The proposed research will evaluate several mechanisms for folate deficiency in chronic alcoholism. Folate deficiency is the most common laboratory sign of malnutrition in chronic alcoholic patients, affecting nucleoprotein synthesis and cellular turnover in all tissues, especially the bone marrow and small intestine. Although dietary lack is a major cause of folate deficiency in the binge-drinking alcoholic, considerable evidence indicates that other factors contribute to this condition. These factors include decreased intestinal folate absorption and alterations in the hepatobiliary circulation of folates. We will use the miniature pig as an experimental model for our studies since this species is known to ingest alcohol ad libitum to intoxicating blood levels, and since we have found that the regulation of folate absorption in the pig is similar to that described in humans. In pigs fed ethanol for 3 months and in a paired-fed control group, folate absorption will be measured by the triple lumen perfusion technique with permanent jejunal stomas for tube access. This approach will permit assessment of hydrolysis of labeled polyglutamyl folates and uptake of the labeled monoglutamyl folates. In vitro, mucosal tissue will be used to measure the activities of intestinal folate conjugases and the binding and transport of labeled folate by brush border vesicles. The kinetics of the enterohepatic folate cycle will be measured in pigs with jejunal and ileal stomas and cannulated bile ducts. This will permit measurement of intestinal absorption while an electronic stream splitter will sample continuously precise fractions of the bile following introduction of labeled folates into the intestine. This model will permit measurements in each group of daily biliary folate secretion and the bile folate pool size, and, with the introduction of labeled folic acid, the fractional biliary appearance of absorbed folate and the t 1/2 of the biliary folate pool. Hepatic folate binding and metabolism will be measured in liver removed after completion of the biliary studies. In vitro studies will include measurement of uptake of labeled folate by isolated liver plasma membranes from chronic ethanol fed and control fed animals. These studies will permit conclusions on the effect of chronic and acute ethanol exposure on a variety of steps required in the intestinal absorption and hepatobiliary metabolism of folates. Overall, the studies will permit further knowledge of the mechanisms of deficiency of this vitamin in alcoholic patients.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
Project #
Application #
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Schools of Medicine
United States
Zip Code
Niemela, O; Parkkila, S; Pasanen, M et al. (1999) Induction of cytochrome P450 enzymes and generation of protein-aldehyde adducts are associated with sex-dependent sensitivity to alcohol-induced liver disease in micropigs. Hepatology 30:1011-7
Parkkila, S; Halsted, C H; Villanueva, J A et al. (1999) Expression of testosterone-dependent enzyme, carbonic anhydrase III, and oxidative stress in experimental alcoholic liver disease. Dig Dis Sci 44:2205-13
Halsted, C H; Villanueva, J; Chandler, C J et al. (1996) Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation. Hepatology 23:497-505
Niemela, O; Parkkila, S; Yla-Herttuala, S et al. (1995) Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol-induced liver disease. Hepatology 22:1208-14
Villanueva, J; Chandler, C J; Shimasaki, N et al. (1994) Effects of ethanol feeding on liver, kidney and jejunal membranes of micropigs. Hepatology 19:1229-40
Niemela, O; Parkkila, S; Yla-Herttuala, S et al. (1994) Covalent protein adducts in the liver as a result of ethanol metabolism and lipid peroxidation. Lab Invest 70:537-46
Halsted, C H; Villanueva, J; Chandler, C J et al. (1993) Centrilobular distribution of acetaldehyde and collagen in the ethanol-fed micropig. Hepatology 18:954-60
Nakamura, M T; Tang, A B; Villanueva, J et al. (1992) Reduced tissue arachidonic acid concentration with chronic ethanol feeding in miniature pigs. Am J Clin Nutr 56:467-74
Chandler, C J; Harrison, D A; Buffington, C A et al. (1991) Functional specificity of jejunal brush-border pteroylpolyglutamate hydrolase in pig. Am J Physiol 260:G865-72
Zidenberg-Cherr, S; Halsted, C H; Olin, K L et al. (1990) The effect of chronic alcohol ingestion on free radical defense in the miniature pig. J Nutr 120:213-7

Showing the most recent 10 out of 13 publications