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Reactive oxygen radicals play an important role in various forms of liver injury. The present study was a trial to evaluate the efficacy of each of vitamin A&C in its clinical dose (80 mg / Kg ip) on experimental model of chronic liver injury in mice using carbon tetrachloride (CCl4). Animals were subdivided into four groups (control, CCl4 treated, CCl4+Vit.A and CCl4+Vit.C). Vitamin A&C were administrated 2 hours prior interaperitoneal administration of 0.2 ml / Kg CCl4 in mice. A significant decrease in serum Glutathione (GSH) and Superoxide dismutase (SOD) activity along with marked elevation of serum malondialdehyde (MDA), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was recorded in response to CCl4 hepatotoxicity. An notable normalizing to this measured parameters was observed in the groups treated by vitamin A & C. On Histopathological basis, hydropic degeneration, steatotic changes and apoptosis was seen obviously in CCl4 treated group but partial improvement in the previous parameters was noted in vitamin A & C treated groups in spite of vitamin C seemed to be less effective as far as vitamin A. These results theorized that vitamin A & C may have a potency to increase the antioxidant and antiapoptotic defense system activity in the CCl4 treated mice. Introduction Hepatotoxins namely carbon tetrachloride (CCl4) induces acute hepatic necrosis, fatty degeneration, advanced fibrosis and many other significant alteration in liver enzymes activities (Turkdo et al., 2001& Nakamoto et al., 2003). A significant elevation in the activities of ALT, AST, alkaline phosphatase (AP) and serum bilirubin was recorded by Datta et al. (1998) following CCl4 hepatotoxicity. In addition to the above variables, lactate dehydrogenase (LDH) elevation, significant decrease in total sulphydryl (-SH) content and catalase activity in hepatic tissues and also a significant increase in lipid peroxidation measured as malondialdhyde (MDA) were considered evidences for CCl4 hepatotoxicity in mice (Mansour, 2000). CCl4 hepatotoxicity is mainly caused by increase the production of oxygen free radicals that causes lipid peroxidation. Kamataki et al (1977) found that oral administration of CCl4 to rats inhibited microsomal NADPHdependent lipid peroxidation. Weber et al. (2003) suggested that CCL4 is activated by cytochrome (cyp) 2E1 or cyp2B2 and possibly cyp3A to form the trichloromethyl radical, CCL3. This radical can bind to cellular molecules (nucleic acid, protein, lipid) impairing crucial cellular processes such as lipid metabolism, with the potential outcome of fatty degeneration (steatosis). Refree by : Prof. Dr. Yehya shaker 30 Sohair A Hassan et al 31 The protective effects of some antioxidant treatments on CCl4 liver toxicity was studied by many authors (Cajanus indicus derivative (Datta et al, 1998); Colchicines (Mizuoka et al, 1999); Vitamin E (Mustafa Naziroglu et al, 1999); Thymoquinone and Desferrioxamine (Mansour, 2000); Captopril (El-Khatib and Mansour, 2001); PMC, a derivative of alphatocopherol (Hsiao et al., 2001); Vitamin C&E, selenium and Nigella sativa (Turkdo et al, 2001); volatile oil constituent of Nigella sativa, Thymoquinone, Pcymene and alphapinene (Mansour et al., 2001); total flavonoids of Astragalus (Wang et al., 2001); Salacia reticulata extracts (Yoshikawa et al, 2002); Aquilegia vulgaris extracts (Adamska et al., 2003); Antrodia camphorata extract (Hsiao et al., 2003); and Gossypitrin (Perez et al., 2003). This study was designed to investigate the antioxidative & antiapoptotic effects of vitamin A and vitamin C on lipid peroxidation, antioxidant enzyme systems, some liver enzymes activities and liver cell apoptosis in carbon tetrachloride induced hepatotoxic mice. Material and methods The animal grouping and treatments: Male Swiss albino mice, weighing 20-25 g kept under good ventilation and balanced diet were used in this study. Animals were subdivided into four groups (15 each). Group 1(control) did not receive any treatment. Group2 received CCl4 (0.2ml / Kg ip Hewawasam et al 2003) daily for 60 days. Group 3 received vitamin., A (80 mg / kg ip Tantcheva et al, 2003) 2hrs prior to CCl4 (0.2ml / kg ip) daily for 60 days. Group 4 received vitamin C (80 mg / kg ip Tantcheva et al., 2003) 2hr prior to CCl4 (0.2ml / kg ip) daily for 60 days.Vitamine A and C were supplied by AL Gomhouria co. for pharmaceuticals and chemical industries. Biochemical analysis: Serum samples were prepared through blood centrifugation at 3000 r.p.m for biochemical determinations. GSH was measured by the procedure of Beutler et al (1963), which is based on extraction of GSH with metaphosphoric acid and then its reaction with dithiobisnitrobenzoic acid (DTNB) to form a yellow color, which is read at 412 nm. MDA, a product of lipid peroxidation was determined by the method of Begonia et al, (1994) using a saturated solution of thiobarbituric