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Journal of Biological Sciences

Year: 2016 | Volume: 16 | Issue: 3 | Page No.: 49-57
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Research Article

Effect of Aqueous Extract of Green Tea (Camellia sinensis) on Hematology and Oxidative Stress Biomarkers in Rats Intoxicated with Carbon Tetrachloride

Ibrahim Albokhadaim

ABSTRACT

The present study aimed to investigate the effects of aqueous extract of green tea (Camellia sinensis) on selected hematological and chemical biomarkers in rats intoxicated with carbon tetrachloride (CCl4). Therefore, 20 rats were fed on standard diet and divided into four groups. Rats in the first and second groups were injected i/p with paraffin oil and received either normal water or aqueous extract of green tea, respectively. Rats in the third and fourth groups were injected i/p with CCl4 and received either normal water or aqueous extract of green tea, respectively. Blood and liver samples were collected at the end of the experiment (5 weeks). Whole blood samples were used for estimation of selected hematological parameters, harvested sera were used for detection of selected biochemical indices and liver tissues were used for estimation of selected oxidative stress biomarkers. Hematological findings revealed that, there was a significant reduction in Total Erythrocytic Count (TEC) and hemoglobin (Hb) concentration with significant increase in Total Leucocytic Count (TLC) in blood of rats that were exposed to CCl4 without treatment with green tea aqueous extract when compared with control. In addition, CCl4 elevated serum transaminases, hepatic lipid peroxidation and hepatic enzymatic antioxidants activities. Oral green tea extract attenuated the detrimental effects of CCl4lain and corrected all examined biomarkers toward the control levels. Further works are recommended for the evaluation of the effect of green tea (Camellia sinensis) on oxidative stress biomarkers at molecular level.
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Received: December 04, 2015;   Accepted: January 26, 2016;   Published: March 15, 2016

INTRODUCTION

Carbon tetrachloride (CCl4) is a highly toxic chemical agent, the most famous drug used to induce liver damage experimentally (Kim et al., 2010). Histological sectioning of liver tissues indicated that CCl4 induced fibrosis, cirrhosis and hepatocarcinoma (Junnila et al., 2000). The toxic effect of CCl4 is attributed to trichloromethyl radical produced during oxidative stress (Stoyanovsky and Cederbaum, 1999). Once the liver became injured, its efficient treatment with famous chemical drugs is limited (Lee et al., 2007). Therefore, interest concerned the use of alternative medicines for the treatment of hepatic disease has been arisen. Natural products received great attention as potentially antitoxic and antioxidants agents (Lee et al., 2007). Polyphenols found in green tea has received special attention as antioxidant and anti-inflammatory agent (Kuroda and Hara, 1999; Varilek et al., 2001). Green tea is produced from the dried leaves of the plant Camellia sinensis and contains several polyphenolic components. Most of ethese polyphenols are flavonols, which is usually called catechins. Epigallocatechin gallate is the most abundant catechin, accounting for about 65% of green tea catechin content and is also the component with the highest antioxidant properties (Guo et al., 1996). Previous publications reported many beneficial effects of green tea such as anti-obesity, anticarcinogenic (Zaveri, 2006), hypochlosterolemic (Cooper et al., 2005), anti-neurodegenerative (Crespy and Williamson, 2004) and antioxidant (Erba et al., 2005) properties. The protective effect of green tea as antitoxic was not investigated so far. Therefore, the present study aimed to investigate the capacity of green tea (Camellia sinensis) water extract against CCl4-induced liver toxicity by assessing hematology, serum biochemistry and hepatic oxidative stress biomarkers.

MATERIALS AND METHODS

Chemicals and kits: Commercial diagnostic kits for glucose (EP37L-660), total proteins (EP56-660), albumin (EP03-570), TAG (EP59-660), cholesterol (EP24-660), ALT (EP07-500), AST (EP15-500), BUN (EP20-420), uric acid (EP61-620), Creatinine (EP33K-660), calcium (EP22-660), phosphorus (EP46-660), magnesium (EP50-660), chloride (EP27-500) were purchased from United Diagnostic Industry, UDI, Dammam, Saudi Arabia. Paraffin oil, carbon tetrachloride (Spectrosol® BHD chemicals Ltd pool, England) and other chemicals and solvents used in the study were of highest grade and commercially available.

