Catabolism and Excretion of Folate

There is very little urinary loss of folate, some 5 to 10 nmol of microbiologically active material per day. Not only is most folate in plasma bound to proteins (either folate binding protein for unsubstituted folate or albumin for methyl-tetrahydrofolate), and thus protected from glomerular filtration, but also the renal brush border has a high concentration of folate binding protein that acts to reabsorb any that is filtered. 

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Murphy, M. and Scott, J, M. (1979). The turnover, catabolism, and excretion of folate administered at physiological concentrations in the rat. BiocMm. Biophys. Acta 583, 535-539. 

DiphenyUiydantoin causes an increased rate of catabolism of folate and increased excretion of folate metabolites (KeUy et al., 1979). 

Protein-free plasma folate is filtered at the glomerulus and most is reabsorbed by the proximal renal tubules. Consequently, intact urinary folate is only a small percentage of intake. Folate is predominantly excreted by catabolism foUowing cleavage of the C9-N10 bond to produce p-aminobenzoylpolyglutamates, which are then hydrolyzed to monoglutamates and hT-acetylated before excretion. Biliary excretion of folate has been estimated at about 100 Xg/day, but much of this is reabsorbed in an enterohepatic circulation. Fecal losses have been studied by radiolabeling and have been found to be similar in type and quantity to urinary losses. ... 

Since the end products of pyrimidine catabolism are highly water-soluble, pyrimidine overproduction results in few clinical signs or symptoms. In hypemricemia associated with severe overproduction of PRPP, there is overproduction of pyrimidine nucleotides and increased excretion of p-alanine. Since A, A -methyl-ene-tetrahydrofolate is required for thymidylate synthesis, disorders of folate and vitamin Bjj metabofism result in deficiencies of TMP. 

Although catabolism of histidine is not a major source of substituted folate, the reaction is of interest because it has been exploited as a means of assessing folate nutritional stams. In folate deficiency, the activity of the formimi-notransferase is impaired by lack of cofactor. After a loading dose of histidine, there is impaired oxidative metabolism of histidine and accumulation of FIGLU, which is excreted in the urine (Section 10.10.4). 

The ability to metabolize a test dose of histidine provides a sensitive functional test of folate nutritional status as shown in Figure 10.6, forrnirninoglu-tamate (FIGLU) is an intermediate in histidine catabolism and is metabolized by the tetrahydrofolate-dependent enzyme FIGLU forrnirninotransferase. In folate deficiency, the activity of this enzyme is impaired, and FIGLU accumulates and is excreted in the urine, especially after a test dose of histidine - the FIGLU test. 

Based on folate concentrations in liver biopsy samples, and assuming that the liver contains about half of ail body stores, total body stores of folate are estimated to be between 12 and 28 Kinetic studies that show both fast-turnover and very-slow-turnover folate pools indicate that about 0.5% to 1% of body stores are catabolized or excreted daily,suggesting a minimum daily requirement of between 60 and 280)Llg to replace losses. In calculating nutritional requirement, the concept of dietary folate equivalents (DFE) has been used to adjust for the nearly 50% lower bioavailabihty of food folate compared with supplemental folic acid, such that 1 p.g DFE = 0.6 Llg of folic acid from fortified food = 1 j,g of food folate 0.5 p.g foUc acid supplement taken on an empty stomach. Before the fortification program of cereal grains with folic acid conducted between 1988 and 1994, the median intake of folate from food in the United States was approximately 250p.g/day this figure is expected to increase by about 100 Llg/day after fortification. Recommendations... 

FIG. 6. Expanded model of in vivo folate metabolism. Tbe pools are defined as follows 1, rapid turnover folate 6, slow turnover folate (tissues) 2, irretrievable losses by fecal excretion and catabolism 3, cumulative excretion of urinary folate 4, fractional (daily) excretion of urinary folate. Analysis was performed with parallel models for labeled and nonlabeled folate. 

The catabolism of folate is largely by cleavage of the C-9—N-10 bond, catalysed by carboxypeptidase G. The -aminobenzoic acid moiety is amidated and excreted in the urine as -acetamidobenzoate and / -acetamidobenzoyl-glutamate pterin is excreted either unchanged or as isoxanthopterin and other biologically inactive metabolites. 

The lack of hard evidence about the extent of supplementation required in pregnancy prompted the development of a laboratory-based assessment of metabolic turnover, which involved the assay of total daily folate catabolites (along with intact folate) in the urine of pregnant women. The rationale of the procedure was that this catabolic product represents an ineluctable daily loss of folate, the replacement of which should constitute the daily requirement. Correcting for individual variation in catabolite excretion and the bioavailability of dietary folate, the recommended allowances based on this mode of assessment are in close agreement with the latest recommendations of the USA/Canada and FAO/WHO. The data produced by the catabolite-excretion method may provide a useful adjunct to current methods... 

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