Moderate Dietary Vitamin B-6 Restriction Raises Plasma Glycine and Cystathionine Concentrations While Minimally Affecting the Rates of Glycine Turnover and Glycine Cleavage in Healthy Men and Women

Lamers, Yvonne; Williamson, Jerry; Ralat, Maria; Quinlivan, Eoin P.; Gilbert, Lesa R.; Keeling, Christine; Stevens, Robert; Newgard, Christopher B.; Ueland, Per Magne; Meyer, K; Fredriksen, Åse; Stacpoole, Peter W.; Gregory, Jesse F.

doi:10.3945/jn.108.099184

Cited by 47 publications

(104 citation statements)

References 52 publications

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“…We did not detect the enrichment of either glycolate or oxalate with a single labeled carbon, indicating that the metabolism did not involve the splitting of the carbon-carbon bond. Whole body flux values were calculated for each of the glycine infusion levels (Table 2) and were similar to those previously reported [23][24][25][26][27]. Our results suggest that glycine metabolism increased at the higher infusion rate when plasma glycine levels were increased, as the flux was 72% higher (P = 0.02).…”

Section: Infusion With [12-13 C 2 ] Glycine At 60 µMoles/kg/hrsupporting

confidence: 70%

2061 Metabolism of Primed, Constant Infusions of [1,2-13c2] Glycine and [1-13c1] Phenylalanine to Urinary Oxalate

et al. 2011

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Objective-Experiments in humans and rodents using oral doses of glycine and phenylalanine have suggested that the metabolism of these amino acids contributes to urinary oxalate excretion. To better define this contribution we have examined the primed, constant infusion of [1-13 C 1 ] phenylalanine and [1,2-13 C 2 ] glycine in the post-absorptive state in healthy adults.Materials/Methods-Subjects were infused for 5 hours, collected hourly urines and had blood drawn every 30 minutes. Ion chromatography/mass spectrometry was used to measure [ 13 C] enrichment in urinary oxalate, glycolate and hippurate, and the enrichment of 13 C-amino acids in plasma samples was measured by gas chromatography/mass spectrometry.Results-Following infusion with either 6 µmoles/kg/hr [1-13 C 1 ] phenylalanine or 6 µmoles/kg/ hr [1,2-13 C 2 ] glycine, no isotopic glycolate or oxalate was detected in urine. Based on the limits of detection of our ion chromatography/mass spectroscopy method, these data indicate that < 0.7% of the urinary oxalate could be derived from phenylalanine catabolism and < 5% from glycine catabolism. Infusions with high levels of [1,2-13 C 2 ] glycine, 60 µmoles/kg/hr, increased mean plasma glycine by 29% and the whole body flux of glycine by 72%. Under these conditions glycine contributed 16.0 ± 1.6% and 16.6 ± 3.2% to urinary oxalate and glycolate excretion, respectively. Experiments using cultured hepatoma cells demonstrated that only at supraphysiological levels (>1mM) did glycine and phenylalanine metabolism increase oxalate synthesis.Conclusions-These data suggest glycine and phenylalanine metabolism make only minor contributions to oxalate synthesis and urinary oxalate excretion.

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Section: Infusion With [12-13 C 2 ] Glycine At 60 µMoles/kg/hrsupporting

confidence: 70%

2061 Metabolism of Primed, Constant Infusions of [1,2-13c2] Glycine and [1-13c1] Phenylalanine to Urinary Oxalate

et al. 2011

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“…However, metabolic changes develop even when plasma PLP is between 20 and 30 nM. As reported in our previous studies, plasma amino acid profiles were altered with elevation of cystathionine and glycine in healthy participants when their plasma PLP is between 20 and 30 nM, which is viewed as a marginal deficiency (12,24). Population-based observational studies show mean concentrations of plasma PLP in healthy people in the range of 50 nM (18,41).…”

mentioning

confidence: 81%

“…One group of cells was cultured in the standard formulation of MEM/EBSS medium containing a nonphysiologically high concentration of pyridoxal (PL, 2,000 nM). Three groups of cells were concurrently cultured in vitamin B-6-free media containing lower concentrations of added PL hydrochloride: 10 nM PL corresponding to vitamin B-6 deficiency (23), 20 nM PL representing marginal vitamin B-6 deficiency (12,24), and 50 nM PL representing adequate vitamin B-6 status as reflected by the range of plasma PLP concentration in humans (18,41).…”

Section: Methodsmentioning

confidence: 99%

Vitamin B-6 restriction impairs fatty acid synthesis in cultured human hepatoma (HepG2) cells

