Alpha-lipoic acid counteracts the promoted oxidative DNA damage in the liver of septic rats

ABSTRACT

Viral, parasitic infections and chemical carcinogens are among the etiological factors of liver cancer. It seems important to study the initiating and promoting agents to evaluate the etiology and prevention of such life threatening disease. Intestine-derived bacterial product, lipopolysaccharide [LPS], is mainly detoxified by the liver. It has shown to induce a state of oxidative stress in the liver but its capability to induce oxidative DNA damage is not fully investigated. Increased oxidative DNA damage and rate of cell proliferation may initiate or even promote cancer. In the present work, the capability of LPS to induce 8-hydroxydeoxyguanosine [8-HDG], a specific DNA adduct for oxidative DNA damage, in rat livers is tested. Furthermore, a possible protective effect of alpha lipoic acid [ALA] is also assessed. Investigated parameters are liver contents of glutathione [GSH], lipid peroxides [MDA], nitric oxide [NO] and 8-HDG in the liver-extracted DNA. Serum activities of ALT, AST, and GGT as liver-function markers as well as serum IL2 are assessed. Moreover, liver histology is examined. LPS was given in doses of 1,3,5,7 and 9 mg/kg once i.p while, the rat mortality was examined 24hrs later. ALA was given in doses of 50,100 and 200 mg/kg once i.p 3h before LPS. LD50 of LPS is found to be 5 mg/kg. LPS increased the level of 8-HDG, MDA and NO in the liver. It also induced an acute liver necrosis and inflammatory cell infiltration as shown in liver-histopathology and in the significant increase in the activities of ALT, AST and GGT. LPS increased the serum level of IL2 as well. The dose 200 mg/kg of ALA revealed a 100% protection against LPS-induced lethality. It also, prevented the LPS-induced increase in 8-HDG in liver-extracted DNA, the liver contents of MDA and NO. ALA also rescued the LPS-induced GSH depletion. It corrected the liver function as shown by the prevention of the increases in the activity of ALT, AST and GGT with a remarkable improvement in liver histology. Moreover, it prevented the increase in serum level of IL2. These data illustrate that LPS can induce oxidative DNA damage which can be prevented by ALA suggesting a potential role for ALA as an adjuvant therapy in a plethora of liver disorders