Folate effects

Antiepileptics, cotrimoxazole, pyrimethamine Increased anti-folate effect. 

Is there any relationship between folate status and methionine intake Methionine has a pro-folate effect, as revealed in the Folate section. In brief, dietary methionine spares the use of 1-carbon units that might otherwise be used for the conversion of homocysteine to methionine. Furthermore, methionine is converted in the cell to SAM, which in turn inhibits 5,i0-methylenc-H4folate reductase. This inhibition prevents the useless accumulation or trapping of 1-carbon units in the form of S-methyl-H folate, and allows the folate cofactors to be used for other purposes, such as the synthesis of thymidylate. 

Ormetoprim. Ormetoprim is a broad spectrum antimicrobial which is a competitive inhibitor of dihydrofolate reductase. The drug is most often used to potentiate the anti-folate effect of sulfa drugs. The combination of sulfadimethoxine and ormetoprim is commonly employed in the treatment of bacterial outbreaks in aquacultured fish. Plasma concentration time curves following intravenous administration of ormetoprim have been described in catfish triexponentially with a, B, and y phases of 0.39, 4.9, and 49 h (48). Similar studies in trout have demonstrated t and values of 0.54 and 17.5 h respectively (57). Total body clearances (Clb) and apparent volumes of distribution (V ) were similar for both species in the respective independent studies. The large volume of distribution (4,851 ml/kg for trout 4,966 ml/kg for catfish) suggests ormetroprim is widely distributed and concentrated in tissues. 

Patring, J. D. M. and Jastrebova, J. A. 2007. Application of hqnid chromatography-elec-trospray ionisation mass spectrometry for determination of dietary folates Effects of buffer nature and mobile phase composition on sensitivity and selectivity. J. Chromatogr. A. 1143 72-82. 

This partially explains the dramatic pro-folate effect of methionine seen in patients with pernicious anemia and perfused livers of cobalamin deficient animals (Herbert and Sullivan, 1963 ... 

Rundles and Brewer (1958) have shown that methionine aggrevates bone marrow megaloblastosis and its addition to bone marrow cultures from vitamin deficient patients does not alleviate defective DNA synthesis (Waxman, 1969 Metz, 1968). This antifolate" effect of methionine in bone marrow cultures is in contrast to the "pro-folate effect described in rat liver. A species difference s not involved because similar results were found in rat bone marrow cultures (Cheng et al., 1975) leading to the hypothesis that methionine exerts its primary effect as an end-product inhibitor of the homocysteinetransmethylase reaction rather than regulation (via SAM) of 5 10 methylene THF reductase. It is also possible that the tissue culture system used to study bone marrow metabolism does not reflect the normal cellular environment. As Krebs et al. (1976) have pointed out, isolated normal hepatocytes have lost low molecular weight constituents including methionine and are incapable of some reactions known to occur in vivo. 

Biochemical Functions. Ascorbic acid has various biochemical functions, involving, for example, coUagen synthesis, immune function, dmg metabohsm, folate metaboHsm, cholesterol cataboHsm, iron metaboHsm, and carnitine biosynthesis. Clear-cut evidence for its biochemical role is available only with respect to coUagen biosynthesis (hydroxylation of prolin and lysine). In addition, ascorbic acid can act as a reducing agent and as an effective antioxidant. Ascorbic acid also interferes with nitrosamine formation by reacting direcdy with nitrites, and consequently may potentially reduce cancer risk. 

L-Tyrosine metabohsm and catecholamine biosynthesis occur largely in the brain, central nervous tissue, and endocrine system, which have large pools of L-ascorbic acid (128). Catecholamine, a neurotransmitter, is the precursor in the formation of dopamine, which is converted to noradrenaline and adrenaline. The precise role of ascorbic acid has not been completely understood. Ascorbic acid has important biochemical functions with various hydroxylase enzymes in steroid, dmg, andhpid metabohsm. The cytochrome P-450 oxidase catalyzes the conversion of cholesterol to bUe acids and the detoxification process of aromatic dmgs and other xenobiotics, eg, carcinogens, poUutants, and pesticides, in the body (129). The effects of L-ascorbic acid on histamine metabohsm related to scurvy and anaphylactic shock have been investigated (130). Another ceUular reaction involving ascorbic acid is the conversion of folate to tetrahydrofolate. Ascorbic acid has many biochemical functions which affect the immune system of the body (131). 

