Adequate vitamin B6 status is important for health, whereas low B6 status is associated with increased risk of cardiovascular disease, venous thrombosis and stroke. The mechanisms responsible are unknown, but the risk largely is independent of plasma homocysteine concentration. Through its coenzyme form pyridoxal phosphate (PLP), B6 plays essential roles in the acquisition and processing of one-carbon (1C) units by the glycine cleavage system and serine hydroxymethyltransferase, inter conversion and catabolism of amino acids, control of homocysteine, and production of glucose and cysteine. Thus, B6 nutrition is linked many vital cellular processes such as the synthesis of nucleotides and glutathione, metabolism of most amino acids, including sulfur amino acids, methylation processes, and gluconeogenesis. Low B6 status potentially can interfere with many of these processes. A large segment of the population, women of reproductive age, has compromised B6 status associated with the use of oral contraceptives (OC). The proposed research will determine the metabolic consequences of chronically low B6 status and the effects of targeted B6-repletion in women using OC. The linkages between vitamin B6 nutrition, B6-dependent metabolism and human health constitute the overarching rationale for these studies. In three protocols, kinetic and metabolomic assessments will be conducted in OC users before and after supplementation with pyridoxine to allow a thorough functional evaluation of unsupplemented OC users and the metabolic restoration provided by supplementation.
The Aim 1 protocol will employ labeled serine and methionine to assess the in vivo kinetics and functional status of 1C metabolism and related processes, and the linkage between 1C metabolism and gluconeogenesis.
Aim 2 studies will use labeled glycine as the primary tracer to determine the rates of in vivo glycine metabolism, glycine-based generation of 1C units, and determine the rate of glutathione synthesis.
The Aim 3 protocol will assess the functional status of the methionine cycle (remethylation, transmethylation and transsulfuration) using labeled methionine tracers.
In Aim 4, the data from these protocols and concurrent metabolic profiling will be subjected to multivariate statistical analysis to determine the relationships among the various kinetic fluxes and metabolite patterns to gain insight into metabolic control relationships. Exploratory mathematical modeling and simulations (Aim 5) of 1C metabolism and related processes also will be conducted to gain further insight into the metabolic effects of chronic OC use and effects of supplementation. Overall, these studies will yield new understanding of the metabolic effects of chronically low vitamin B6 status associated with OC use and the restorative effects of appropriate vitamin B6 supplementation. These findings will yield important new insight into mechanisms responsible in part for elevated risk of vascular disease in a major segment of women of reproductive age.

Public Health Relevance

Many women using oral contraceptives (OC) have chronically low vitamin B6 nutritional status, which may have little relation to vitamin B6 intake level. Chronic vitamin B6 deficiency is associated with increased risk of several forms of vascular disease including cardiovascular disease, venous thrombosis and stroke. These studies will expand our understanding of the functional impact of vitamin B6 inadequacy in OC users and will provide a metabolically validated supplementation strategy to alleviate low B6 status and promote health in OC users.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Maruvada, Padma
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University of Florida
Schools of Earth Sciences/Natur
United States
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da Silva, Vanessa R; Ralat, Maria A; Quinlivan, Eoin P et al. (2014) Targeted metabolomics and mathematical modeling demonstrate that vitamin B-6 restriction alters one-carbon metabolism in cultured HepG2 cells. Am J Physiol Endocrinol Metab 307:E93-101
Andridge, Rebecca R; Shoben, Abigail B; Muller, Keith E et al. (2014) Analytic methods for individually randomized group treatment trials and group-randomized trials when subjects belong to multiple groups. Stat Med 33:2178-90
Simpson, Sean L; Edwards, Lloyd J; Styner, Martin A et al. (2014) Separability tests for high-dimensional, low sample size multivariate repeated measures data. J Appl Stat 41:2450-2461
DeRatt, Barbara N; Ralat, Maria A; Kabil, Omer et al. (2014) Vitamin B-6 restriction reduces the production of hydrogen sulfide and its biomarkers by the transsulfuration pathway in cultured human hepatoma cells. J Nutr 144:1501-8
da Silva, Vanessa R; Rios-Avila, Luisa; Lamers, Yvonne et al. (2013) Metabolite profile analysis reveals functional effects of 28-day vitamin B-6 restriction on one-carbon metabolism and tryptophan catabolic pathways in healthy men and women. J Nutr 143:1719-27
Rios-Avila, Luisa; Nijhout, H Frederik; Reed, Michael C et al. (2013) A mathematical model of tryptophan metabolism via the kynurenine pathway provides insights into the effects of vitamin B-6 deficiency, tryptophan loading, and induction of tryptophan 2,3-dioxygenase on tryptophan metabolites. J Nutr 143:1509-19
Zhao, Mei; Ralat, Maria A; da Silva, Vanessa et al. (2013) Vitamin B-6 restriction impairs fatty acid synthesis in cultured human hepatoma (HepG2) cells. Am J Physiol Endocrinol Metab 304:E342-51
Gregory 3rd, Jesse F; Park, Youngja; Lamers, Yvonne et al. (2013) Metabolomic analysis reveals extended metabolic consequences of marginal vitamin B-6 deficiency in healthy human subjects. PLoS One 8:e63544
Chi, Yueh-Yun; Gribbin, Matthew J; Johnson, Jacqueline L et al. (2013) Power calculation for overall hypothesis testing with high-dimensional commensurate outcomes. Stat Med :
Chi, Yueh-Yun; Gribbin, Matthew; Lamers, Yvonne et al. (2012) Global hypothesis testing for high-dimensional repeated measures?outcomes. Stat Med 31:724-42

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