Green tea (Camellia sinensis) aqueous extract: Green tea extract was made according to Maity et al. (1998) by soaking 30 g of green tea powder in 1 L of boiling distilled water for 5 min. The solution was filtered to make 3% green tea extract. This solution was provided to rats as their sole source of drinking water.

Animals and treatment: A total of 20 albino rats (200-250 g) was obtained from Laboratory House of College of Veterinary Medicine and Animal Resources, King Faisal University, Al-Ahsa, Saudi Arabia and acclimated for 10 days before starting the experiment. All animals were housed in standard cages (5 rats/cage), fed with standard laboratory diet and tap water ad libitum. The experimental animals were housed in air-conditioned rooms at 21-23°C and 60-65% of relative humidity and kept on a 12 h light/12 h dark cycle. The animals received humane care in accordance with the Guide for the Care and Use of Laboratory Animals, published by ethics of scientific research committee of king Faisal University, Saudi Arabia.

Induction of hepatotoxicity by CCl4: Liver toxicity was induced by the intraperitoneal injection of CCl4 (1 mL kg–1 b.wt.), 1:1 diluted with paraffin oil, for two successive days of the experiment (Althnaian et al., 2013; El-Bahr, 2014; Al-Sultan and El-Bahr, 2015).

Experimental groups and protocol: The rats were divided randomly into 4 groups comprising 5 rats in each group and fed the same diet throughout the experimental period. Group 1: Control rats fed only with diet and tap water and injected i/p with paraffin oil, group 2: Rats injected i/p with paraffin oil and received green tea (Positive control, 3%) as their sole source of drinking water, group 3: Diseased control group intoxicated with CCl4 (1 mL kg–1 b.wt.), 1:1 diluted with paraffin oil in first two days of the experiment and received normal tap water and group 4: Rats were intoxicated with CCl4 (1 mL kg–1 b.wt.), 1:1 diluted with paraffin oil on first two days of the experiment and treated with green tea 3% as their sole source of drinking water.

Samples collection: At the end of the experiment (5 weeks), the overnight fasted rats were anesthetized with diethyl ether. Blood samples were collected by cardiac puncture before incision of the abdomen in plain and EDTA vacutainers. Whole blood was used for the determination of selected hematological parameters. Sera were harvested and stored at -30°C until the time of analysis of serum glucose, total proteins, albumin, triglyceride, total cholesterol, ALT, AST, BUN, uric acid, creatinine, calcium, phosphorus, magnesium and chloride using commercial assay kits according to the manufacture instruction. The liver tissues were removed and liver fragments were immediately frozen and stored at -80°C for biochemical analysis of selected antioxidant enzymes, namely catalase (CAT) and glutathione peroxidase (GPX).

Hematological analysis: The TEC and TLC were determined by standard hematological techniques (Feldman et al., 2000). The Hb% was assessed according to Drabkin (1946).

Analysis of selected biochemical parameters: Serum glucose, total proteins, Albumin, TAG, cholesterol, ALT, AST, BUN, uric acid, creatinine, calcium, phosphorus, magnesium and chloride levels were determined by using commercial kits (United Diagnostic Industry, UDI, Dammam, Saudi Arabia) on ELIPSE full automated chemistry analyzer (Rome, Italy). Concentration of the biochemical constituents was calculated according to the manufacture instruction.

Analysis of hepatic lipid peroxidation and selected hepatic Antioxidant enzymes: The concentration of TBARS (μM, Cayman Chemical Company, USA, Catalog No. 10009055) and the activities of CAT (nmol/min/g tissue; Cayman Chemical Company, USA, Catalog No. 707002) and GPX (nmol/min/g tissue; Cayman Chemical Company, USA, Catalog No.703102) were determined by ELISA reader (Absorbance Microplate Reader ELx 800TM BioTek®, USA). Results were calculated according to the manufacture instructions.

Statistical analysis: All data are presented as the mean±standard error of the mean using one way analysis of variance (ANOVA). All tests were performed using a statistical analysis system program (SAS., 2002).

