Application of the Key Events Dose-response Framework to Folate Metabolism

Jing Hu, Bing Wang, Nadine R. Sahyoun

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Folate is a vitamin that plays a role as a cofactor and coenzyme in many essential reactions. These reactions are interrelated and any change in folate homeostasis could affect other reactions. With food fortified with folic acid, and use of multivitamin, unmetabolized folic acid (UMFA) has been detected in blood circulation, particularly among older adults. This has raised concern about the potential harmful effect of high folic acid intake and UMFA on health conditions such as cognitive dysfunction and cancer. To examine what is known about folate metabolism and the release of circulating UMFA, the Key Events Dose-Response Framework (KEDRF) was used to review each of the major key events, dose-response characteristics and homeostatic mechanisms of folate metabolism. The intestine, liver and kidneys each play essential roles in regulating body folate homeostasis. But the determining event in folate metabolism leading to the release of UMFA in circulation appears to be the saturation of dihydrofolate reductase in the liver. However, at each of the key events in folate metabolism, limited information is available on threshold, homeostatic regulation and intracellular effects of folic acid. More studies are needed to fill in the knowledge gaps for quantitatively characterizing the dose-effect relationship especially in light of the call for extending folate fortification to other foods.

Original languageEnglish (US)
Pages (from-to)1325-1333
Number of pages9
JournalCritical Reviews in Food Science and Nutrition
Issue number8
StatePublished - Jun 10 2016
Externally publishedYes


  • Folate
  • folic acid
  • food fortification
  • key events dose-response framework
  • unmetabolized folic acid

ASJC Scopus subject areas

  • Food Science
  • Industrial and Manufacturing Engineering


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