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Pharmacologia
Year: 2016  |  Volume: 7  |  Issue: 4  |  Page No.: 229 - 233

Hepatoprotective Effects of Propofol in Cisplatin Induced Rat Liver Oxidative Damage

Sami Ghazal, Soleymanian Tayebeh, Khoshraftar Ebrahim and Ranjbar Akram    

Abstract: Background and Objective: Cisplatin is a widely used chemotherapeutic agent to treat solid tumors. The aim of this study is to evaluate the effects of propofol as a antioxidant on the level of liver enzymes (ALT and AST) in plasma and oxidative damages in liver tissue in rats induced by cisplatin. Methodology: In this study 20 male Wistar rats were at random separated to four groups (n = 4) and then, treated intraperitoneally (IP) for one week. The groups were as follows: Propofol group, control group, cisplatin group, propofol and cisplatin group. Then, propofol was administered (10 mg kg–1 day–1, IP) alone or in mixture with cisplatin (7 mg kg–1 day–1, IP). Also, control group received only normal saline. Oxidative stress parameters, such as: Total Antioxidant Capacity (TAC), catalase (CAT) and total thiol molecules (TTG) in liver tissue and the levels of ALT and AST in serum were measured. Results: Cisplatin hepatotoxicity was manifested by an increase in serum ALT and AST and decrease in TAC in liver tissues. Serum ALT was found to decreased significantly (p<0.008) in the combination group (propofol+cisplatin) in comparison with the cisplatin group. Conclusion: In conclusion, the present results suggest that propofol decrease liver injury induced by cisplatin treatment in liver rats. Further study is needed to clarify the pharmacological significance of its effects on cisplatin poisoning.

1,2. Inspite of its benefits in treatment of solid tumors, it has some large side effects: Hepatotoxicity, neurotoxicity, nausea, ototoxicity and other toxicity effects, limiting it in clinical treatment3,4. Cisplatin as a chemotherapeutic drug change biochemical parameters in blood, liver, kidney and other important organs. In vitro studies showed cisplatin increase ALT and AST in serum and free radicals in liver tissues5,6. Some antioxidant agents can reduce cisplatin induced toxicity. The decrease in the activity of the antioxidant enzymes may be also involved in oxidative stress observed in cisplatin-treated rats6. Several free radical scav-engers and antioxidants including vitamin C, vitamin E and flavonoids were reported to show some protective effects in cisplatin-induced toxicity7. Propofol (2, 6-diisopropylphenol) is a commonly used intravenous anesthetic agent for inducting anesthesia in therapeutic and surgical procedures or as a slow infusion to maintain anesthesia and inducing sedation in some patients in clinical procedures. It has some advantages that make it better than other sedative drugs. Recently studies showed propofol as an antioxidant agent reduce the degree of the high oxidative stress in rat brain tissues8,9. Polyphenols have antioxidant effects and react against reactive chemical agents that cause oxidative damages. In the past three decade research have been done, showed antioxidative and anti-tissue damaging properties of propofol10,11. The aim of this study is to evaluate the effects of propofol on the level of liver enzymes (ALT and AST) in plasma and oxidative damages in liver tissues, in rats induced by cisplatin.

MATERIALS AND METHODS

Reagents and chemicals: Ethylenediamine tetra acetic acid (EDTA), dithiobis-2-nitrobenzoic acid (DTNB), tris base and 2, 4, 6-tripyridyl-s-triazine (TPTZ), hydrogen peroxide (H2O2) and cisplatin were used in this study. All other chemicals were obtained from the sigma.

Animals and treatments: In this study 20 male Wistar rats with 180-250 g weight maintained on a 12 h light/dark cycle with free access to tap water and standard laboratory chow were used. Animals were at random separated to four groups (n = 4) and then, treated intraperitoneally (IP) for one week.

The design of these treatments resulted in four experimental groups, the groups were as follows: Propofol, control, cisplatin, propofol and cisplatin group. Then, propofol was administered (10 mg kg–1 day–1, IP)12 alone or in mixture with cisplatin (7 mg kg–1 day–1, IP)13. Also, control group received only normal saline.

Sample collection: The liver were rinsed with saline solution and then also stored at liquid nitrogen. Liver tissues were homogenized in 1:5 V of PBS (pH 7.4). The homogenate was centrifuged at 3000 rpm for 10 min. And then, the supernatant was used as liver total homogenate sample. Then centrifuged at 3000×g for 15 min at 4°C, supernatant was kept at -80°C for further biochemical measurements14.

Experimental protocols Estimation of marker enzymes: Levels of various liver marker enzymes such as ALT and AST in serum were estimated according to the standard procedure of kits (Pars Azemon kit, Iran).

Measurement of biomarkers of oxidative stress Measurement of Total Antioxidant Capacity (TAC): Ferric reducing ability of plasma (FRAP) is an antioxidant capacity assay. The FRAP assay is often used to measure the antioxidant capacity of foods, beverages and nutritional supplements containing polyphenols. The FRAP is based on the ability of plasma to reduce Fe+3 to Fe+2 in the presence of TPTZ. The reaction of Fe+2 with TPTZ created a blue color complex which had the maximum absorbance at the wavelength of 593 nm in spectrophotometer15.