RESULTS

The effects of CCl4 administration and the modulatory activities of green tea aqueous extract on the hematological parameters of rats are shown in Table 1. There was a significant reduction (p<0.05) in the TEC and Hb concentration in rats that were exposed to CCl4 without treatment with green tea aqueous extract (group 3) when compared with those of the normal control (group 1). However, there was an increase in these parameters in the rats that were treated with green tea extract (group 2). The TLC increased significantly (p<0.05) in rats exposed to CCl4 when compared to those of the control. However there was a decrease in these parameters in the rats that were treated with green tea extract (group 2).

The activities of AST and ALT were estimated in serum samples as indictors of liver function. These results are given in Table 2. The CCl4 treatment markedly affected the liver specific enzymes.

Table 1:Effects of CCl4 and green tea water extract on hematological parameters in rats
Image for - Effect of Aqueous Extract of Green Tea (Camellia sinensis) on Hematology and Oxidative Stress Biomarkers in Rats Intoxicated with Carbon Tetrachloride
Each value represents the mean±standard error of means (SEM) of 5 rats, TEC: Total erythrocyte count, TLC: Total leucocyte count, Hb: Hemoglobin, *Significantly different from control group (p<0.05), **Significantly different from CCl4 group (p<0.05), C: Control, GT: Green tea, CCl4: Carbon tetrachloride

Table 2:Effects of CCl4 and green tea water extract on serum liver transaminases in rats
Image for - Effect of Aqueous Extract of Green Tea (Camellia sinensis) on Hematology and Oxidative Stress Biomarkers in Rats Intoxicated with Carbon Tetrachloride
Each value represents the mean±standard error of means (SEM) of 5 rats, *Significantly different from control group (p<0.05), **Significantly different from CCl4 group (p<0.05), C: Control, GT: Green tea, CCl4: Carbon tetrachloride

Table 3:Effects of CCl4 and green tea water extract on kidney biomarkers in rats
Image for - Effect of Aqueous Extract of Green Tea (Camellia sinensis) on Hematology and Oxidative Stress Biomarkers in Rats Intoxicated with Carbon Tetrachloride
Each value represents the mean±standard error of means (SEM) of 5 rats, C: Control, GT: Green tea, CCl4: Carbon tetrachloride, *Significantly different from control group (p<0.05)

A significant increase (p<0.05) of serum AST and ALT activities was observed in untreated CCl4 intoxicated rats (group 3) compared to controls (group 1 and 2). This result suggests that these hepatic biomarkers are elevated in the serum due to release of the enzymes from damaged liver. However, a significant decrease (p<0.05) was observed in the respective serum activities in rats intoxicated with CCl4 and treated with aqueous extract of green tea (group 4) compared to untreated CCl4 intoxicated rats (group 3). The levels of serum kidney biomarkers of rats in all groups showed in Table 2. Serum kidney biomarkers (BUN, uric acid and creatinine) levels remained unchanged in all treated group (p>0.05). The profiles of serum protein, lipid and glucose are presented in Table 3. A significant decrease (p<0.05) in serum glucose, total proteins and albumin (p<0.05) was observed in untreated CCl4 intoxicated rats (group 3) compared to controls (group 1 and 2).

Table 4:Effects of CCl4 and green tea water extract on protein, lipids and glucose profiles in rats
Image for - Effect of Aqueous Extract of Green Tea (Camellia sinensis) on Hematology and Oxidative Stress Biomarkers in Rats Intoxicated with Carbon Tetrachloride
Each value represents the mean±standard error of means (SEM) of 5 rats, *Significantly different from control group (p<0.05), **Significantly different from CCl4 group (p<0.05), C: Control, GT: Green tea, CCl4: Carbon tetrachloride

Table 5:Effects of CCl4 and green tea water extract on minerals profile in rats
Image for - Effect of Aqueous Extract of Green Tea (Camellia sinensis) on Hematology and Oxidative Stress Biomarkers in Rats Intoxicated with Carbon Tetrachloride
Each value represents the mean±standard error of means (SEM) of 5 rats, C: Control, GT: Green tea, CCl4: Carbon tetrachloride

