Effect of zinc on hepatic tumor necrosis factor-alpha, cytochrome P450 and antioxidant status of alcohol fed male rats

ABSTRACT

Alcohol consumption is associated with increased incidence of variety of illnesses including liver cirrhosis and cancers. Studies have shown that ethanol consumption may result in increased some cytokines such as tumor necrosis factor-alpha [TNF-alpha], oxidative stress with increased formation of lipid peroxides and free radicals. Zinc has been shown to have antioxidant actions. This study was carried out to investigate the hepatoprotective and antioxidant properties of zinc using acute and chronic ethanol intoxication as a model of hepatotoxic and oxidative damage. Therefore we studied the effect of zinc on TNF-alpha, cytochrome p450, serum and hepatic enzymes. Also the acute phase protein, C-reactive protein [CRP], was measured to assess the inflammatory activity. Sixty four male rats were assigned to the following groups control, ethanol fed group, received 3ml of 35% ethanol/rat/day; zinc treated, received 5 mg/kg zinc sulphate solution subcutaneously/ day; alcohol plus zinc group, received zinc pretreatment, 3 days before beginning of ethanol, in the same doses daily for either one or eight weeks. At the end of each period half of each group were sacrificed, blood sample were collected for determination of ALT, total bilirubin, alkaline phosphatase [ALP] and CRP in the sera; while glutathione peroxidase [GPX], superoxide dismutase [SOD], malondialdehyde [MDA],CYP 450 and TNF-alpha were determined in liver homogenates. Ethanol administration caused significant elevation of serum ALT, ALP, CRP, and hepatic MDA, CYP 450 and TNF-alpha after one and eight weeks. While serum total bilirubin increased significantly only after 8 weeks. On the other hand ethanol feeding caused significant reduction of hepatic GPX and SOD after one and eight weeks compared to control rats. Zinc administration to ethanol fed rats could reduce all serum enzymes and hepatic MDA and CYP 450 significantly after one and eight weeks and TNF-alpha after one week only compared to ethanol fed rats, to reach insignificant differences with control values except for CRP and TNF-alpha. CYP 450 activity was correlated to the degree of lipid peroxidation and oxidative stress as indicated by the MDA levels. we concluded that, the higher levels of total bilirubin and ALP in chronic alcohol intoxication might reflect the beginning of liver cirrhosis; together with serial measurement of CRP appear to be useful indices in assessing the clinical activity of chronic alcohol intoxication, as these conventional tests are widely available and relatively inexpensive. CYP 450 activity is correlated to the degree of alcohol induced oxidative stress. Also we concluded that zinc could reduce the elevated TNF-alpha and has antioxidant effects, as it could normalize the hazardous CYP 450 and MDA levels. Therefore it can protect the liver from alcohol induced hepatic injury specially the acute form