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PubMed1981

Hepatic folate metabolism in the chronic alcoholic monkey.

To assess the role of altered hepatic folate metabolism in the pathogenesis of the folate deficiency of chronic alcoholism, the hepatic metabolism of a tracer dose of 3H-PteGlu was compared in monkeys given 50% of energy as ethanol for 2 years and in control monkeys. Long-term ethanol feeding resulted in mild hepatic injury, with a significant decrease in hepatic folate levels. Chromatographic studies of liver biopsies obtained after the tracer dose indicated that the processes of reduction, methylation, and formylation of reduced folate and the synthesis of polyglutamyl folates were not affected by long-term ethanol feeding. Hepatic tritium levels were significantly decreased in the ethanol-fed group. These studies suggest that the decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decreased ability to retain folates in the liver, whereas reduction and further metabolism of folates is not affected.

Alcoholism↗
PubMed1993

Zinc deficiency and dietary folate metabolism in pregnant rats.

Five groups of pregnant Wistar rats (zinc-deficient diet without folate supplementation; folinic acid, folate monoglutamate, folate polyglutamate-supplemented groups receiving zinc-deficient diet; pair-fed groups as controls) were fed from day one of fertilization with a semisynthetic zinc-deficient diet containing 0.2 mg/kg of Zn in the diet for the 4 deficient groups and 100 mg/kg for the pair-fed group. After 20 days, the zinc status (plasma, liver, femoral bone) was significantly decreased in the zinc-deficient groups. The liver and plasma folate levels were lower in the zinc-deficient groups compared to the pair-fed group. Moreover, the folinic acid and the polyglutamate folate supplementations (100 mg/kg diet) did not normalize the folate status of the animals. Only the supplementation with folate monoglutamate led to correct folate levels in the pregnant rats. Nevertheless, no form of folate supplementation prevented fetal growth retardation in any of the zinc-deficient groups. These results indicate that zinc deficiency in pregnant rats decreases folate bioavailability of folinic acid, folate polyglutamates and, to a lesser extent, that of folate monoglutamate. However, no form of folate supplementation (i.e., folate monoglutamate) prevents fetal growth defect and the incidence of malformation in zinc-deficient rats.

Animals↗
PubMed2001

An examination of polymorphic genes and folate metabolism in mothers affected by a spina bifida pregnancy.

The effect of four polymorphic genes of folate-dependent methionine biosynthesis have been investigated in mothers affected by a neural tube defect pregnancy (NTD) and matched controls. The influence of the various genotypes on total red cell 5-methyl-H(4)folate,5,10-methenyl-H(4)folate, and 5-formyl-H(4)folate is reported, as is the effect on homocysteine and radioassay folate in both serum and red cells. All of the single nucleotide polymorphisms studied would seem to contribute to the cellular folate profile in some way. From the data presented, and from the work of others, it is likely that C677T 5,10-methylenetetrahydrofolate reductase is the most important of these polymorphisms. Control mother folate profiles seem reasonably predictive of any given methionine cycle mutation, but profiles in NTD mothers do not. On this basis, it seems likely that some other, as yet unidentified folate lesion is causal for NTD. In NTD-C677T 5,10-methylenetetrahydrofolate reductase in particular, indexes of folate depletion such as high-performance liquid chromatography (HPLC) folate level, oligo-gamma-glutamyl chain length, homocysteine, and radioassay folate values all seem to deteriorate with increased mutant allele carriage. This indicates that this folate polymorphism may provide a critical threshold effect that helps to promote NTD occurrence in the presence of another, as yet unidentified folate-related factor. In more general terms, on a by genotype basis, all 11 genotypes studied give NTD mothers a higher homocysteine compared to controls. Furthermore, a trend that is less universal indicates that NTD mothers have higher 5,10-methenyl-H(4)folate and 5-methyl-H(4)folate levels and lower 5-formyl-H(4)folate and H(4)PteGlu(1) levels than do controls. One of the most consistent, and possibly specific, differences between participant groups is a statistically significant elevation of 5,10-methenyl-H(4)folate in NTD mothers (affects three genotypes). Possible interpretations of this finding are discussed.

Adult↗
PubMed1983

Folylpoly-gamma-glutamate synthetases: properties and regulation.

The substrate specificities of folylpolyglutamate synthetases from Corynebacterium species, Lactobacillus casei, Streptococcus faecalis, and Chinese hamster ovary (CHO) cells are described. The purified Corynebacterium enzyme catalyzes the addition of glutamate moieties to reduced pteroylmonoglutamates, and to 5,10-methylenetetrahydropteroyldi- and triglutamates. The purified protein also possesses a separate dihydrofolate synthetase activity. Binding of pteroate substrates to dihydrofolate synthetase impairs folate binding to folylpolyglutamate synthetase. The in vivo distribution of folylpolyglutamates in bacteria and mammalian cells, which differs from source to source, appears to be a reflection of the ability of folylpolyglutamates to act as substrates for folylpolyglutamate synthetases from different sources. Bacterial synthetases use a variety of pteroylmonoglutamates as their preferred monoglutamate substrate, but use 5,10-methylenetetrahydropteroyl polyglutamates as their preferred, and sometimes only, polyglutamate substrates. Mono- and polyglutamyl forms of tetrahydrofolate are the preferred substrates of the CHO cell synthetase. Products of one carbon metabolism do not affect the in vivo distribution of folylpolyglutamates in CHO cells. Although adenine changes the distribution of folylpolyglutamates in bacteria, this effect is mediated by changing the substrate availability for the synthetase reaction, and not by regulating the levels of the synthetase per se.

Animals↗
PubMed1996

Exploitation of folate and antifolate polyglutamylation to achieve selective anticancer chemotherapy.