However, administration of aqueous extract of green tea corrected the values of glucose and total protein towards the control values in CCl4 intoxicated rats. A significant increase (p<0.05) in serum cholesterol and triglyceride was observed in untreated CCl4 intoxicated rats (group 3) compared to controls (group 1 and 2) (Table 4). However, administration of aqueous extract of green tea corrected the values of glucose and total protein towards the control values in CCl4 intoxicated rats. A significant change was not observed in calcium, phosphorus, magnesium and chloride levels of control and all treated groups (p>0.05) throughout the experimental period. Results in Table 5 shows that the TBARS level was significantly (p<0.05) increased in the liver of CCl4 intoxicated compare to the controls. Treatment of CCl4 intoxicated rats with aqueous extract of green tea caused significant (p<0.05) decrease in TBARS level of liver tissue compared to that in liver from untreated CCl4 intoxicated rats. Administration of aqueous extract of green tea only did not affect significantly (p>0.05) the level of TABARS in rat liver compare to the control. The results that presented in the same table (Table 5) indicated that, All the antioxidant enzyme activities were reduced significantly (p<0.05) in CCl4 intoxicated rats compare to the control. However, all activities of these enzymes showed a significant (p<0.05) recovery in response to administration of aqueous extract of green tea to CCl4 intoxicated rats compare to untreated CCl4 intoxicated rats. The activities of hepatic antioxidant enzymes of rats treated only with aqueous extract of green tea were comparable to that of the control (Table 5).

DISCUSSION

The current study demonstrated clearly that, CCl4 administration produced microcytic hypochromic anemia as evidenced by the reduction in the RBC and Hb concentration. Similar result was reported in rats (Saba et al., 2010). The current findings indicated that, CCl4 administration induced leucocytosis. The reduction in the formed elements in the blood and leucocytosis are stress induced phenomenon (Saba et al., 2010). Acute stress in animals has been widely reported to be associated with increased white blood cell count occasioned by significant increase in the neutrophil count and the neutrophil/lymphocyte ratio (Larson et al., 1985; Huff et al., 2005). Previous study on the effects of CCl4 on haematological parameters showed that acute CCl4 toxicity led to transient decrease in the Hb concentration and RBC counts (Mortiz and Pankow, 1989). Parallel to the current findings, a significant increase of Hb and TEC was observed in rats administered green tea (El-Kott and Bin-Meferij, 2008; Gad and Zaghloul, 2013). In the same way of the current findings, administration of different concentrations of green tea produced significant decrease of TLC and significant increase of Hb and TEC in rats (Al-Shawi, 2014).

In the present study serum hepatic biomarkers, AST and ALT activities were greatly increased in untreated CCl4 intoxicated rats compared to control animals. The increased serum levels of hepatic transaminases biomarkers have been attributed to the liver injury, because these enzymes are place in cytoplasmic area of the cell and are released into circulation in case of cellular damage (Brent and Rumack, 1993; Recknagel et al., 1989). The CCl4 induced the increase of serum ALT and AST levels which source from cell membrane and mitochondrial damages in liver cells (Zimmerman et al., 1965; El-Bahr, 2014; Al-Sultan and El-Bahr, 2015). Many publications rep orted that, hepatic transaminases enzymes activities (ALT and AST) were significantly elevated after CCl4 treatment (Arici and Cetin, 2011; Althnaian et al., 2013; Das, 2014; El-Bahr, 2014; Al-Sultan and El-Bahr, 2015).

Table 6: Effects of CCl 4 and green tea water extract on lipid peroxidation and oxidative stress biomarkers in rats
Image for - Effect of Aqueous Extract of Green Tea (Camellia sinensis) on Hematology and Oxidative Stress Biomarkers in Rats Intoxicated with Carbon Tetrachloride
Each value represents the mean±standard error of means (SEM) of 5 rats, *Significantly different from control group (p<0.05), ** Significantly different from CCl 4 group (p<0.05), C: Control, GT: Green tea, CCl 4: Carbon tetrachloride, TBARS: Lipid peroxidation biomarke, CAT: Catalase, GPX: Glutatnione peroxidase

