Within the intestinal lumen, folate conjugates are hydrolyzed by glutamate carboxypeptidase (pteroylpolyglutamate hydrolase, also known as conjugase), a zinc-dependent enzyme of the pancreatic juice, bile, mucosal brush border, and lysosomes of enterocytes and other cells. In the rat, conjugase is mainly a pancreatic enzyme, acting in the intestinal lumen, whereas in human beings the conjugase of the mucosal brush border and enterocytes is more important.
Conjugase is a general poly-y-glutamyl hydrolase, with a broad specificity for the pterin moiety. It acts randomly as both an exopeptidase removing y-glutamyl groups sequentially and as an endopeptidase removing oligo-y-glutamyl peptides, suggesting that there may be more than one enzyme. Similar endo- and exopeptidase conjugases are found in all tissues; the extent to which the conjugases in foods may contribute to the hydrolysis of folate polyglutamates is not known. Some foods contain conjugase inhibitors that will reduce the availability of conjugated folates.
Because conjugase is a zinc metallo-enzyme, zinc deficiency can impair the absorption of conjugated food folates, but not folate monoglutamate.
Conjugase responds rapidly to zinc depletion and repletion, and it has been suggested that the absorption of a test dose of folate polyglutamates may provide a sensitive index of zinc nutritional status (Canton and Cremin, 1990). The absorption of folate monoglutamates (from pharmaceutical preparations or foods) is not affected.
Free folate, released by conjugase action, is absorbed by a carrier-mediated mechanism in the jejunum. However, the folate in milk is mainly bound to a specific binding protein (which has been used in radioligand binding assays for folate); the protein-folate complex is absorbed intact, mainly in the ileum, by a mechanism that is distinct from the jejunal transport system for free folate. The biological availability of folate from milk, or of folate from diets to which milk has been added, is considerably greater than that of unbound folate, whereas that of folate from cereal foods, or of free folic acid taken with cereal foods, is lower.
Most of the dietary folate undergoes reduction and methylation within the intestinal mucosa and what enters theportal bloodstream is alargely 5-methyl-tetrahydrofolate. Single doses of more than about 200 fig of folic acid saturate the intestinal dihydrofolate reductase, so that free folic acid is absorbed and circulates in the bloodstream. It can be taken upby tissues, reduced to tetrahy-drofolate, and utilized.
There is considerable enterohepatic circulation of folate, equivalent to about one-third of the dietary intake. Methyl-tetrahydrofolate is secreted in the bile, then reabsorbed in the jejunum together with food folates. In experimental animals, bile drainage for 6 hours results in a reduction of serum folate to 30% to 40% of normal (Steinberg et al., 1979). There is very little loss of folate; jejunal absorption is very efficient, and the fecal excretion of 450 nmol (200 f g) of folates per day largely represents synthesis by intestinal flora and does not reflect intake to any significant extent.
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