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Daily variation and effect of dietary folate on urinary pteridines

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Abstract

Introduction

Urinary pteridines are putative molecular biomarkers for noninvasive cancer screening and prognostication. Central to their translational biomarker development is the need to understand the sources and extent of their non-epidemiological variation.

Objectives

This study was designed to characterize the two primary sources of urinary pteridine variance: daily variation and the effect of dietary folate.

Methods

Daily variation was studied by collecting urine specimens (n = 81) three times daily for 3 days. The effect of dietary folate was investigated in a treatment study in which urine specimens (n = 168) were collected daily during a control week and a treatment week during which participants received dietary folate supplements. Measurements of six urinary pteridines were made using high-performance liquid chromatography–tandem mass spectrometry. Coefficients of variation were calculated to characterize daily variance between and within subjects, while nearest neighbor non-parametric analyses were used to identify diurnal patterns and measure dietary folate effects.

Results

Daily variance was approximately 35 % RSD for both within-day and between-day periods for most pteridines. Diurnal patterns in response to circadian rhythms were similarly observed for urinary pteridines. Folate supplementation was shown to alter urinary pteridine profiles in a pathway dependent manner, suggesting that dietary folate may regulate endogenous neopterin and biopterin biosynthesis.

Conclusions

Urinary pteridine levels were found to be responsive to both daily variation and folate supplementation. These findings provide new insights into pteridine biosynthesis and regulation as well as useful information for the design of future clinical translational research.

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References

  • Alessio, L., Berlin, A., Dell’Orto, A., Toffoletto, F., & Ghezzi, I. (1985). Reliability of urinary creatinine as a parameter used to adjust values of urinary biological indicators. International Archives of Occupational and Environmental Health, 55(2), 99–106.

    Article  CAS  PubMed  Google Scholar 

  • Álvarez-Sánchez, B., Priego-Capote, F., Mata-Granados, J., & de Castro, M. L. (2010). Automated determination of folate catabolites in human biofluids (urine, breast milk and serum) by on-line SPE–HILIC–MS/MS. Journal of Chromatography A, 1217(28), 4688–4695.

    Article  PubMed  Google Scholar 

  • Auzéby, A., Bogdan, A., Krosi, Z., & Touitou, Y. (1988). Time-dependence of urinary neopterin, a marker of cellular immune activity. Clinical Chemistry, 34(9), 1866–1867.

    PubMed  Google Scholar 

  • Bailey, R. L., Dodd, K. W., Gahche, J. J., Dwyer, J. T., McDowell, M. A., Yetley, E. A., et al. (2010). Total folate and folic acid intake from foods and dietary supplements in the United States: 2003–2006. The American Journal of Clinical Nutrition, 91(1), 231–237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blau, N., De Klerk, J., Thöny, B., Heizmann, C., Kierat, L., Smeitink, J., et al. (1996). Tetrahydrobiopterin loading test in xanthine dehydrogenase and molybdenum cofactor deficiencies. Biochemical and Molecular Medicine, 58(2), 199–203.

    Article  CAS  PubMed  Google Scholar 

  • Burton, C., Shi, H., & Ma, Y. (2013). Simultaneous detection of six urinary pteridines and creatinine by high-performance liquid chromatography–tandem mass spectrometry for clinical breast cancer detection. Analytical Chemistry, 85(22), 11137–11145.

    Article  CAS  PubMed  Google Scholar 

  • Burton, C., Shi, H., & Ma, Y. (2014). Normalization of urinary pteridines by urine specific gravity for early cancer detection. Clinica Chimica Acta, 435, 42–47.

    Article  CAS  Google Scholar 

  • Bush, D. M. (2008). The US mandatory guidelines for federal workplace drug testing programs: Current status and future considerations. Forensic Science International, 174(2), 111–119.

    Article  PubMed  Google Scholar 

  • Cabrerizo, F. M., Thomas, A. H., Lorente, C., Dántola, M. L., Petroselli, G., Erra-Balsells, R., et al. (2004). Generation of reactive oxygen species during the photolysis of 6-(hydroxymethyl) pterin in alkaline aqueous solutions. Helvetica Chimica Acta, 87(2), 349–365.

