There is a well-established association between alcohol consumption (AC) and folate deficiency (FD). FD is linked to altered mental status and to neuroabnormalities such as subacute combined degeneration of the spinal cord. The latter may be caused by decreased ability to generate methyl groups for methylation reactions essential for synthesis of choline, a major component of the myelin sheath, and biogenic amines. Little is known about folate metabolism in the brain or about the effects of AC or FD on one-carbon metabolism in the brain. The applicant proposes a hypothesis that membrane transport of folates is neurons or glial cells is up-regulated in FD, and this is the reason for the difficulty in depleting folate in the CNS. The applicant also postulated a hypothesis that chronic AC perturbs folate metabolism, which results in decreased methylation of tissue components of the CNS. The applicant will clone the cDNA for the mitochondrial carriers for folate and S-adenosylmethionine (SAM) and determine if FD and/or AC result in up- or down-regulation of expression of these carriers. Since 5,10-methylenetetrahydrofolate (MeTHF) is at a critical juncture in folate metabolism, the applicant hypothesized that its concentration is regulated by conditions, which alter the levels of SAM or 5- methyltetrahydrofolate.
Specific aims i nclude: 1) to investigate the effects of alcohol and/or FD on the uptake of folate by brain tissue using primary cultures of cerebellar granule cells and glial cells. It will also evaluate whether FD and or AC results in up- or down- regulation of the plasma membrane carriers; 2) to examine the effects of AC and/or FD on the metabolism of methyl group and folate in the brain; 3) to examine the effects of AC and/or FD on the methylation of brain phospholipids; to clone and sequence the cDNA for the mitochondrial carriers for folate and SAM and determine if they are regulated by FD and/or AC; and to evaluate the effects of nitrous oxide inactivation of methionine synthase and of administered methionine on the level of MeTHF.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK032189-18
Application #
6517054
Study Section
Nutrition Study Section (NTN)
Program Officer
May, Michael K
Project Start
1983-06-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2004-06-30
Support Year
18
Fiscal Year
2002
Total Cost
$173,981
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Horne, Donald W (2003) Neither methionine nor nitrous oxide inactivation of methionine synthase affect the concentration of 5,10-methylenetetrahydrofolate in rat liver. J Nutr 133:476-8
Horne, Donald W; Reed, Kathleen A (2003) Uptake of 5-methyltetrahydrofolate into PC-3 human prostate cancer cells is carrier-mediated. J Nutr Biochem 14:473-9
Cai, Songmin; Horne, Donald W (2003) Transport of 5-formyltetrahydrofolate into primary cultured cerebellar granule cells. Brain Res 962:151-8
Cai, Songmin; Horne, Donald W (2003) Transport of 5-formyltetrahydrofolate into primary cultured rat astrocytes. Arch Biochem Biophys 410:161-6
Roje, Sanja; Chan, Sherwin Y; Kaplan, Fatma et al. (2002) Metabolic engineering in yeast demonstrates that S-adenosylmethionine controls flux through the methylenetetrahydrofolate reductase reaction in vivo. J Biol Chem 277:4056-61
Horne, Donald W; Reed, Kathleen A (2002) Transport of methotrexate into LNCaP human prostate cancer cells. Biofactors 16:19-27
Horne, D W (2001) High-performance liquid chromatographic measurement of 5,10-methylenetetrahydrofolate in liver. Anal Biochem 297:154-9
Horne, D W; Reed, K A (2001) Transport of methotrexate into PC-3 human prostate cancer cells. Arch Biochem Biophys 394:39-44
Koury, M J; Horne, D W; Brown, Z A et al. (1997) Apoptosis of late-stage erythroblasts in megaloblastic anemia: association with DNA damage and macrocyte production. Blood 89:4617-23
Horne, D W; Holloway, R S (1997) Compartmentation of folate metabolism in rat pancreas: nitrous oxide inactivation of methionine synthase leads to accumulation of 5-methyltetrahydrofolate in cytosol. J Nutr 127:1772-5

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