Measurement of catalase (CAT) activity assay: The primary principles of the reaction consist of the breakdown of the substrate (hydrogen peroxide) by catalase and measuring the decrease in absorbance at 240 nm and this reaction took place with the lowest amount of H2O2 (10 mM) and sodium phosphate buffer (50 mM, pH = 7.0). Changes in the rate of absorbance in the unit of time is an index of the activity of catalase. The activity of catalase is measured as the amount of substrate (H2O2) that is disintegrated by catalase in 1 min which is reported as the unit of the enzyme in milliliter of plasma (units per milliliter plasma)16.

Measurement of total thiol molecules (TTG): To evaluate the total thiol molecules of saliva, DTNB was used as the reagent. The DTNB reacted with thiol molecules and created a yellow complex with them which had the maximum absorbance at the wavelength of 421 nm in spectrophotometer17.


Total protein: Protein concentrations in the samples were measured by the Bradford method using concentrated coomassie blue reagent. Bovine serum albumin was used as the standard18.

Statistical analysis: Mean and standard error values were determined for all the parameters and the results were expressed as Mean±SE. All data were analyzed with SPSS version 16 employing one-way ANOVA followed by Tukey post hoc test. Differences between groups was considered significant when p<0.05.

RESULTS

Table 1 shows the effects of cisplatin, propofol and their combination on levels of Total Antioxidant Capacity (TAC), catalase (CAT) and total thiol molecules (TTG) in liver tissues. Administration of 7 mg kg–1 day–1, cisplatin for 7 consecutive days resulted in a significant decrease (218.45±43.79 vs 446.41±168.06) in TAC (p<0.05), insignificant decrease (0.32±0.13 vs 0.35±0.11) in TTG (p>0.05) and insignificant increase (0.82±0.05 vs 0.66±0.33) in CAT (p>0.05), respectively, as compared with the control group.

Administration of 10 mg kg–1 day–1 propofol for 7 consecutive days induced no significant change (p>0.05) on levels of TAC, CAT and TTG in liver tissues as compared to controls.

Treatment with propofol for 7 consecutive days prior to a single injection of cisplatin resulted in an insignificant increase in the level of TAC and TTG (p>0.05), respectively, as compared with cisplatin alone and insignificant decrease in CAT (p>0.05) compared with cisplatin alone.

Administration of 7 mg kg–1 day–1 cisplatin for 7 consecutive days resulted in a significant increase in the level of serum ALT and AST (p<0.001), respectively compared to control. Administration of propofol (10 mg kg–1 day–1 for 7 days) induced significant decrease in serum ALT (p<0.05) and insignificant change in serum AST, respectively compared to control.

Prior treatment with propofol before cisplatin, significantly decreased the level of ALT in serum (p = 0.008) and non-significant change in the level of AST (p>0.05), respectively compared to cisplatin group (Table 2).

DISCUSSION

This work evaluated the antioxidant capacity of propofol against the hepatic toxicity induced by cisplatin in rats. Cisplatin induced oxidative stress in liver tissues and significant difference in serum ALT and AST was observed. Additionally, the level of TAC were decreased by cisplatin treatment. Propofol reduced the alterations in the levels of serum ALT. It can be inferred that cisplatin causes injuries via the propagation of free radicals and increasing the level of ALT and AST, while propofol prevented the liver injuries by stabilizing serum status. Significant increase in the enzymatic activities of AST and ALT in serum indicating severe damage to liver samples4. In this study, the results showed that cisplatin induced ALT and AST concentration in blood. But it was significantly improved with propofol.

Antioxidant enzymes works in a coordinated fashion to prevent the oxidative stress. The metabolic role of liver in detoxification of xenobiotics results in the generation of ROS, where SOD, CAT and GPx play an important role in prevention of oxidative stress in liver samples19,20. In this study cisplatin induced oxidative stress as was evidenced by a significant decrease in TAC content. Although a definitive mechanism of toxicity of cisplatin has not been delineated, a cyclic single electron reduction/oxidation is a critical mechanistic event21. Recognizing that cisplatin induces its toxic effects mainly via oxidative stress-induced mechanisms, researchers and clinicians have placed great emphasis on the use of antioxidants as a treatment modality for cisplatin nephrotoxicity7,22. The role of vitamin E in cisplatin toxicity was demonstrated in several studies where deficiency of vitamin E potentiated the development of acute cisplatin toxicity in animals22. Recently, interest has increased considerably in finding drug occurring antioxidants for use in foods or medicinal materials to replace synthetic antioxidants, in treatment poisoning19. Moreover, our results show that feeding with only lisosan G induced antioxidant enzymes such as catalase, gluthatione peroxidase23. Propofol reduced the oxidative stress possibly by scavenging of free radicals produced by cisplatin with subsequent restoration in enzymatic activities. Data from the previous studies19,22 support this potential of propofol. Animals treated with propofol showed a marked improvement in the depleted level of protein concentration sulfhydryl compounds are known to be an antioxidant substances such as vitamin E structure involved in the scavenging of oxygen-derived free radicals in various tissues of the body20.

**ad4**

CONCLUSION

The present results suggest that propofol effectively decreased the level of serum ALT induced by cisplatin treatment in rats. Many remains to be learned about the role of intracellular and extracellular antioxidants in cisplatin toxicity. Thus, further research is warranted to determine the effects of a combination of antioxidants in the treatment of cisplatin poisoning and these studies may be a potential aid to manage patients suffering from cisplatin intoxication.

ACKNOWLEDGMENT

This study was supported by a grant from Vice Chancellor of Research of Hamadan University of Medical Sciences.

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