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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:1045-1050, May 2005

Nutrient-Gene Interactions

Homocysteine Synthesis Is Elevated but Total Remethylation Is Unchanged by the Methylenetetrahydrofolate Reductase 677C->T Polymorphism and by Dietary Folate Restriction in Young Women1,2,3

Steven R. Davis*, Eoin P. Quinlivan*, Karla P. Shelnutt*, Haifa Ghandour{ddagger}{ddagger}, Antonieta Capdevila#,§, Bonnie S. Coats{dagger}, Conrad Wagner#,§, Barry Shane{dagger}{dagger}, Jacob Selhub{ddagger}{ddagger}, Lynn B. Bailey*, Jonathan J. Shuster{ddagger}, Peter W. Stacpoole{dagger},** and Jesse F. Gregory, III*,4

* Food Science & Human Nutrition Department, Institute of Food and Agricultural Sciences, {dagger} Division of Endocrinology and Metabolism, Department of Medicine, ** Department of Biochemistry and Molecular Biology, and {ddagger} Department of Statistics, College of Medicine, University of Florida, Gainesville, FL 32611-0370; {dagger}{dagger} Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA; {ddagger}{ddagger} Vitamin Metabolism, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111; # Department of Biochemistry, Vanderbilt University, and § Department of Veterans Affairs Medical Center, Nashville, TN 37232

4To whom correspondence should be addressed. E-mail: jfgy{at}ufl.edu.

The effects of folate status and the methylenetetrahydrofolate reductase (MTHFR) 677C->T polymorphism on the kinetics of homocysteine metabolism are unclear. We measured the effects of dietary folate restriction on the kinetics of homocysteine remethylation and synthesis in healthy women (20–30 y old) with the MTHFR 677 C/C or T/T genotypes (n = 9/genotype) using i.v. primed, constant infusions of [13C5]methionine, [3-13C]serine, and [2H3]leucine before and after 7 wk of dietary folate restriction (115 µg dietary folate equivalents/d). Dietary folate restriction significantly reduced folate status (~65% reduction in serum folate) in both genotypes. Total remethylation flux was not affected by dietary folate restriction, the MTHFR 677C->T polymorphism, or their combination. However, the percentage of remethylation from serine was reduced ~15% (P = 0.031) by folate restriction in C/C subjects. Further, homocysteine synthesis rates of T/T subjects and folate-restricted C/C subjects were twice that of C/C subjects at baseline. In conclusion, elevated homocysteine synthesis is a cause of mild hyperhomocysteinemia in women with marginal folate status, particularly those with the MTHFR 677 T/T genotype.

KEY WORDS: • methionine • one-carbon metabolism • S-adenosylmethionine • S-adenosylhomocysteine • women




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