Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 10/3/2004
Publication Date: 3/15/2005
Citation: Baumgardener, J.N., Yarberry, B.N., Badeaux, J.V., Hidestrand, M., Shankar, K., Badger, T.M., Ronis, M.J. 2005. Undernutrition fails to exacerbate alcohol-induced liver damage despite evidence of increased oxicative stress. The Toxicologist. 84(S-1):15. Interpretive Summary: Nutritional status is a know risk factor in development of certain diseases. For example, it has been known for years that mild undernutrition tends to prolong life in both humans and animals and this is associated with reduced chronic diseases such as cancer and cardiovascular disease. Of course, undernutrition can also be associated with adverse health effects and severe undernutrition shortens life expectancy. This study investigated the effects of undernutrition on alcohol-induced liver damage and found no significant difference between the effects of alcohol in rats fed the recommended level of calorie and those fed reduced calories. However, there appeared to be some protective effects of undernutrition related to lower oxidative stress.
Technical Abstract: Mechanisms and risk factors leading to alcohol-induced liver damage (ALD) remain obscure although it is widely accepted that nutrition plays important roles in modulating liver damage. Undernutrition is often present in alcoholics. To investigate the effects of undernutrition in ALD, female Sprague-Dawley rats (200g) were infused by Total Enteral Nutrition (TEN) with or without EtOH (11 g/kg/d). Diets were infused for 14h using the overnight infusion model (1800 to 800h). Twenty-four hour urine EtOH concentrations were measured. Rats were sacrificed on day 50 and serum samples for assessment of alanine aminotransferase (ALT) and livers were collected. A combination of undernutrition and EtOH increased induction of both cytochrome P450 (CYP) 2E1 and CYP4A1 mRNA (p<0.05). Western blotting showed that CYP2E1 apoprotien was elevated 3- and 6-fold in the 187 kcal EtOH and 154 kcal EtOH groups, respectively (p<0.05). This was accompanied by a significantly enhanced activation of carbon tetrachloride-dependent lipid peroxidation, a CYP2E1 active marker, accompanied by an increase of thiobarbituric acid-reactive substances in liver homogenates only in the 154 kcal EtOH group (p>0.05), indicating oxidative stress. In addition, EtOH clearance was impaired (p<0.05), but was not accompanied by changes in ADH mRNA. Despite evidence of P450-dependent increases in reactive oxygen species production and significantly impaired EtOH clearance in the 154 kcal EtOH group, alcoholic liver pathology showed comparable steatosis, macrophage infiltration and focal necrosis in both EtOH groups. ALT levels were elevated, but not significantly different between the two EtOH groups. This suggests that undernutrition does not exacerbate ALD, but appears to provide a protective response to enhanced oxidative stress.