QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Quinlivan, E. P. Articles by Gregory, J. F. Search for Related Content PubMed PubMed Citation Articles by Quinlivan, E. P. Articles by Gregory, J. F., III

---

Nutrient-Gene Interactions

Methylenetetrahydrofolate Reductase 677CT Polymorphism and Folate Status Affect One-Carbon Incorporation into Human DNA Deoxynucleosides^1,2

Eoin P. Quinlivan, Steven R. Davis, Karla P. Shelnutt, George N. Henderson^*, Haifa Ghandour^**, Barry Shane, Jacob Selhub^**, Lynn B. Bailey, Peter W. Stacpoole^*, and Jesse F. Gregory, III³

Food Science & Human Nutrition Department, Institute of Food and Agricultural Sciences, ^* Division of Endocrinology and Metabolism, College of Medicine, Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32611; ^** Vitamin Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111; and Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA

³To whom correspondence and reprint requests should be addressed. E-mail: jfgy{at}ufl.edu.

The methylenetetrahydrofolate reductase (MTHFR) 677CT polymorphism is thought to influence the partitioning of 1-carbon units between methylation and other components of 1-carbon metabolism and to influence the risk and etiology of several major cancers and cardiovascular disease. Our objective was to determine the effect of the MTHFR 677CT polymorphism and folate status on the relative rate and extent of in vivo synthesis of DNA precursors. Adequately nourished, healthy women (9 CC, 9 TT) were infused with [3-¹³C]serine and [¹³C₅]methionine for 9 h before and after 7 wk of consumption of a low-folate diet. Blood was drawn over 5 d for monocyte DNA isolation. Isotopic enrichment of the nucleosides in DNA digests was determined by LC-MS/MS. Maximum thymidine enrichment tended to be higher (P = 0.07) in TT than in CC subjects, suggestive of marginally higher mean thymidylate synthesis. However, the subset of TT subjects who exhibited formyltetrahydrofolate in erythrocytes (an indicator of 1-carbon partitioning) had greater (P = 0.036) thymidine enrichment than CC subjects, who had no erythrocyte formyltetrahydrofolate. Purine enrichment was not affected by genotype or folate depletion. However, the deoxyadenosine to deoxyguanosine enrichment ratio was significantly higher in TT subjects, suggesting a greater relative rate of adenine synthesis. The 40% greater (P = 0.012) labeling of the methyl group of methyldeoxycytidine during folate depletion suggests a change in the origin of this 1-carbon unit. This is the first time that 1-carbon incorporation into human DNA has been measured in vivo after infusion of ¹³C-labeled 1-carbon precursors. These findings support the feasibility of further assessment of factors affecting deoxynucleotide synthesis and DNA methylation in human 1-carbon metabolism.

KEY WORDS: • thymidine • methyldeoxycytidine • deoxypurine • LC-MS/MS • isotope

This article has been cited by other articles:

				Y. Lamers, J. Williamson, M. Ralat, E. P. Quinlivan, L. R. Gilbert, C. Keeling, R. D. Stevens, C. B. Newgard, P. M. Ueland, K. Meyer, et al. 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 J. Nutr., March 1, 2009; 139(3): 452 - 460. [Abstract] [Full Text] [PDF]

				C. M. Ulrich, M. Neuhouser, A. Y. Liu, A. Boynton, J. F. Gregory III, B. Shane, S. J. James, M. C. Reed, and H. F. Nijhout Mathematical Modeling of Folate Metabolism: Predicted Effects of Genetic Polymorphisms on Mechanisms and Biomarkers Relevant to Carcinogenesis Cancer Epidemiol. Biomarkers Prev., July 1, 2008; 17(7): 1822 - 1831. [Abstract] [Full Text] [PDF]

				A D. Smith, Y.-I. Kim, and H. Refsum Is folic acid good for everyone? Am. J. Clinical Nutrition, March 1, 2008; 87(3): 517 - 533. [Abstract] [Full Text] [PDF]

				U. Lim, S. S. Wang, P. Hartge, W. Cozen, L. E. Kelemen, S. Chanock, S. Davis, A. Blair, M. Schenk, N. Rothman, et al. Gene-nutrient interactions among determinants of folate and one-carbon metabolism on the risk of non-Hodgkin lymphoma: NCI-SEER Case-Control Study Blood, April 1, 2007; 109(7): 3050 - 3059. [Abstract] [Full Text] [PDF]

				M. C. Reed, H. F. Nijhout, M. L. Neuhouser, J. F. Gregory III, B. Shane, S. J. James, A. Boynton, and C. M. Ulrich A Mathematical Model Gives Insights into Nutritional and Genetic Aspects of Folate-Mediated One-Carbon Metabolism J. Nutr., October 1, 2006; 136(10): 2653 - 2661. [Abstract] [Full Text] [PDF]

				P. J Stover Influence of human genetic variation on nutritional requirements Am. J. Clinical Nutrition, February 1, 2006; 83(2): 436S - 442S. [Abstract] [Full Text] [PDF]

				C. M. Ulrich, K. Curtin, J. D. Potter, J. Bigler, B. Caan, and M. L. Slattery Polymorphisms in the Reduced Folate Carrier, Thymidylate Synthase, or Methionine Synthase and Risk of Colon Cancer Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2509 - 2516. [Abstract] [Full Text] [PDF]

				C. M. Ulrich Nutrigenetics in Cancer Research--Folate Metabolism and Colorectal Cancer J. Nutr., November 1, 2005; 135(11): 2698 - 2702. [Abstract] [Full Text] [PDF]

				C. M. Ulrich, K. Curtin, W. Samowitz, J. Bigler, J. D. Potter, B. Caan, and M. L. Slattery MTHFR Variants Reduce the Risk of G:C->A:T Transition Mutations within the p53 Tumor Suppressor Gene in Colon Tumors J. Nutr., October 1, 2005; 135(10): 2462 - 2467. [Abstract] [Full Text] [PDF]