Zhao

Ralat

Silva

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Vitamin B-6 deficiency has been reported to alter n-6 and n-3 fatty acid profiles in plasma and tissue lipids; however, the mechanisms underlying such metabolic changes remain unclear. The objective of this study was to determine the effects of vitamin B-6 restriction on fatty acid profiles and fatty acid synthesis in HepG2 cells. Cells were cultured for 6 wk in media with four different vitamin B-6 concentrations (10, 20, 50, and 2,000 nM added pyridoxal, representing deficient, marginal, adequate, and supraphysiological conditions) that induced a range of steady-state cellular concentrations of pyridoxal phosphate. Total cellular lipid content was greatest in the deficient (10 nM pyridoxal) medium. The percentage of arachidonic acid and the ratio of arachidonic acid to linoleic acid in the total lipid fraction were ∼15% lower in vitamin B-6-restricted cells, which suggests that vitamin B-6 restriction affects n-6 fatty acid interconversions. Metabolic flux studies indicated significantly lower fractional synthesis rate of oleic acid and arachidonic acid at 10, 20, and 50 nM pyridoxal, whereas that of eicosapentaenoic acid was lower in the cells cultured in 10 nM pyridoxal. Additionally, relative mRNA expressions of Δ5 and Δ6 desaturases were 40–50% lower in vitamin B-6-restricted cells. Overall, these findings suggest that vitamin B-6 restriction alters unsaturated fatty acid synthesis, particularly n-6 and n-3 polyunsaturated fatty acid synthesis. These results and observations of changes in human plasma fatty acid profiles caused by vitamin B-6 restriction suggest a mechanism by which vitamin B-6 inadequacy influences the cardiovascular risk.

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“…42 Moreover, vitamin B6 restriction has been demonstrated to lead to an increase of plasma glycine concentration. 37 In addition, in a cross-sectional study, plasma concentrations of glycine and serine were lower in individuals with metabolic syndrome compared to those without. 43 We observed that betaine, DMG, sarcosine and glycine concentrations were significantly lower among men with a high BMI.…”

Section: Amino Acid Profiles In Prostate Cancermentioning

confidence: 99%

“…Reduced activity of the glycine cleavage system, as would occur during vitamin B6 deficiency, causes accumulation of glycine. 37 In this way, plasma glycine is a functional biomarker of vitamin B6 status. The glycine cleavage system is a major contributor to cellular 5,10-methylene THF, which is needed for thymidylate synthesis.…”

Section: One-carbon Balance and Prostate Cancermentioning

confidence: 99%

Sarcosine and other metabolites along the choline oxidation pathway in relation to prostate cancer—A large nested case–control study within the JANUS cohort in Norway

Vogel

Ulvik

Meyer

et al. 2013

Intl Journal of Cancer

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Methyl group donors and intermediates of one-carbon metabolism affect DNA synthesis and DNA methylation, and may thereby affect prostate carcinogenesis. Choline, the precursor of betaine, and the one-carbon metabolite sarcosine have been associated with increased prostate cancer risk. Within JANUS, a prospective cohort in Norway (n 5 317,000) with baseline serum samples, we conducted a nested case-control study among 3,000 prostate cancer cases and 3,000 controls. Using conditional logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for prostate cancer risk were estimated according to quintiles of circulating betaine, dimethylglycine (DMG), sarcosine, glycine and serine. High sarcosine and glycine concentrations were associated with reduced prostate cancer risk of borderline significance (sarcosine: highest vs. lowest quintile OR 5 0.86, CI 5 0.72-1.01, p trend 5 0.03; glycine: OR 5 0.83, CI 5 0.70-1.00, p trend 5 0.07). Serum betaine, DMG and serine were not associated with prostate cancer risk. However, individuals with a high glycine/serine ratio were at decreased prostate cancer risk (OR 5 0.74, CI 5 0.69-0.85, p trend < 0.001). This population-based study suggested that men with high serum sarcosine or glycine concentrations have modestly reduced prostate cancer risk. Ratios of metabolites reflecting one-carbon balance may be associated with prostate cancer risk, as demonstrated for the glycine/serine ratio, and should be explored in future studies.The folate-mediated one-carbon metabolism, which involves B-vitamins as enzymatic cofactors, is characterized by the transfer of methyl groups and may affect carcinogenesis by influencing methylation and synthesis of DNA.1 Betaine and its precursor choline may act as methyl group sources, 2 whereas intermediates involved in the transfer of one-carbon units may be hypothesized to reflect bioavailability of methyl groups.3 These factors may therefore affect the development and growth of cancer and should be investigated when studying the role of one-carbon metabolism in carcinogenesis. Interestingly, a high S-adenosylmethionine/S-adenosylhomocysteine ratio, which facilitates transmethylation reactions, has been associated with carcinogenesis. 4 Similarly, it may be hypothesized that ratios of one-carbon metabolites, which might reflect one-carbon balance, are related to carcinogenesis.Prostate cancer is the second most frequently diagnosed cancer among men globally. 5 Results from observational studies suggest that high concentrations of circulating folate or high vitamin B12 status are associated with increased prostate cancer risk, although reported associations were modest and sometimes inconsistent.6-8 Although increased prostate cancer risk was suggested in one trial among subjects receiving folic acid supplements, 9 recent meta-analyses did not suggest an association with increased prostate cancer risk. 10,11 Nevertheless, an observational population-based study previously showed

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Moderate Dietary Vitamin B-6 Restriction Raises Plasma Glycine and Cystathionine Concentrations While Minimally Affecting the Rates of Glycine Turnover and Glycine Cleavage in Healthy Men and Women

Cited by 47 publications

References 52 publications

2061 Metabolism of Primed, Constant Infusions of [1,2-13c2] Glycine and [1-13c1] Phenylalanine to Urinary Oxalate

2061 Metabolism of Primed, Constant Infusions of [1,2-13c2] Glycine and [1-13c1] Phenylalanine to Urinary Oxalate

Vitamin B-6 restriction impairs fatty acid synthesis in cultured human hepatoma (HepG2) cells

Sarcosine and other metabolites along the choline oxidation pathway in relation to prostate cancer—A large nested case–control study within the JANUS cohort in Norway

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