Mathematical Modeling Predicts the Effect of Folate Deficiency and Excess on Cancer-Related Biomarkers

Abstract

Folate is an essential B-vitamin that mediates one-carbon metabolism reactions, including nucleotide synthesis and others related to carcinogenesis. Both low- and high-folate status influences carcinogenesis. We used a mathematical model of folate-mediated one-carbon metabolism to predict the effect of a range of intracellular epithelial folate concentrations (0.25-15.0 μmol/L) on methylation rate and purine and thymidylate synthesis. We also examined the interaction of these folate concentrations with polymorphisms in two enzymes [methylene tetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS)] in relation to the biochemical products. TS enzyme reaction rate increased markedly in response to the modeled higher intracellular folate concentrations. Changes in methylation rate were modest, whereas purine synthesis was only minimally related to increases in folate concentrations with an apparent threshold effect at 5.0 to 6.0 μmol/L. The relationship between folate concentrations and thymidylate synthesis was modified by genetic variation in TS but less so by variation in MTHFR. These gene-folate interactions modestly influenced purine synthesis in a nonlinear manner but only affected methylation rate under conditions of very high MTHFR activity. Thymidylate synthesis is very sensitive to changes in epithelial intracellular folate and increased nearly fivefold under conditions of high intracellular folate. Individuals with genetic variations causing reduced TS activity may present even greater susceptibility to excessive folate. Our observation that thymidylate synthesis increases dramatically under conditions of very elevated intracellular folate provides biological support to observations that excessive folic acid intake increases risk of both precursor lesions (i.e., colorectal adenomas) and cancer.