation of APAP-induced hepatotoxicity. Further studies are therefore needed; studies however have reported that vanadium sulfate improves oxidative stress. ^[6]

In conclusion, the results of this study showed that deferoxamine has protective effect similar to vanadium at least in prophylaxis of APAP-induced hepatotoxicity in rats.

Acknowledgement

The authors wish to express their gratitude to the Research Council of Shahid Chamran University for their financial support.

References

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