Disease relevance of CH3-FH4

• The selective toxicity of antifolates for a variety of cancers can be improved, as illustrated by the combined administration of N5-methyltetrahydrofolate and methotrexate in tissue culture [1].
• In addition, the characteristics of N5-methyltetrahydrofolate uptake in these cells were compared with those in folate transport-defective human breast cancer cells that were manipulated to express functionally by transfection the cloned human folate receptor and the human reduced-folate transporter [2].
• Methotrexate with N5-methyl-tetrahydrofolic acid in the treatment of non-Hodgkin's lymphomas and acute leukemias [3].
• These observations also support the hypothesis of the methyl-folate-trap in vitamin B12 deficiency [4].
• Methyl-THF also neutralized MTX in pernicious anemia, but its effect was certainly enhanced by addition of CN-Cbl [5].

High impact information on CH3-FH4

• These observations show that MTX-resistant cell established in vitro in culture media containing PGA instead of 5-methyl-THF, a physiological folate, cannot be expected to grow in vivo [6].
• Some apparent differences in the rescue of these cell lines with 5-methyl-THF were attributable to their different sensitivity to MTX [7].
• Production of formaldehyde from N5-methyltetrahydrofolate by normal and leukemic leukocytes [8].
• Cobalamin-independent methionine synthase (MetE) catalyzes the synthesis of methionine by a direct transfer of the methyl group of N5-methyltetrahydrofolate (CH3-H2PteGlun) to the sulfur atom of homocysteine (Hcy) [9].
• A heterologous functional expression assay using MTX(R)-ZR-75-1 cells showed that the folate receptor alpha cDNA obtained by RT-PCR from the RPE/choroid complex and the neural retina was functional as assessed by the binding of folic acid and by the uptake of N5-methyltetrahydrofolate [10].

Chemical compound and disease context of CH3-FH4

• Cobalamin dependent methionine synthesis and methyl-folate-trap in human vitamin B12 deficiency [4].

Biological context of CH3-FH4

• Folic acid, 5-methyl-tetrahydrofolate and 5-formyl-tetrahydrofolate exhibit equivalent intestinal absorption, metabolism and in vivo kinetics in rats [11].
• Due to the lower clearance of CH3-THF, its AUC (2,132 microM x min) exceeds that of 1-CHO-THF (1445 microM x min) by approximately 50% [12].
• These findings may be explained in terms of the requirements for serine in homocysteine metabolism, both as a source of methyl carbon atoms in the methylation of homocysteine by N5-methyltetrahydrofolate and as a substrate in the cystathionine B-synthase reaction [13].
• In addition to the essential role of the intracellular pool of polyglutamates in de novo biosynthesis of deoxyribonucleotides which allow cell growth and division, the reduced and methylated form of folate, N5-methyltetrahydrofolate, is required for the remethylation of homocysteine to methionine [14].
• Red cell N5-methyltetrahydrofolate concentrations and C677T methylenetetrahydrofolate reductase genotype in patients with stroke [15].

Anatomical context of CH3-FH4

• CONCLUSIONS: Transport of N5-methyltetrahydrofolate in human retinal pigment epithelial cells occurs exclusively through the reduced-folate transporter [2].
• Hepatocytes were cultured in serum-free, low-folate media [5 nM 5-methyl-tetrahydrofolate (THF)] with or without 50 nM 5,10-methylene-THF (MTHF) or 5-formyl-THF (FTHF) [16].
• Fibroblast activity of N5-methyltetrahydrofolate: homocysteine methyltransferase was reduced to approximately 10% of concurrent controls [17].
• Red blood cell partitioning of N5-methyl-tetrahydrofolic acid after i.v. administration [18].

Associations of CH3-FH4 with other chemical compounds

• The action of the ethanol results in an increase in the hepatic level of the substrate N5-methyltetrahydrofolate but as an adaptive mechanism, betaine homocysteine methyltransferase, is induced in order to maintain hepatic S-adenosylmethionine at normal levels [19].
• Influx of [3H]-MTX in CEM-7A cells was found to be down-regulated 6-7-fold after preincubation of cells with adenosine, 5-formyl-THF or 5-methyl-THF, but could be prevented exclusively by inhibitors of dihydrofolate reductase [20].
• In order to study this, 15 normal human volunteers were given leucovorin mouth wash and then had plasma determinations of 5-methyl-tetrahydrofolate and citrovorum factor [21].
• These data suggest that the betaine lowering seen in livers of choline-fed rats may be due to utilization as a means of compensating for the MTX-induced loss of N5 methyltetrahydrofolate for the vital methylation of homocysteine in methionine biosynthesis [22].

Gene context of CH3-FH4

• Fibroblast methylenetetrahydrofolate reductase activity and its inhibition by S-adenosylmethionine were also normal, indicating normal regulation of N5-methyltetrahydrofolate-dependent homocysteine remethylation [23].
• An E. coli folC mutant suppressed the phage mutant under conditions where it presumably accumulated methyl-tetrahydrofolate (methyl-THF) [24].
• Reduced-folate transporter-1 (RFT-1) transports reduced-folates, such as N5-methyltetrahydrofolate (MTF), the predominant circulating form of folate [25].
• During the fourth weekly MTX-LV treatment, 0 and 72 hr serum and CSF determinations of MTX, 5-methyl-tetrahydrofolate (5-MTHF) and LV were made [26].
• Methionine synthase plays another role: it converts circulating N5-methyltetrahydrofolate into tetrahydrofolate [27].

Analytical, diagnostic and therapeutic context of CH3-FH4

• Two groups of rats were daily injected with either saline solution (control group) or 5-methyl-tetrahydrofolate (MTHF) solution (MTHF group) for 15 days [28].
• For this purpose, we developed a simple and rapid assay by combining reversed-phase HPLC to determine total levels of d,1-CHO-THF and CH3-THF and chiral HPLC to separate the biologically active 1-CHO-THF from the inactive d-CHO-THF [12].
• Folate and chemoprevention of colorectal cancer: Is 5-methyl-tetrahydrofolate an active antiproliferative agent in folate-treated colon-cancer cells [29]?

References