Our present understanding of the in vivo dynamics of folate is inadequate in light of the importance that folate plays in the pathogenesis of many diseases. The marginal to poor folate nutrition status of at least one in ten Americans is associated with several chronic and developmental diseases that include neural tube defects, cancer, and homocysteinemia, an independent risk factor for coronary heart disease. The mechanisms behind the pathology are believed to involve a dysfunction in the dynamic and kinetic behavior of folate metabolism; accordingly, quantitative information on the in vivo metabolism of folate has emerged as a high scientific priority. New isotope tracer methodologies employing radiocarbon tagged folates coupled with Accelerator Mass Spectrometry (AMS) detection promise to revolutionize in vivo tracer studies in humans. Using this approach, [14C]folate is reliably detected at attomole concentrations (moles x 10-18) in plasma, erythrocytes, urine and feces up to 200 days following a single, physiologic (35 mug) oral dose. At these levels of sensitivity, doses are virtually non-radioactive, permitting testing in both healthy subjects and at-risk subpopulations for folate-dependent disease. Our long-range goal is to understand the dynamics of human folate metabolism in terms of known hereditary and environmental factors that modulate incidence and progression of folate-related diseases. Relevant examples include how derangements of the genetic material, such as the common methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (a key folate metabolizing enzyme) may lead to homocysteinemia, or how pregnancy effects the mobilization and utilization of body folate stores. In pursuit of this goal, we propose long-term (7 month) tracer studies using [14C]folic acid and AMS detection to define the kinetics of folate metabolism in healthy female and male subjects. These investigations will fill a critical knowledge-gap surrounding folate metabolism. A kinetic approach offers a precise mode of quantitating the relative importance of absorption, distribution and elimination in the individual response to folic acid. Analysis of kinetic data will facilitate the construction of kinetic models and the establishment of metabolic phenotypes; this information will serve as a reference point for future investigations within at-risk sub-populations and individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045939-05
Application #
6380761
Study Section
Nutrition Study Section (NTN)
Program Officer
May, Michael K
Project Start
1997-01-01
Project End
2002-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
5
Fiscal Year
2001
Total Cost
$278,391
Indirect Cost
Name
University of California Davis
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Clifford, Andrew J; Rincon, Gonzalo; Owens, Janel E et al. (2013) Single nucleotide polymorphisms in CETP, SLC46A1, SLC19A1, CD36, BCMO1, APOA5, and ABCA1 are significant predictors of plasma HDL in healthy adults. Lipids Health Dis 12:66
Clifford, Andrew J; Chen, Kehui; McWade, Laura et al. (2012) Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2, CETP, and SCARB1 are significant predictors of plasma homocysteine normalized by RBC folate in healthy adults. J Nutr 142:1764-71
Kim, Seung-Hyun; Chuang, Jennifer C; Kelly, Peter B et al. (2011) Carbon isotopes profiles of human whole blood, plasma, red blood cells, urine and feces for biological/biomedical 14C-accelerator mass spectrometry applications. Anal Chem 83:3312-8
Kim, Seung-Hyun; Kelly, Peter B; Clifford, Andrew J (2010) Calculating radiation exposures during use of (14)C-labeled nutrients, food components, and biopharmaceuticals to quantify metabolic behavior in humans. J Agric Food Chem 58:4632-7
Kim, Seung-Hyun; Kelly, Peter B; Ortalan, Volkan et al. (2010) Quality of graphite target for biological/biomedical/environmental applications of 14C-accelerator mass spectrometry. Anal Chem 82:2243-52
Kim, Seung-Hyun; Kelly, Peter B; Clifford, Andrew J (2009) Accelerator mass spectrometry targets of submilligram carbonaceous samples using the high-throughput Zn reduction method. Anal Chem 81:5949-54
Ho, Charlene C; de Moura, Fabiana F; Kim, Seung-Hyun et al. (2009) A minute dose of 14C-{beta}-carotene is absorbed and converted to retinoids in humans. J Nutr 139:1480-6
Kim, Seung-Hyun; Kelly, Peter B; Clifford, Andrew J (2008) Biological/biomedical accelerator mass spectrometry targets. 1. optimizing the CO2 reduction step using zinc dust. Anal Chem 80:7651-60
Kim, Seung-Hyun; Kelly, Peter B; Clifford, Andrew J (2008) Biological/biomedical accelerator mass spectrometry targets. 2. Physical, morphological, and structural characteristics. Anal Chem 80:7661-9
Owens, Janel E; Holstege, Dirk M; Clifford, Andrew J (2005) Quantitation of total folate in whole blood using LC-MS/MS. J Agric Food Chem 53:7390-4

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