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). 

One unwanted side-effect of phenytoin is its anti-folate activity. A programme of synthetic chemistry to manipulate the structure of the anti-folate compound pyri-methium to try to replace that property with anticonvulsant activity resulted in the synthesis of lamotrigine. It proved to be an effective AED in partial and generalised epilepsy but experience has found it also to be of value in absence seizures. 

With investigations of phytochemicals and functional foods, the outcome measure is generally going to be a biomarker of disease, such as serum cholesterol level as a marker of heart disease risk, or indicators of bone turnover as markers of osteoporosis risk. Alternatively, markers of exposure may also indicate the benefit from a functional food by demonstrating bioavailability, such as increased serum levels of vitamins or carotenoids. Some components will be measurable in both ways. For instance, effects of a folic acid-fortified food could be measured via decrease in plasma homocysteine levels, or increase in red blood cell folate. 

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... 

In mammals and in the majority of bacteria, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, catalyzing the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate via two methyl transfer reactions. This cytoplasmic reaction is catalyzed by methionine synthase (5-methyltetrahydrofolate-homocysteine methyl-transferase), which requires methyl cobalamin (MeCbl) (253), one of the two known coenzyme forms of the complex, as its cofactor. 5 -Deoxyadenosyl cobalamin (AdoCbl) (254), the other coenzyme form of cobalamin, occurs within mitochondria. This compound is a cofactor for the enzyme methylmalonyl-CoA mutase, which is responsible for the conversion of T-methylmalonyl CoA to succinyl CoA. This reaction is involved in the metabolism of odd chain fatty acids via propionic acid, as well as amino acids isoleucine, methionine, threonine, and valine. 

In the Kohn-Sham Hamiltonian, the SVWN exchange-correlation functional was used. Equation 4.12 was applied to calculate the electron density of folate, dihydrofolate, and NADPH (reduced nicotinamide adenine dinucleotide phosphate) bound to the enzyme— dihydrofolate reductase. For each investigated molecule, the electron density was compared with that of the isolated molecule (i.e., with VcKt = 0). A very strong polarizing effect of the enzyme electric field was seen. The largest deformations of the bound molecule s electron density were localized. The calculations for folate and dihydrofolate helped to rationalize the role of some ionizable groups in the catalytic activity of this enzyme. The results are,... 

Drug efficacy is directly related to its intracellular concentration level, so it is necessary to evaluate the MTX concentration in cells. In particular, MTX is a folate antagonist, thus it binds to dihydrofolate reductase in competition with folate [71-77]. A low intracellular level of MTX caused by high efflux and low uptake in resistant cells is also the main disadvantage of MTX medication [78,79]. This leads to a high dosage of MTX for cancer treatment, which is also directly associated with adverse effects. 

Patients sustain convulsions and neurological deterioration. The urine contains low levels of the metabolites of serotonin, norepinephrine and dopamine. The reductase also plays a role in the maintenance of tetrahydrofolate levels in brain, and some patients have had low folate levels in the serum and CNS. Treatment has been attempted with tryptophan and carbidopa to improve serotonin homeostasis and with folinic acid to replete diminished stores of reduced folic acid. This therapy is sometimes effective. Diagnosis involves assay of DHPR in skin fibroblasts or amniotic cells. Phenylalanine hydroxylase activity is normal. 

Cephalexin is considered safe and effective. Nitrofurantoin should not be used after week 37 due to concern for hemolytic anemia in the newborn. Sulfa-containing drugs may increase risk for kernicterus in the newborn and should be avoided during the last weeks of gestation. Folate antagonists, such as trimethoprim, are relatively contraindicated during the first trimester because of their association with cardiovascular malformations. Fluoroquinolones and tetracyclines are contraindicated. 

Although affinity chromatography has not been used directly as an analytical method, it may be modified in the future to produce a viable technique. Leucovorin has been used as an effective spacer in obtaining active samples of dihydrofolate reductase.79 If the enzyme could be immobilized without losing its activity, perhaps it could be used to separate folates. 

C. M. Paulos, B. Varghese, W. R. Widmer, G. J. Breur, E. Vlashi, and P. S. Low. Folate-targeted immunotherapy effectively treats established adjuvant and collagen-induced arthritis. Arthritis Res. Then 28 R77 Epub ahead of print (2006). 

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