Intestines folates

Folate antagonists (eg, methotrexate and certain antiepileptics) are used ia treatment for various diseases, but their adininistration can lead to a functional folate deficiency. Folate utilization can be impaired by a depletion of ziac (see Zinc compounds). In humans, the intestinal bmsh border folate conjugase is a ziac metaHoenzyme (72). One study iadicates that the substantial consumption of alcohol, when combiaed with an iaadequate iatake of folate and methionine, may iacrease the risk of colon cancer (73). Based on this study, it is recommended to avoid excess alcohol consumption and iacrease folate iatake to lower the risk of colon cancer. 

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). 

Formation of strictures, abscesses, fistulae, and obstructions in patients with CD is possible. Patients with CD may develop significant weight loss or nutritional deficiencies secondary to malabsorption of nutrients in the small intestine, or as a consequence of multiple small- or large-bowel resections. Common nutritional deficiencies encountered in IBD include vitamin B12, fat-soluble vitamins, zinc, folate, and iron. Malabsorption in children with CD may contribute to significant reductions in growth and development. 

The risk of colon cancer appears to be inversely related to calcium and folate intake. Calciums protective effect may be related to a reduction in mucosal cell proliferation rates or through its binding to bile salts in the intestine, whereas dietary folate helps in maintaining normal bowel mucosa. Additional micronutrient deficiencies have been demonstrated through several studies to increase colorectal cancer risk and include selenium, vitamin C, vitamin D, vitamin E, and 3-carotene however, the benefit of dietary supplementation does not appear to be substantial.11... 

Nguyen, T. T., et al. Human intestinal folate transport cloning, expression, and distribution of complementary RNA. Gastroenterology 1997, 3 32, 783-791. 

Said, H. M., et al. Intestinal folate transport identification of a cDNA involved in folate transport and the functional expression and distribution of its mRNA. Biochim. Biophys. Acta... 

Itoh, T., et al. Stereoselectivity of the folate transporter in rabbit small intestine studies with amethopterin enantiomers. Chirality 2001, 13, 164-169. 

Levels of folate in both the blood and the cerebrospinal fluid have been very low. The anemia is correctable with injections of folate, or with the administration of large oral doses, but the concentration in the CSF is still low, suggesting that a distinct carrier system mediates folate uptake into the brain and that this system is the same as that facilitating intestinal transport. 

On the other hand, several probe substrates of carrier-mediated transport systems in the small intestine have been reported to be not absorbed by carrier-mediated mechanism in the rat colon in situ. Those include L-carnitine [23], methotrexate [18], cephradine [18], and 5-fluorouracil [18], as substrates of the L-carnitine carrier, folate carrier, peptide carrier, and pyrimidine carrier, respectively (Table 3.3). It is based on the nonsaturable nature of their transport. Particularly, the apparent membrane permeabilities of L-carnitine and methotrexate are negligibly low, suggesting that these compounds are practically unabsorbable from the colon. In the case of 5-fluorouracil, Na+-independence of transport was observed in situ [18] and also in everted sacs in vitro in the colon [21], while its carrier in the small intestine is known to be Na+-dependent. Furthermore, for ascorbate and nicotinate, as described in everted sacs in vitro [21], and L-dopa, as described in situ [24], carrier-mediated transport cannot be observed in the rat colon. 

Give orally, except in severe intestinal malabsorption. Although most patients with malabsorption cannot absorb food folates, they are able to absorb folic acid given orally. 

Folate and anemia Inadequate serum levels of folate can be caused by increased demand (for example, pregnancy and lactation), poor absorption caused by pathology of the small intestine,... 

Colman, N., Hettiarachchy, N. and Herbert, V. 1981. Detection of a milk factor that facilitates folate uptake by intestinal cells. Science 211, 1427-1429. 

Phosphonoformic acid (Foscarnet), an antiviral drug, which consists of carboxylic acid and phosphate linked together, was shown to be absorbed in the small intestine by the phosphate carrier-mediated mechanism [154], The transport of folic acid was investigated in biopsy specimens of intestinal mucosa from healthy volunteers. A pH-dependent, active transport of folic acid was found in the proximal small intestine, whereas in the mucosa of the colon, folic acid uptake was driven by a facilitated diffusion, mediated by a low-affinity carrier [155]. The existence of folate receptors in the human colonic mucosa is logical due to the large amounts of folic acid produced by the colonic flora [145],... 

Unaltered folic acid is readily and completely absorbed in the proximal jejunum. Dietary folates, however, consist primarily of polyglutamate forms of N 5-methyltetrahydrofolate. Before absorption, all but one of the glutamyl residues of the polyglutamates must be hydrolyzed by the enzyme -1-glutamyl transferase ("conjugase") within the brush border of the intestinal mucosa. 

Bovine milk also contains binding proteins for vitamins B12, folic acid and riboflavin. It has been suggested that the folate-binding protein contributes to the absorption of folate in the intestines (Parodi, 1998). 

Deficiencies of vitamin B12 can result from either low dietary levels or, more commonly, from poor absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia) or to a loss of activity of the receptor needed for intestinal uptake of the vitamin.5 Nonspecific malabsorption syndromes or gastric resection can also cause vitamin B12 deficiency. The vitamin may be administered orally (for dietary deficiencies), or intramuscularly or deep subcutaneously (for pernicious anemia). [Note Folic acid administration alone reverses the hematologic abnormality and thus masks the B12 deficiency, which can then proceed to severe neurologic dysfunction and disease. Therefore, megaloblastic anemia should not be treated with folic acid alone, but rather with a combination of folate and vitamin B12.] Therapy must be continued for the remainder of the life of a patient suffering from pernicious anemia. There are no known adverse effects of this vitamin. 

The pteroic acid moiety of tetrahydrofolate consists of a reduced pteridine ring and p-aminobenzoic acid. Folate from the diet is absorbed by the intestinal mucosa and in two enzymatic steps is reduced to tetrahydrofolate which is the active form of the coenzyme. Mammals cannot synthesize folate this normally does not present a problem because microorganisms of the intestinal tract readily do so. 

Folic acid is involved in DNA synthesis and is needed to form three of the four bases of DNA. It is absorbed in the upper small intestine, but this does not require intrinsic factor. Folate deficiency may occur in alcoholics and other chronically malnourished people. 

Most of the dietary folate undergoes reduction and methylation within the intestinalmucosa and what enters theportal bloodstream is alargely 5-methyl-tetrahydrofolate. Single doses of more than about 200 /xg of folic acid saturate the intestinal dUiydrofolate reductase, so that free folic acid is absorbed and circulates in the bloodstream. It can be taken up by 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 bUe, then reabsorbed in the jejunum together with food folates. In experimental animals, bUe drainage for 6 hours results in a reduction of serum folate to 30% to 40% of normal (Steinberg et al., 1979). There is very litde loss of folate jejunal absorption is very efficient, and the fecal excretion of 450 nmol (200 /xg) of folates per day largely represents synthesis by intestinal flora and does not reflect intake to any significant extent. 

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