Folate metabolism intestines

The function of folate binders in folate metabolism remains unclear, except in the case of milk where they have recently been shown to enhance the absorption of folate in breast-fed infants and possibly protect the folate against utilization by intestinal bacteria (C7). The binder may also have a function in sequestering folate from the mother s circulation. It has not been shown to have a role in polyglutamate synthesis nor does it appear to play a part in enabling cells to take up folate on the contrary, Waxman and Schrei-ber (W12) have shown that the binder prevents the uptake of folate by cells in tissue culture. 

Impaired absorption has been found in some patients with malignant disease, but this is probably related to active disease close to or actually involving the small intestine (P3, K9). Little information is available on folate metabolism in patients with hepatic carcinoma and its effect on the recycling of folate in bile. 

In view of the well-documented inhibition of dihydrofolate reductase by aminopterin (325), methotrexate (326) and related compounds it is generally accepted that this inhibitory effect constitutes the primary metabolic action of folate analogues and results in a block in the conversion of folate and dihydrofolate (DHF) to THF and its derivatives. As a consequence of this block, tissues become deficient in the THF derivatives, and this deficiency has many consequences similar to those resulting from nutritional folate deficiency. The crucial effect, however, is a depression of thymidylate synthesis with a consequent failure in DNA synthesis and arrest of cell division that has lethal results in rapidly proliferating tissues such as intestinal mucosa and bone marrow (B-69MI21604, B-69MI21605). 

Homocysteine is metabolized in the liver, kidney, small intestine and pancreas also by the transsulfuration pathway [1,3,89]. It is condensed with serine to form cystathione in an irreversible reaction catalyzed by a vitamin B6-dependent enzyme, cystathionine-synthase. Cystathione is hydrolyzed to cysteine that can be incorporated into glutathione or further metabolized to sulfate and taurine [1,3,89]. The transsulfuration pathway enzymes are pyridoxal-5-phosphate dependent [3,91]. This co-enzyme is the active form of pyridoxine. So, either folates, cobalamin, and pyridoxine are essential to keep normal homocysteine metabolism. The former two are coenzymes for the methylation pathway, the last one is coenzyme for the transsulfuration pathway [ 1,3,89,91 ]. 

Mason JB. Intestinal transport of monoglutamyl folates in mamalian systems. In Picciano MF, Stokstad ELR. Gregory JF, eds. Folic acid metabolism in health and disease. New York Wdey-Liss, 1990 47-64. 

ABSORPTION, DISTRIBUTION, AND ELIMINATION As with vitamin Bj, the diagnosis and management of folic acid deficiency depend on an understanding of the transport pathways and intracellular metabolism of the vitamin (Figure 53-10). Folates present in food are largely in the form of reduced polyglutamates, and absorption requires transport and the action of a pteroyl-glutamyl carboxypeptidase associated with mucosal cell membranes. The mucosae of the duodenum and upper part of the jejunum are rich in dihydrofolate reductase and can methylate most or aU of the reduced folate that is absorbed. Since most absorption occurs in the proximal small intestine, it is not unusual for folate deficiency to occur with jejunal disease. Both nontropical and tropical sprues are common causes of folate deficiency. 

The pathophysiology and clinical setting of the blind-loop syndrome have been reviewed recently by Donaldson (30). It is clear that a resident bacterial flora in the proximal small intestine has a major role in the development of the absorptive and luminal defects which have been observed repeatedly in these patients (20,31-35), who have a variety of basic illness, and in experimental animals (31,36) in which an antiperistaltic pouch has been constructed either in the proximal or middle jejunum. However, the presence and extent of the absorptive defects, i.e., vitamin B12, folate, xylose, and lipid, as well as the extent of luminal metabolic alteration of bile salts have varied in individual patients. This variability is probably related to... 

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