The mechanism of CCl
4-induced liver damage is considered to be due to the enzymatic activation (cytochrome P450) of CCl
4 into the trichloromethyl free radical (CCl
3) within the membrane of the endoplasmic reticulum. This is followed by chloromethylation, saturation, peroxidation and progressive destruction of the unsaturated fatty acid of the endoplasmic reticulum membrane phospholipids
23. These processes are known as lipid peroxidation, leading to its functional and structural disruption
24. It has been shown that both the fixed oil of N. Sativa, as well as thymoquinone (the main compound of the essential oil), inhibit non-enzymatic lipid peroxidation in liposomes
25.
It has also been shown that compounds isolated from N. Sativa (including thymoquinone, carvacol, t-anethole and 4-terpineol) have appreciable free radical scavenging properties 13. Generation of free radicals may be, at least partially, the basis of many human diseases and conditions. Therefore, the antioxidant action of N. sativa may explain its claimed usefulness in folk medicine. This antioxidant property would explain its action against CCl4 hepatotoxicity 26, liver fibrosis and cirrhosis 27, and hepatic damage induced by Schistosoma Mansoni infection 28.
In some countries N. Sativa seeds are sold to treat conditions that include liver diseases 29. The mechanism of the hepatoprotective action of thymoquinone is not certain, but may be related to the preservation of intracellular glutathione (the depletion of which by oxidative stress is known to increase the susceptibility of cells to irreversible injury). It has been shown that pretreatment of rats with N. Sativa oil for 4 weeks was effective in protecting against carbon tetrachloride and D-galactosamine-induced hepatic damage 30.
The protection against the former hepatotoxicity was partial, while that of the latter was complete. In rabbits, experimental liver cirrhosis and fibrosis (induced by carbon tetrachloride) was shown to be prevented by the prior administration of N. sativa. The seed extract improved the histological picture and the indices of oxidative status of the liver 27. In mice, thymoquinone (8 mg/ kg/day for 5 days before and 1 day after carbon tetrachloride was administered with the drinking water) was also found to protect against the biochemical and histological markers of liver damage 31. The protection was suggested to be related to the ability of thymoquinone to inhibit lipid peroxidation.
In the present study, plasma liver enzymes and MDA levels were found to be significantly higher in CCl4 induced group as compared to the other groups whereas, mean these parameter levels in treated groups were also found decreases. Superoxide dismutase (SOD) acts as a cellular defence element against potentially harmful effects of superoxide ions by catalyzing the dismutation of these ions. We found that CCl4 induced group had significantly lower mean erythrocyte SOD and GSH-PX activities than the control and NS treatment groups. These results indicate that SOD and GSH-PX which have an antioxidative effect as a defensive role are intracellular enzymes in erythrocytes in CCl4-induced hepatotoxic rats. CCl4 induced hepatotoxicity produced in rats leading to hepatic injury, triggers the peroxidation cascade of membrane lipids and results in the generation of toxic radicals. Although both injuries occur due to oxidative stress, it is indispensable to use a correct antioxidant in adequate amount. But, studies in mice and rats have shown that treatment with NS extract significantly protects from cisplatin-induced falls in leukocytes counts, hemoglobin levels, mean osmotic fragility and haematocrit increase, influences leukocytes activities and causes the death of mice lymphocytes in vitro 32. The slowdown of body weight evolution in NS treated rats might be related to the serum lipids and glucose levels decrease as a consequence of a possible reduction in food intake by the drug administration. Other explanations are also possible, like a toxic effect. In conclusion, these results support the traditional use of NS and its derived products as a treatment for the dyslipidemia and the hyperglycemia, and related abnormalities; however, indicate a relative toxicity of this plant extract. Acute and chronic toxicity and the mode of the action of the ns fixed oil must be studied.
This protection was evident from the significant increase in SOD and GSH-Px levels and the significant decrease in serum aminotransferases and MDA. Treatment with N. sativa decreased the elevated aminotransferases and MDA concentrations, increased the lowered GSH-Px and SOD concentrations, and prevented lipid-peroxidation-induced liver damage in hepatotoxic rats.
It is concluded that NS decrease the liver enzymes and increase the antioxidant defence system activity in the CCl4-treated rats. N. sativa may be used in CCl4-induced hepatotoxicity rats to prevent lipid peroxidation, increase anti-oxidant defence system activity and also prevent liver damage.
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