Ethanol-induced changes in hepatic free radical defense mechanisms and fatty-acid composition in the miniature pig

Abstract

In the miniature pig, ethanol consumption has been reported to induce alterations in hepatic antioxidant defense capacity, which could result in increased risk of peroxidative damage. However, ethanol may also induce changes in membrane fatty acid composition, which could reduce the risk of peroxidative damage. This study examined lipid peroxidation, antioxidant defense and fatty acid composition in livers from miniature pigs fed ethanol in diets containing 12% of their calories as fat for 20 mo. After 12 and 20 mo of feeding, ethanol-fed pigs had higher hepatic manganese-superoxide dismutase activity, lower hepatic copper concentrations and low hepatic copper-zinc-superoxide dismutase and glutathione peroxidase activities compared with controls. Lipid peroxidation as assessed by thiobarbituric acid reacting substance assay was lower in liver homogenate and mitochondrial and microsomal fractions from ethanol-fed pigs than in controls. The percentage contribution of highly unsaturated fatty acids to total fatty acids in liver homogenates (after 12 mo of feeding) and microsome fractions (after 20 mo of feeding) was lower in the ethanol-fed pigs than in the controls, resulting in a lower peroxidizability index. Ethanol-fed pigs had minimal or no hepatic damage as assessed by histological methods. We suggest that the relative resistance of microsomes to lipid peroxidation is due to the lower peroxidizability index in the ethanol-fed pigs and may account in part for the absence of significant histopathological findings after 20 mo of ethanol feeding.

Increased lipid peroxidation and impaired antioxidant enzyme function is associated with pathological liver injury in experimental alcoholic liver disease in rats fed diets high in corn oil and fish oil

“…In their study, the levels of copper and manganese in liver tissue reflected the activities of CuZnSOD and MnSOD. 7,8 Our results also support the hypothesis that enzymatic free radical defense systems can be impaired in ethanol-fed rats and that the resultant enhanced oxidative stress can contribute to pathological liver injury. Furthermore, feeding fatty acids, which are easily peroxidized, enhanced injury as well as inhibition of cellular antioxidants.…”

“…6 On the basis of the hypothesis that a decrease in antioxidant defense may contribute to the detrimental effects of pro-oxidants in alcoholic liver disease (ALD), many investigators have evaluated the role of antioxidant enzymes after administration of ethanol. [7][8][9][10][11] Many of these studies have used animal models that do not show evidence of pathological liver injury. Furthermore, the inconsistent results obtained in these studies may also reflect variations in experimental design, diet, and duration of ethanol administration.…”

Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase

“…[35][36][37] With respect to the effects of long-term ethanol administration, some studies have shown a decrease in Sod1 activity in rat liver after alcohol administration. 16,38 In the intragastric infusion model of ethanol administration, Cu, Zn-SOD overexpression by adenoviral delivery blunted free radical formation, nuclear factor B activation, and subsequent cytokine production and the liver injury caused by ethanol. 39 These studies prompted our investigation as to whether longterm ethanol administration would cause liver injury if Sod1 was absent.…”

Mitochondrial alterations in livers of Sod1−/− mice fed alcohol

“…Because alcoholic liver injury has been linked to oxidative stress, we reasoned that a compromised antioxidant defensive system in the liver could exaccerbate liver injury produced by ethanol. Several studies have shown a decrease in SOD1 activity in rat liver after alcohol treatment (17,18) and adenoviral delivery of SOD1 protected against liver injury caused by alcohol (19). A model of chronic alcoholinduced liver injury using Cu, Zn-superoxide dismutase -deficient mice (Sod1 −/− ) was developed (20).…”