    Article  CAS  Google Scholar 

  • Cañada-Cañada, F., Espinosa-Mansilla, A., de la Peña, A. M., & de Llanos, A. M. (2009). Determination of marker pteridins and biopterin reduced forms, tetrahydrobiopterin and dihydrobiopterin, in human urine, using a post-column photoinduced fluorescence liquid chromatographic derivatization method. Analytica Chimica Acta, 648(1), 113–122.

    Article  PubMed  Google Scholar 

  • Dántola, M. L., Denofrio, M. P., Zurbano, B., Gimenez, C. S., Ogilby, P. R., Lorente, C., et al. (2010). Mechanism of photooxidation of folic acid sensitized by unconjugated pterins. Photochemical & Photobiological Sciences, 9(12), 1604–1612.

    Article  Google Scholar 

  • Denofrio, M. P., Hatz, S., Lorente, C., Cabrerizo, F. M., Ogilby, P. R., & Thomas, A. H. (2009). The photosensitizing activity of lumazine using 2′-deoxyguanosine 5′-monophosphate and HeLa cells as targets. Photochemical & Photobiological Sciences, 8(11), 1539–1549.

    Article  CAS  Google Scholar 

  • Fukushima, T., & Shiota, T. (1974). Biosynthesis of biopterin by Chinese hamster ovary (CHO K1) cell culture. Journal of Biological Chemistry, 249(14), 4445–4451.

    CAS  PubMed  Google Scholar 

  • Gamagedara, S., Gibbons, S., & Ma, Y. (2011). Investigation of urinary pteridine levels as potential biomarkers for noninvasive diagnosis of cancer. Clinica Chimica Acta, 412(1), 120–128.

    Article  CAS  Google Scholar 

  • Garcia-Gonzalez, M., Dominguez-Rodriguez, A., & Abreu-Gonzalez, P. (2006). Diurnal variations in serum neopterin levels are associated with the pineal hormone melatonin circadian rhythm in healthy human subjects. Journal of Pineal Research, 40(3), 288–289.

    Article  CAS  PubMed  Google Scholar 

  • Gross, S. S., & Levi, R. (1992). Tetrahydrobiopterin synthesis. An absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle. Journal of Biological Chemistry, 267(36), 25722–25729.

    CAS  PubMed  Google Scholar 

  • Han, F., Huynh, B. H., Shi, H., Lin, B., & Ma, Y. (1999). Pteridine analysis in urine by capillary electrophoresis using laser-induced fluorescence detection. Analytical Chemistry, 71(7), 1265–1269.

    Article  CAS  PubMed  Google Scholar 

  • Huber, C., Batchelor, J. R., Fuchs, D., Hausen, A., Lang, A., Niederwieser, D., et al. (1984). Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma. The Journal of Experimental Medicine, 160(1), 310–316.

    Article  CAS  PubMed  Google Scholar 

  • Huber, C., Fuchs, D., Hausen, A., Margreiter, R., Reibnegger, G., Spielberger, M., et al. (1983). Pteridines as a new marker to detect human T cells activated by allogeneic or modified self major histocompatibility complex (MHC) determinants. The Journal of Immunology, 130(3), 1047–1050.

    CAS  PubMed  Google Scholar 

  • Jang, Y. J., Hong, H. N., Lee, J. D., & Hwang, O. (2000). Down-regulation of GTP cyclohydrolase I and tetrahydrobiopterin by melatonin. NeuroReport, 11(16), 3627–3630.

    Article  CAS  PubMed  Google Scholar 

  • Konishi, M., Shibasaki, K., Hiroyasu, K., Toya, S., Kuwahara, T., Yamaguchi, A., et al. (1999). Clinical evaluation of urinary 6-hydroxymethylpterin (6-HMP) in patients with cancer of the digestive organs. Shigaku = Odontology, 86(4), 849–853.

