Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements

• Published in: The American journal of clinical nutrition Vol. 76; no. 2; pp. 436 - 441
• Main Authors: McNulty, Helene, McKinley, Michelle C, Wilson, Barbara, McPartlin, Joseph, Strain, J.J, Weir, Donald G, Scott, John M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Clinical Nutrition 01.08.2002; American Society for Clinical Nutrition, Inc
• Subjects: Adult; Analysis of Variance; Biological and medical sciences; cross-sectional studies; Diet; disease prevention; erythrocytes; Feeding. Feeding behavior; Female; folic acid; Folic Acid - blood; Fundamental and applied biological sciences. Psychology; Genotype; glutathione-disulfide reductase; homocysteine; Homocysteine - blood; homozygosity; Humans; in vitro studies; issues and policy; Male; Metabolism; methylenetetrahydrofolate reductase; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Nutrition; Nutritional Requirements; Nutritional Status; Oxidoreductases Acting on CH-NH Group Donors - genetics; Oxidoreductases Acting on CH-NH Group Donors - metabolism; Polymerase Chain Reaction; riboflavin; Riboflavin - blood; Riboflavin - physiology; risk; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vitamin B; Human; Temperature; Enzyme; Vitamin; Riboflavin; Environmental factor; ); Genotype; Metabolism; Genetic determinism; 5,10-Methylenetetrahydrofolate reductase (FADH; Feeding; Sensitivity resistance; Enzymatic activity; Homocystein; Oxidoreductases; Nutritional status
• ISSN: 0002-9165; 1938-3207
• DOI: 10.1093/ajcn/76.2.436

Background: Methylenetetrahydrofolate reductase (MTHFR; EC 1.7.99.5) supplies the folate needed for the metabolism of homocysteine. A reduction in MTHFR activity, as occurs in the homozygous state for the 677C to T (so-called thermolabile) enzyme variant (TT genotype), is associated with an increase in plasma total homocysteine (tHcy). Objective: In vitro studies suggest that the reduced activity of thermolabile MTHFR is due to the inappropriate loss of its riboflavin cofactor. We investigated the hypothesis that MTHFR activity in the TT genotype group is particularly sensitive to riboflavin status. Design: We studied tHcy and relevant B-vitamin status by MTHFR genotype in a cross-sectional study of 286 healthy subjects aged 19-63 y (median: 27 y). The effect of riboflavin status was examined by dividing the sample into tertiles of erythrocyte glutathionine reductase activation coefficient, a functional index of riboflavin status. Results: Lower red blood cell folate (P = 0.0001) and higher tHcy (P = 0.0082) concentrations were found in the TT group than in the heterozygous (CT) or wild-type (CC) groups. However, these expected relations in the total sample were driven by the TT group with the lowest riboflavin status, whose mean tHcy concentration (18.09 μmol/L) was almost twice that of the CC or CT group. By contrast, adequate riboflavin status rendered the TT group neutral with respect to tHcy metabolism. Conclusions: The high tHcy concentration typically associated with homozygosity for the 677C to T variant of MTHFR occurs only with poor riboflavin status. This may have important implications for governments considering new fortification policies aimed at the prevention of diseases for which this genotype is associated with increased risk.