DIFFERENTIAL EXPRESSION OF PRO‐ AND ANTI‐APOPTOTIC GENES UNDER THE INFLUENCE OF OXIDATIVE STRESS DURING CCL4‐MEDIATED LIVER INJURY IN MICE

Abstract

Although past few decades made substantial progress in the understanding of the mechanisms of the liver injury, it has not been possible to design non‐hepatotoxic drugs or identify ‘effective’&’clinically‐safe’ antidotes. This is because our comprehension of mechanisms of cell injury and cell death at the molecular level is incomplete. From a mechanistic standpoint, CCL4‐liver injury has emerged as a prominent model. Therefore, this study investigated modulation of a series of key death regulatory genes, such as, Bcl‐2, Bcl‐xl, Bax, Bad, & p53 during the progression of liver injury. Female ICR mice (28–35g) were gavaged with toxic doses of CCL4 (1 ml/kg) in corn oil, and sacrificed 0, 6, 12, 18, 24 h later. Blood was collected for serum chemistry and livers for measurement of oxidative stress (MDA, SOD, NO2+NO3) and western blot analysis. CCL4‐mediated liver injury was confirmed by increases in ALT activity (U/L in CON‐57±10, 6hr‐196±41, 18hr‐20635±1678). Analysis of the liver biochemistry showed increased lipid peroxidation, nitric oxide production, genomic DNA fragmentation and SOD activity. Expression of both pro‐ and anti‐apoptotic genes (Bax, Bad, Bcl‐2, Bcl‐xl) including p53 and Cyt c release were significantly elevated at 18 & 24 hr. In conclusion, this study undoubtedly extends our understanding of some of the complex interplay between cell‐death regulating genes during CCL4‐liver injury.