    CAS  Google Scholar 

  • Kośliński, P., Bujak, R., Daghir, E., & Markuszewski, M. J. (2011). Metabolic profiling of pteridines for determination of potential biomarkers in cancer diseases. Electrophoresis, 32(15), 2044–2054.

    Article  PubMed  Google Scholar 

  • Kośliński, P., Jarzemski, P., Markuszewski, M. J., & Kaliszan, R. (2014). Determination of pterins in urine by HPLC with UV and fluorescent detection using different types of chromatographic stationary phases (HILIC, RP C8, RP C18). Journal of Pharmaceutical and Biomedical Analysis, 91, 37–45.

    Article  PubMed  Google Scholar 

  • Lorente, C., Petroselli, G., Dántola, M. L., Oliveros, E., & Thomas, A. H. (2011). Electron transfer initiated reactions photoinduced by pterins. Pteridines, 22(1), 111–119.

    Article  CAS  Google Scholar 

  • Ma, Y., & Burton, C. (2013). Pteridine detection in urine: The future of cancer diagnostics? Biomarkers in Medicine, 7(5), 679–681.

    Article  CAS  PubMed  Google Scholar 

  • Makoto, N., Wakako, M., Tsutomu, T., Miyuki, O., & Kasan, P. (1994). Inhibition of tryptophan hydroxylase by dopamine and the precursor amino acids. Biochemical Pharmacology, 48(1), 207–210.

    Article  Google Scholar 

  • Manjula, S., Aroor, A. R., Raja, A., Rao, S., & Rao, A. (1993). Urinary excretion of 6-hydroxymethylpterin in brain tumours. Acta Oncologica, 32(1), 29–31.

    Article  CAS  PubMed  Google Scholar 

  • Miller, R. C., Brindle, E., Holman, D. J., Shofer, J., Klein, N. A., Soules, M. R., et al. (2004). Comparison of specific gravity and creatinine for normalizing urinary reproductive hormone concentrations. Clinical Chemistry, 50(5), 924–932.

    Article  CAS  PubMed  Google Scholar 

  • Niesser, M., Demmelmair, H., Weith, T., Moretti, D., Rauh-Pfeiffer, A., van Lipzig, M., et al. (2013). Folate catabolites in spot urine as non-invasive biomarkers of folate status during habitual intake and folic acid supplementation. PLoS One, 8(2), e56194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Off, M. K., Steindal, A. E., Porojnicu, A. C., Juzeniene, A., Vorobey, A., Johnsson, A., et al. (2005). Ultraviolet photodegradation of folic acid. Journal of Photochemistry and Photobiology B, 80(1), 47–55.

    Article  CAS  Google Scholar 

  • Oliveros, E., Dántola, M. L., Vignoni, M., Thomas, A. H., & Lorente, C. (2010). Production and quenching of reactive oxygen species by pterin derivatives, an intriguing class of biomolecules. Pure and Applied Chemistry, 83(4), 801–811.

    Article  Google Scholar 

  • Petroselli, G., Bartsch, J. M., & Thomas, A. H. (2006). Photoinduced generation of H2O2 and O2·-by 6-formylpterin in aqueous solutions. Pteridines, 17(3), 82–89.

    Article  CAS  Google Scholar 

  • Reibnegger, G., Hetzel, H., Fuchs, D., Fuith, L. C., Hausen, A., Werner, E. R., et al. (1987). Clinical significance of neopterin for prognosis and follow-up in ovarian cancer. Cancer Research, 47(18), 4977–4981.

    CAS  PubMed  Google Scholar 

  • Schallreuter, K. U., Moore, J., Wood, J. M., Beazley, W. D., Peters, E. M., Marles, L. K., et al. (2001). Epidermal H2O2 accumulation alters tetrahydrobiopterin (6BH4) recycling in vitiligo: Identification of a general mechanism in regulation of All 6BH4-dependent processes? Journal of Investigative Dermatology, 116(1), 167–174.