The hepatotoxic effects of CCl4 were attributed to lipid peroxidation caused by its active metabolite CCl3 radicals (Park et al., 2005). These activated radicals bind covalently to the macromolecules and induce peroxidative degradation of membrane lipids of endoplasmic reticulum which are rich in polyunsaturated fatty acids. This leads to formation of lipid peroxides, which in turn gives products like melanodialdehyde (MDA) that cause damage to the membrane. This lipid peroxidative degradation of biomembrane is one of the principle causes of hepatotoxicity of CCl4 (Park et al., 2005). On the other hand, current findings indicated that, the increase in serum AST and ALT activities induced in untreated CCl4 intoxicated rats was significantly corrected towards normal control values when these rats treated with aqueous extract of green tea. This finding implies that, green tea aqueous extract challenge to protect liver tissue from CCl4 injury. The reversal of increased serum enzymes in CCl4-induced liver damage by green tea aqueous extract may be due to the prevention of the leakage of intracellular enzymes by its membrane stabilizing activity (Issabeagloo et al., 2012). This is in agreement with the commonly accepted view that serum levels of transaminases return to normal with the healing of hepatic parenchyma and the regeneration of hepatocytes (Thabrew et al., 1987). Similar findings have provided a considerable support for evidencing the protective effects of green tea aqueous extract on liver damage at the level of tansaminases enzymes (Almurshed, 2006; Hashimoto et al., 2007; Sengottuvelu et al., 2008; Issabeagloo et al., 2012). Green tea aqueous extract decreased CCl4 induced elevated enzyme levels in tested groups, indicating the protection of structural integrity of hepatocytic cell membrane or regeneration of damaged liver cells (Palanivel et al., 2008). It has been demonstrated that, the protective effect of green tea aqueous extract against CCl4-induced oxidative stress in rats was due to its antioxidant properties (Sengottuvelu et al., 2008). The antioxidant activity of green tea could be attributed to the presence of epicatechins which act as scavengers of reactive oxygen species (El-Beshbishy, 2005; Issabeagloo et al., 2012). The antioxidant activity of green tea aqueous extract has been approved in the current study as reflected on significant reduction of lipid peroxidation biomarker (TBARS) and significant elevation of antioxidant enzymes activities (CAT and GPX) in liver of CCL4 intoxicated rats (Table 6). As in the current experiment, previous experimental studies have shown that CC14 decreased total protein (Fahim et al., 1999; Khan and Alzohairy, 2011; Althnaian et al., 2013) and albumin (Fahim et al., 1999; Khan and Alzohairy, 2011; Althnaian et al., 2013) levels. However, there is a controversy about the effect of CC14 on serum creatinine level. While, some investigator (Cruz et al., 1993) found a decrease in serum creatinine in CCl 4 toxicity, parallel to the present study others (Palaparthy et al., 2001; Wirth et al., 1997; Khan and Alzohairy, 2011; Althnaian et al., 2013) found no significant changes (Table 2). The restoration of total protein and albumin in serum of rats intoxicated with CCl4 and treated with green tea aqueous extract compared to untreated CCl4 intoxicated rats might attributed to the antioxidant properties of green tea which improves organ functions (El-Beshbishy, 2005). The enhancement of protein biosynthesis may accelerates the regeneration process and protect the liver cells against CCl4 toxicity.

The current study reported that, calcium, phosphorus, chloride and magnesium values in CC14 administrated rats were not statistically different from control values (Ogeturk et al., 2004).

In the present study, serum glucose was reduced in CCl4-treated rats which were prevented by green tea aqueous extract. Studies have demonstrated decreased hepatic glycogen content after treatment with CCl4, reflecting decreased gluconeogenesis by the liver Muriel et al. (2001). It has been known that, hypoglycemia is main feature of carbon tetrachlorid toxicity (Mion et al., 1996). The same author reported that liver cirrhotic rats exhibited hypoglycemia. The normoglycemic (antihyperglycemic) effect of green tea extract may be due to the fact that, green tea extract contains polyphenols namely catechin, epicatechin, epigallocatechin and their gallates (Kasahara and Kato, 2003; Haidari et al., 2012). Several mechanisms have been suggested for antihyperglycemic effect of green tea that include enhancing insulin-stimulated glucose uptake, suppressing glucose absorption by sodium dependent glucose transporter (Babu et al., 2006a), suppressing gluconeogenesis by decreasing the expression some genes such as phosphoenolpyrovate carboxykinase and glucose-6-phosphotase (Waltner-Law et al., 2002) and ameliorating insulin resistance by increasing expression of glucose transporter IV (Wu et al., 2004).

