Folate

BACKGROUND

Folate is the commonly used group name for folic acid (pteroyl glutamic acid, or PGA) and its derivatives with similar activity. In foods and in the body folates are usually in the reduced form (tetrahydrofolate, or THF) and conjugated with up to seven glutamate residues and one of several types of one-carbon groups. PGA is used in supplements and for food fortification as it is more stable than the other derivatives.

Folate functions as a coenzyme in single-carbon transfers in the metabolism of nucleotides and amino acids. It is essential for the formation of thymidylate (TMP) for DNA synthesis, so that without folate, living cells cannot divide. The need for folate is higher when cell turnover is increased, such as in fetal development. It is also involved in purine synthesis, in the generation of formate and in amino acid interconversions. Homocysteine is methylated by methyl-THF to produce methionine, which is in turn used for the synthesis of S-adenosyl-methionine an important methylating agent in vivo (Wagner 1996).

Food folates are hydrolysed to monoglutamate forms in the gut to allow their absorption across the intestine. The monoglutamates enter the portal circulation and are metabolised to polyglutamate derivatives in the liver. They are either retained, or released to the blood as reconverted monoglutamates or to bile. The liver contains about 50% of the body stores of folate.

Folate is a substrate and vitamin B 12 is a coenzyme for the formation of MTHF that depends on the regeneration of THF, the parent compound in the homocysteine-to-methionine conversion. If either folate or vitamin B 12 is deficient, megaloblastic changes occur in bone marrow and other replicating cells from lack of 5,10-MTHF for DNA synthesis.

The bulk of excretion products are folate cleavage products. Intact urinary folate accounts for only a small percentage of dietary folate. Biliary excretion of folate can be as high as 100 µg/day (Herbert & Das 1993, Whitehead 1986), however much of this is reabsorbed.

Folate is difficult to measure in foods because it is present in different forms, so food databases can be inaccurate. However, the main sources of folate in Australia and New Zealand according to the National Nutrition Surveys undertaken in 1995 and 1997, respectively (ABS 1998, MOH 1999), are cereals, cereal products and dishes based on cereals (about 27%) and vegetables and legumes (about 29%). Fruit provides about 8–10%. Orange juice is contributing a greater amount than in the past due to the recent introduction of fortification with folate.

Folate requirements can be affected by bioavailability, nutrient interactions, smoking, certain drugs and genetic variations. Notably, the C667T polymorphism that causes MTHF reductase deficiency is found in 2–16% of white populations (van der Put et al 1995). It is likely that individuals who are homozygous for this polymorphism may have a higher requirement for folate.

Bioavailability of folates in food is about 50–60% whereas that of the folic acid used to fortify foods or as a supplement is about 85% (Sauberlich et al 1987, Gregory 1989, 1995, 1997, Pfeiffer et al 1997, Cuskelly et al 1996). Folic acid as a supplement is almost 100% bioavailable on an empty stomach. Picciano et al (2004) have recently demonstrated that the inclusion of cows' milk in the diet enhances the bioavailability of food folate as assessed by changes in erythrocyte folate and plasma total homocysteine concentrations, but not when assessed by plasma folate concentrations. Some controlled studies to assess requirements have used a defined diet containing food folate and supplemented with folic acid, so the term dietary folate equivalents (DFE) has been used to accommodate the varying bioavailabilities.

1 µg dietary folate equivalent (DFE) = 1 µg food folate
= 0.5 µg folic acid on an empty stomach
= 0.6 µg folic acid with meals or as fortified foods

Inadequate folate intake leads to decreased serum folate, then decreased erythrocyte folate, a rise in homocysteine and megaloblastic changes in bone marrow and other rapidly dividing tissues (Eichner & Hillman 1971). As depletion progresses, macrocytic cells are produced and macrocytic anaemia develops. Eventually, full-blown anaemia results in weakness, fatigue, irritability and palpitations. Folic acid supplementation in pregnancy can reduce both the occurrence and recurrence of neural tube defects in the newborn (Bower & Stanley 1989, CDC 1992, Czeizel & Dudas 1992, Kirke et al 1993, Laurence et al 1981, Wald et al 1991).

Indicators of folate requirement include erythrocyte, serum or urinary folate, plasma homocysteine and haematological status measures as well as clinical endpoints such as neural tube defects or chronic degenerative disease. Of these, erythrocyte folate is generally regarded as the primary indicator as it reflects tissue folate stores. For some age groups, erythrocyte folate is used in conjunction with plasma homocysteine and plasma or serum folate.