| The hazardous effects of chemicals are of great concern and widely studied in an effort to determine the mechanisms underlying their toxicity and carcinogenicity. Chemicals such as carbon tetrachloride (CCl4) induce liver injury through free radical mechanism. CCl4 is considered as a prototype for better understanding of free radical-mediated hepatotoxicity. The hepatotoxicity of CCl4 is believed to be mediated by cytochrome P4502E1 (CYP2E1) that belongs to P-450 (P-450s) superfamily of hemoproteins, which carry out oxidative metabolism of many endogenous and xenobiotic chemicals. Definitive proof was obtained from the studies in which CYP2E1 knockout mice were used. It was confirmed that mice, which lack CYP2E1 expression, were resistant to liver damage after i.p. administration of CCl4 (1 ml/kg) for 24 h. In order to extend our understanding on CYP2E1-mediated CCl4 hepatotoxicity, the present study aimed at observing the time-dependent changes that occur at morphological, histopathological, biochemical and molecular levels in both CYP2E1+/+ and CYP2E1-/- mice after treating with either corn oil or CCl4 (1 ml/kg) for 2, 6, 12, 24 and 48 h.; At morphological level, a pale orange colored liver was observed in CYP2E1 +/+ mice treated with CCl4 for 24 and 48 h, while the CYP2E1 +/+ mice treated with corn oil and CYP2E1-/- mice treated with either corn oil or CCl4 showed normal reddish brown color livers. This pale orange color observed in the livers of CYP2E1 +/+ mice was an apparent indication of fatty infiltration resulting from the exposure to CCl4. Ballooned hepatocytes with multiple vacuoles in their cytoplasm, degenerating cells with pyknotic nucleus and collapsed hepatic sinusoids were also observed in the livers of CYP2E1 +/+ mice 24 h after treating with CCl4 and continued till 48 h. Furthermore, the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), markers for liver injury, were significantly higher at 12 h, and were peaked at 24 h with a gradual decrease at 48 h after CCl4 intoxication.; Taken together, our studies at morphological, biochemical, histopathological and molecular levels provided an insight into the CYP2E1-mediated and CCl 4-induced hepatotoxicity, and the genes identified may serve as potential marker genes for understanding the free radical-mediated chemical-induced hepatotoxicity. (Abstract shortened by UMI.)... |