acid and the developed color read at 532 nm. SOD activity was assayed using a kit obtained from Randox. The method employs xanthine and xanthine oxidase to generate super oxide radicals, which react with 2-(4iodophenyl)-3(4-nitrophenyl)-5 phenyltetrazolium chloride (I.N.T.) to form a red formazon dye. The SOD activity is then measured by the degree of inhibition of this reaction at 560 nm. ALT &AST were estimated colorimetrically using kits from BioMerieux (Marcy 1 Etoile, France) Histopathological test: Mice liver specimens was obtained and fixed in 10% formaline. Sections were prepared and stained by Fulgen stain for histopathological investigation. Fulgen stain for liver cells: Slides putted in oven for 10 minutes then putted in xylene for 10 minutes, then in a series of alcohols 100%, 90% and 70% for 5 minutes. The slides were washed by distilled water, rinsed in 5N HCl solution for 50 minutes, and then washed twice by distilled water. Ten drops of schiff Antioxidative and antiapoptotic effects of 32 reagent were added and left to act for 10 minutes, the slides rinsed in sodium metabisulphite solution for 2 minutes then rerinsed in distilled water, again the slides were dehydrated in 70%, 90% and 100% alcohol and finally mounted by xylene. Statistical evaluation: All calculated data were collected in a database for further statistical evaluation. Using soft ware (SPSS version 9) student “t” test was made to determine the level of significance of difference between different parameters in different groups. Probability values (P < 0.05) were considered significant. Results Results of the effects of vitamin A and vitamin C administration on serum glutathione (GSH), superoxide dismutase (SOD), Malondialdehyde (MDA), Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) of CCl4 induced hepatotoxicity in mice was recorded in table (1) and represented in fig. (1) and (2). The results show significant decreease (P < 0.05) in serum glutathione (GSH) level of CCI4 treated groups compared to control group, on the other hand significant increase (P < 0.05) was observed in its level in Vitamin A and Vitamin C administrated groups if compared to CCl4 group. Statistical analysis shows significant decrease (P < 0.05) in superoxide dismutase (SOD) activity in CCl4 compared to control group. In contrast Vitamin A and Vitamin C administrated groups showed significant increase (P < 0.05) in its activity if compared to CCl4 group and no significant difference with control group. Serum Malondialdehyde (MDA) was significantly increased (P < 0.05) in CCl4 treated groups compared to control group. Vitamin A supplemented CCl4 group showed significant decrease (P < 0.05) in serum MDA level in comparison with both CCl4 treated group and CCl4+Vitamin C group. CCl4 induced hepatotoxicity significantly increased (P < 0.05) serum Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT). No significant difference was recorded between CCl4+Vit.A group and control group. Vitamin C markedly decreased the observed elevation in both serum AST and ALT of CCl4 treated groups. The histopathological effects of CCl4 and vitamin A&C was studied in the liver of mice and the results are shown in table (2) and fig. (3:7). Control group (fig. 3) showed well-preserved lobular architecture with almost no pathological changes. It is appeared that mice’s treated with CCl4 (fig. 4) had a loss of lobular architecture (100% cirrhotic). Mean percent of cirrhotic cells in CCl4+Vit.A group was 65% while in CCl4+Vit.C group was 80%. Hydropic degeneration was recorded in all tested samples of CCl4 treated group with the percentage of 70%. It was found in 12 out of 15 animals of CCl4+Vit.A group (fig. 5) with the percentage of 60% and in 10 out of 15 animals of CCl4+Vit.C group (fig. 6) with the percentage of 70%. A steatotic change was observed in 8 cases out of 15 with the mean percentage of 75% in CCl4 treated group. This changes was also found in 7 out of 15 with the percentage of 50% in CCl4+Vit.A group and in 8 out of 15 in CCl4+Vit.C group with the percentage of 60%. The apoptotic changes was found in 8 out of 15 cases with the percentage of 20% in CCl4 treated group and the apoptotic bodies were found in hepatocytes adjacent to the porbel Sohair A Hassan et al 33 treats. In CCl4+Vit.A group (fig. 7), apoptosis was found takes place in 4 out of 15 cases with the percentage of 10% and in 7 out of 15 cases with the percentage of 18% in CCl4+Vit.C group. Table (1): Effect of Carbon tetrachloride (CCL4) hepatotoxicity and the possible role of Vitamin A and Vitamin C supplementation on serum Glutathione (GSH), blood Superoxide dismutase (SOD), serum Malondialdehyde (MDA), Aspartate aminotransferase (AST) and Alanin aminotransferase (ALT) of mice. Parameters Treatment groups Control CCl4 CCl4 +Vit A CCl4 +Vit C

Antioxidative and antiapoptotic effects of vitamin A and vitamin C against carbon tetrachloride induced hepatotoxicity in mice