Plant Natural Products and Health
Folates, folic acid and health
Primary Objective
- Understanding the absorption, metabolism and biological consequences of folate and folic acid in the diet.
Observational studies indicate associations between low folate status and disease risk: neural tube defects, cardiovascular disease, stroke, dementia and Alzheimer's disease, altered methylation of DNA that may affect gene expression and uracil induced genomic instability. These observational studies have led to the fortification of staple foods in some countries with folic acid, and dietary advice to increase folate intake. However, recently there has been concern that the chronic appearance of unmetabolised folic acid in systemic blood circulation as a result of folic acid supplements or fortification may induce detrimental effects on health.
Research at IFR builds upon our current knowledge of folate absorption and metabolism, and our unique hypothesis that folic acid is not reduced and methylated to 5-methyltetrahydrofolic acid in the absorptive mucosa, but is actually transferred unmetabolised into the hepatic portal vein. The human metabolism of folic acid and folates is also characterised by polymorphisms in several genes that affect metabolism, and also influence the relationship between folate status and risk of chronic disease. Foremost amongst these is the pivotal MTHFR 677 C→T (Methylenetetrahydrofolate reductase) polymorphism that regulates the amount of folate directed towards the methylation cycle or towards purine and thymidylate synthesis for DNA synthesis & repair. The MTHFR 677 C→T variant has been associated with a widespread alteration in red cell folate speciation indicative of abnormal folate metabolism, where the normally expected predominant methylfolate form is replaced by a significant amount of non-methylfolate forms. However, a wide variation in the amount of non-methylfolate forms (CT 0-14%; TT 0-70%) has been reported by two groups in the Netherlands and USA but has, as yet, not been followed up by a more systematic investigation of this phenomenon and the wider implications for folate metabolism and disease risk.
This variation has not been seen with any other SNPs in genes for other folate-related enzymes. Hence, whilst possession of the MTHFR 'T' allele appears to be an absolute requirement for aberrant folate metabolism, possession of the 'T' allele per se does not predict that such alteration will take place. The recent development and application of a more specific LC-MSMS technique allowing the characterisation of folate phenotype in terms of the monoglutamate/polyglutamate ratio and 1-carbon form will enable us to fully assess the impact of MTHFR 677 C→T on metabolism.
The unique aspect of IFR folate research is our expertise in folate absorption and metabolism. This provides the underpinning knowledge which is required to interpret epidemiological studies and to guide studies on biological activity.
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