    Article  CAS  PubMed  Google Scholar 

  • Serrano, M. P., Lorente, C., Borsarelli, C. D., & Thomas, A. H. (2015). Unraveling the degradation mechanism of purine nucleotides photosensitized by pterins: The role of charge-transfer steps. ChemPhysChem, 16(10), 2244–2252.

    Article  CAS  PubMed  Google Scholar 

  • Serrano, M. P., Lorente, C., Vieyra, F. E. M., Borsarelli, C. D., & Thomas, A. H. (2012). Photosensitizing properties of biopterin and its photoproducts using 2′-deoxyguanosine 5′-monophosphate as an oxidizable target. Physical Chemistry Chemical Physics, 14(33), 11657–11665.

    Article  CAS  PubMed  Google Scholar 

  • Sprenger, H., Jacobs, C., Nain, M., Gressner, A., Prinz, H., Wesemann, W., et al. (1992). Enhanced release of cytokines, interleukin-2 receptors, and neopterin after long-distance running. Clinical Immunology and Immunopathology, 63(2), 188–195.

    Article  CAS  PubMed  Google Scholar 

  • Stea, B., Backlund, P. S., Berkey, P. B., Cho, A. K., Halpern, B. C., Halpern, R. M., et al. (1978). Folate and pterin metabolism by cancer cells in culture. Cancer Research, 38(8), 2378–2384.

    CAS  PubMed  Google Scholar 

  • Thomas, A. H., Lorente, C., Capparelli, A. L., Martínez, C. G., Braun, A. M., & Oliveros, E. (2003). Singlet oxygen (1 Δ g) production by pterin derivatives in aqueous solutions. Photochemical & Photobiological Sciences, 2(3), 245–250.

    Article  CAS  Google Scholar 

  • Thomas, A. H., Serrano, M. P., Rahal, V., Vicendo, P., Claparols, C., Oliveros, E., et al. (2013). Tryptophan oxidation photosensitized by pterin. Free Radical Biology and Medicine, 63, 467–475.

    Article  CAS  PubMed  Google Scholar 

  • Thompson, D. K., Sloane, R., Bain, J. R., Stevens, R. D., Newgard, C. B., Pieper, C. F., et al. (2012). Daily variation of serum acylcarnitines and amino acids. Metabolomics, 8(4), 556–565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thony, B., Auerbach, G., & Blau, N. (2000). Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochemical Journal, 347, 1–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, L., Erlandsen, H., Haavik, J., Knappskog, P. M., & Stevens, R. C. (2002). Three-dimensional structure of human tryptophan hydroxylase and its implications for the biosynthesis of the neurotransmitters serotonin and melatonin. Biochemistry, 41(42), 12569–12574.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Special thanks are given to Sunghee Choi and Henry Meyer for their assistance toward the urine specimen collection, to Dr. V. A. Samaranayake for statistical consultation, and to the 30 study participants who enthusiastically supported this work. The authors also thank AB Sciex, Millipore, and the Center for Single Cell, Single Nanoparticle, and Single Molecule Monitoring at Missouri University of Science and Technology for their valuable support.

Funding

C. Burton received financial support through a National Science Foundation Graduate Research Fellowship (#DGE-1011744).

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Authors and Affiliations

  1. Department of Chemistry and Center for Single Nanoparticle, Single Cell, and Single Molecule Monitoring, Missouri University of Science and Technology, Rolla, MO, 65409, USA

    Casey Burton, Honglan Shi & Yinfa Ma

  2. Department of Chemistry, Missouri University of Science and Technology, 400 West 11th Street, Rolla, MO, 65409, USA

    Yinfa Ma

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  1. Casey Burton
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  2. Honglan Shi
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Correspondence to Yinfa Ma.

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Conflicts of Interest

C. Burton, H. Shi, and Y. Ma declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

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Burton, C., Shi, H. & Ma, Y. Daily variation and effect of dietary folate on urinary pteridines. Metabolomics 12, 78 (2016). https://doi.org/10.1007/s11306-016-1019-4

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