The results of the present study have also established that the CCl4 treatment could have affected the lipid metabolism of liver (triglyceride and cholesterol levels). This is evidenced from the present observations that, CCl4 was caused a significant increase in the levels of lipid parameters. Muller et al. (1974) stated that CCl4 intoxication is similar the hepatitis in case of the triglycerides catabolism. This situation could be also attributed to the reduction of lipase activity, which could lead to decrease in triglyceride hydrolysis (Jahn et al., 1985). On the other hand, it can be assumed that hypercholesterolemia in CCl4 intoxicated rats has resulted in damage of hepatic parenchymal cells that lead to disturbance of lipid metabolism in liver (Havel, 1986). When CCl4 intoxicated rats treated with green tea aqueous extract, a significant decline in above mentioned parameters (triacylglycerol and cholesterol) has been observed compare with untreated CCl4-intoxicated rats. Similar work demonstrated the hypocholesterolemic effect of green tea in rats (Babu et al., 2006b; Haidari et al., 2012). The hypolipidemic effect of green tea observed in the current study agrees with previous work (Velayutham et al., 2008; Amanolahi and Rakhshande, 2013). It has been reported that, catechins contents of green tea are responsible for the improvement of lipid profile of treated animals (Koo and Noh, 2007). The possible mechanisms by which green tea extract can exert cholesterol lowering effect are reducing the absorption of dietary and biliary cholesterol and promoting its fecal excretion (Koo and Noh, 2007). Furthermore, recent study (Singh et al., 2009) indicated that, green tea extract decreased the synthesis of cholesterol in cultured rat hepatoma cells.

The significant increase of TBARS in liver of untreated CCl4 intoxicated rats suggests enhanced peroxidation leading to tissue damage and the failure of the antioxidant mechanisms in preventing of excessive free radicals (Romero-Alvira and Roche, 1996). This confirmed by the results of the current study which reported a significant decrease of activities of antioxidant enzymes (CAT and GPX) in CCl4 intoxicated rats compare to controls which impose in elevation of TBARS levels. Presumably a decrease in CAT activity could be attributed to cross linking and inactivation of the enzyme protein in the lipid peroxides. Decreased CAT activity is linked to exhaustion of the enzyme as a result of oxidative stress caused by CCl4. These findings were found to be in agreement with other previous studies in rats liver intoxicated with CCl4 (Yousef, 2004; Aranda et al., 2010; Al-Fartosi et al., 2012; Bona et al., 2012; Pirinccioglu et al., 2012; El-Bahr, 2014). The significant decrease of TBARS in liver of rats intoxicated with CCl4 and treated with green tea aqueous extract compare to untreated CCl4 intoxicated rats suggested the antioxidant effect of green tea aqueous extract against CCl4-induced oxidative stress and agrees with previous results in rats (Sengottuvelu et al., 2008).

The protective effect of green tea aqueous extract was augmented by increasing the activities of antioxidant enzymes (CAT and GPX) when administered to CCl4 intoxicated rats. Consistent to the current findings, stimulation of antioxidant enzymes activities by green tea has been documented previously (Sengottuvelu et al., 2008). Epicatechins contents of green tea may be responsible for the antioxidant enzyme activation and subsequent scavenging of free radical species (El-Beshbishy, 2005).

CONCLUSION

Administration of CCl4 to rats induced elevation of hepatic transaminases, lipid peroxidation and antioxidant enzymes activities. Oral green tea aqueous extract attenuated the detrimental effects of CCl4 and corrected all examined biomarkers toward the control values. The ameliorative effects of green tea aqueous extract were in the form of improving of serum transaminases, attenuation of hepatic lipid peroxidation and activation of hepatic antioxidant enzymes. Further work is suggested for the evaluation of the effect of green tea (Camellia sinensis) on oxidative stress biomarkers at molecular level.

ACKNOWLEDGMENT

The author is greatly indebted to King Faisal University, Saudi Arabia whose financial support made this study possible.

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