Folates excretion

Vitamin M Vitamin M is also called pteroylglutaminic add or folic acid. It was isolated from yeast extract by Wills in 1930. Its structure was described by Anger in 1946. Folic add is made up of pteridine + p-aminobenzoic add + glutamic add. There are several known derivatives, called folates, which are capable of mutual restructuring. The coenzyme tetrahydrofolic acid, which plays a role in many biochemical reactions, is formed with the help of Bi2. Around 50% of total body folate are stored in the liver. A folate-binding protein (FBP) is available for transport. Folate undergoes enterohepatic circulation. The release of folate from the liver cells is stimulated by alcohol, which increases urine excretion. Folate deficiency (e.g. in the case of alcohol abuse) is accompanied by the development of macrocytosis. 

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. 

Biochemical findings are variable. The blood cobala-min and folate levels often are normal. Patients often have homocysteinemia with hypomethioninemia, the latter finding discriminating this group from homocystinuria secondary to cystathionine- P-synthase deficiency. Urinary excretion of methylmalonic acid may be high, reflecting the fact that vitamin B12 serves as a cofactor for the methyl-malonyl-CoA (coenzyme A) mutase reaction. 

In humans and rats, early investigations showed that large doses of folic acid resulted in increased excretion of a substance that stimulated the growth of P. cerevisiae and that was presumed to be citrovorum factor.45 This response is now also associated with other reduced folates. 

Vitamin deficiency can cause a megaloblastic anemia of the same type seen in folate deficiency (discussed in Chapter 17). In a patient with megaloblastic anemia, it is important to determine the underlying cause because Bjj defidency, if not corrected, produces a peripheral neuropathy owing to aberrant fatty acid incorporation into the myelin sheets associated with inadequate methylmalonyl CoA mutase activity. Excretion of methylmalonic acid indicates a vitamin Bjj deficiency rather than folate. 

Recently it was shown that folate transport from the basolateral site occurs as readily as that from the luminal site, indicating that changes in secretion can mediate excess urinary folate excretion [56]. 

Interestingly, after intravenous administration of a radiolabelled folate conjugate ( -In-dium-diethylenetriaminepenta acid (DTPA)-folate) in the rat, the conjugate was rapidly excreted in the urine. Moreover, after intravenous administration to athymic mice with a human tumour cell implant, the radiotracer was not only taken up by the subcutaneous tumour but was also taken up by the kidneys in significant quantities [63], indicating substantial renal selectivity of the folate conjugate. In addition to the kidney, the liver also has a high concentration of the folate-receptor [64]. 

Folic acid appears in the plasma approximately 15 to 30 minutes after an oral dose peak levels are generally reached within 1 hour. After IV administration, the drug is rapidly cleared from the plasma. Folic acid is metabolized in the liver. Normal serum levels of total folate have been reported to be 5 to 15 ng/mL normal CSF levels are approximately 16 to 21 ng/mL. In general, folate serum levels less than 5 ng/mL indicate folate deficiency, and levels less than 2 ng/mL usually result in megaloblastic anemia. A majority of the metabolic products appeared in the urine after 6 hours excretion was generally complete within 24 hours. 

Impaired glucose tolerance decreased pregnanediol excretion reduced response to metyrapone test reduced serum folate concentration. 

Well absorbed by the oral or IM route and is rapidly converted to biologically active folate. Distribution occurs to all body tissues and it is concentrated in the CSF. It is excreted in the urine. 

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. 

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). 

Experimental animals that have been exposed to ititrous oxide to deplete vitamin B12 show an increase in the proportion of liver folate present as methyl-tetrahydrofolate (85% rather than the normal 45%), largely at the expense of unsubstituted tetrahydrofolate and increased urinary loss of methyl-tetrahydrofolate (Horne et al., 1989). Tissue retention of folate is impaired because methyl-tetrahydrofolate is a poor substrate for polyglutamyl-folate synthetase, compared with unsubstituted tetrahydrofolate (Section 10.2.2.1). As a result of this, vitamin B12 deficiency is frequently accompanied by biochemical evidence of functional folate deficiency, including impaired metabolism of histidine (excretion of formiminoglutamate Section 10.3.1.2) and impaired thymidylate synthetase activity (as shown by abnormally low dUMP suppression Section 10.3.3.3), although plasma concentrations of methyl-tetrahydrofolate are normal or elevated. 

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

Chronic therapy of experimental animals with primidone depletes liver folate pentaglutamates, suggesting inhibition of folate polyglutamate synthetase (Carl et al 1987). This would be expected to lead to increased excretion of folate metabolites. 

Methylmalonyl CoA mutase is especially sensitive to vitamin B12 depletion, so methylmalonic aciduria is the most sensitive index of vitamin B12 status. Folate deficiency does not cause methylmalonic aciduria. However, up to 25% of patients with confirmed pernicious anemia excrete normal amounts of methylmalonic acid, even after a loading dose of valine (Chanarin et al., 1973). 

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. 

Although the FIGLU test depends on folate nutritional status, the metabolism of histidine wUl also be impaired and a positive result obtained, in vitamin B12 deficiency, because of the secondary deficiency of folate (Section 10.3.4.1). About 60% of vitamin Bi2-deficient subjects show increased FIGLU excretion after a histidine load. 

The total body pool of folate in adults is 17 ixmo (7.5 mg), with a biological half-life of 101 days. This suggests a minimum requirement for replacement of 85 nmol (37 /xg) per day (Herbert, 1987a). Studies of the urinary excretion of acetamido-p-aminobenzoyl glutamate in subjects maintained on folate-free diets suggest that there is catabolism of 170 nmol (80 /xg) of folate per day. 

Thiamine status is influenced by the diet and by a variety of other factors, including its bioavailability in food products, ethanol consumption, the presence of antithiamine factors in the diet as well as folate and protein status. Ingested thiamine is fairly well absorbed, rapidly converted to phosphorylated forms, stored poorly, and excreted in the urine in a variety of hydrolyzed and oxidized products (TanPhaichitr et al., 1999). 

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