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Nutrient-Gene Interactions

Mice Deficient in Methylenetetrahydrofolate Reductase Exhibit Tissue-Specific Distribution of Folates¹

Vitamin Metabolism and Aging, Jean Mayer U.S. Department of Agriculture, Human Nutrition Research Center on Aging, Tufts University, Boston, MA and ^* Departments of Human Genetics, Pediatrics and Biology, McGill University-Montreal Children’s Hospital Research Institute, Montréal, QC, Canada

²To whom correspondence should be addressed. E-mail: rima.rozen{at}mcgill.ca.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), which is used for homocysteine remethylation to methionine, the precursor of S-adenosylmethionine (SAM). Impairment of MTHFR will increase homocysteine levels and compromise SAM-dependent methylation reactions. Mild MTHFR deficiency is common in many populations due to a polymorphism at bp 677. To assess how impaired MTHFR activity affects folate metabolism in various tissues in vivo, we used affinity/HPLC with electrochemical detection to analyze the distribution of folates in plasma, liver, and brain of Mthfr-deficient mice. The most pronounced difference in total folate was observed in plasma. In Mthfr –/– mice, plasma total folate levels were 25% of those in wild-type (Mthfr +/+) mice. Only 40% of plasma folate in Mthfr –/– mice was comprised of 5-methylTHF, compared with at least 80% in the other 2 genotype groups. In liver and brain, there were no differences in total folate. However, the proportion of 5-methylTHF in both tissues was again markedly reduced in mice with the Mthfr –/– genotype. In this genotype group, 5-methylTHF is likely derived from the diet. Our study demonstrated reduced total circulatory folate and altered distribution of folate derivatives in liver and brain in Mthfr deficiency. Decreased methylfolates and increased nonmethylfolates would affect the flux of one-carbon units between methylation reactions and nucleotide synthesis. This altered flux has implications for several common disorders, including cancer and vascular disease.

KEY WORDS: • folate distribution • methyltetrahydrofolate • formylated-folates • MTHFR deficiency

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