Synthesis of poly(gamma-glutamate) metabolites of natural folates and antifolates is a critical process. Folypolyglutamates are essential for cell proliferation. Polyglutamates of glutamate (Glu)-containing antifolates are often critical for their cytotoxic action and are relevant to antifolate resistance. However, the role of polyglutamate synthesis in selectivity is less clear. We have undertaken a research program to further define the significance of polyglutamate metabolism and to devise ways to exploit this metabolism to achieve greater therapeutic selectivity in cancer chemotherapy. This article briefly reviews several approaches tested thus far. Inhibition of folypolyglutamate synthesis should lead to cell death. Current ornithine (Orn)-containing folate-based inhibitors of the enzyme responsible for their synthesis, folypolyglutamate synthetase (FPGS), are poorly transported, apparently because of interference by the protonated delta-amine. Replacement of Orn with 4, 4-difluoroOrn, the delta-amine of which has a much lower pKa and is thus less protonated at physiological pH, was explored. Since it is unclear how polyglutamylation contributes to selectivity, we explored generic means either to eliminate or to enhance polyglutamylation. The data indicate that substitution for Glu in an antifolate by some Glu analogs in which the gamma-COOH is either altered or replaced (e.g., gamma-tetrazole-Glu) leads to loss of both FPGS substrate activity and binding; antifolate target specificity is unchanged, while uptake is actually enhanced. Substitution of 3,3-difluoroGlu for Glu leads to enhanced polyglutamylation (although probably only to the diglutamate), retention of target specificity, and at least equal uptake. Comparative studies of the same antifolate containing different replacements for Glu, such as gamma-tetrazole-Glu (no polyglutamylation) or 3,3-difluoroGlu (enhanced polyglutamylation), will be useful in exploring the role and significance of polyglutamylation.

Antineoplastic Agents↗
PubMed1982

Cell cycle patterns of thymidylate synthetase and 5,10-methylenetetrahydrofolate polyglutamates in cultured mouse hepatoma cells.

The regulation of thymidylate synthetase activity was investigated throughout the first cell cycle after release from an isoleucine block in synchronous cultures of mouse hepatoma (Hepa) cells. Activity in cell extracts increased with the onset of S phase and the increased activity was attributed to a parallel increase in enzyme concentration as determined by titration with tritiated fluorodeoxyuridylate. The polyglutamate chain length of reduced folate cofactors, which could also influence thymidylate synthetase activity, was unchanged.

Animals↗
PubMed1984

Hormonal alteration of methotrexate and folate polyglutamate formation in cultured hepatoma cells.

Glutamylation of the antifolate methotrexate in H35 hepatoma cells was stimulated by physiologic concentrations of insulin and dexamethasone. At saturating concentrations of the hormone a 2.7-fold stimulation could be obtained with insulin (65 nM, 16-h exposure) and a 1.8-fold stimulation with dexamethasone (100 nM, 16-h exposure). The increases in glutamylation caused by the hormones were not additive, and both were inhibited by actinomycin D and cycloheximide. N6,O2'-dibutyryl cAMP and theophylline caused a modest reduction of glutamylation in control and dexamethasone-treated cultures, but repressed the stimulation caused by insulin by approximately one-third. Enhancement of synthesis by dexamethasone and insulin was associated with increases in the tri-, tetra-, and pentaglutamate derivatives of methotrexate, with little change in intracellular methotrexate and methotrexate diglutamate. When the conversion of folinic acid into the folylpolyglutamate pool was examined in folate-depleted H35 cells, insulin and dexamethasone had similar effects. The results suggest that these hormones play a role in the glutamylation of the folate coenzymes in a liver-derived transformed cell line in culture and that these effects are also reflected in the interaction of the cells with antifolates such as methotrexate.

Animals↗
PubMed1990

Mechanism of leucovorin reversal of methotrexate cytotoxicity in human MCF-7 breast cancer cells.

Previous studies have suggested that metabolic inhibition by methotrexate (MTX) is multifactorial and that cytotoxicity can be reversed by the reduced folate leucovorin. In this report we investigated the mechanism of leucovorin rescue in the MCF-7 human breast cancer cell line. Cells were exposed to various concentrations of MTX (0.5, 1.0, 3.0, and 10.0 microM) for 24 hr followed by rescue with labelled leucovorin (0.5 to 50 microM). The changes in the intracellular folate pools 24 hr following the addition of leucovorin were quantitated by high-pressure liquid chromatographic methods. The changes in the folate pools during rescue were compared with the ability of various concentrations of leucovorin to affect cellular rescue from MTX using a cloning assay. Our studies show that the total labelled intracellular folate pools increased in a log-linear fashion with respect to leucovorin exposure concentrations up to 100 microM. The degree of accumulation at a given leucovorin concentration was not significantly different in the absence or presence of MTX over the concentration range of 0.5 to 10 microM. Individual folate pool levels (tetrahydrofolate, 10-formyl tetrahydrofolate, 5-formyl tetrahydrofolate, 5-methyl tetrahydrofolate, and 5,10-methylene tetrahydrofolate) reached those present in cells not exposed to MTX at concentrations of leucovorin that were not adequate to rescue the MTX-treated cells. With exposure to concentrations of leucovorin capable of rescue, the individual folate pool levels were up to twelve times greater than those found in untreated cells, consistent with competition for catalytic activity at folate-dependent enzymes in addition to dihydrofolate reductase. The dihydrofolate pool also increased with increasing leucovorin concentration: but, unlike the reduced folates, this oxidized folate reached a maximal level that was dependent on the MTX concentration to which the cells had been exposed. This suggests that competition between MTX and leucovorin occurs at the level of dihydrofolate reductase via a competitive interaction with dihydrofolate in this intact cell system. The ability of leucovorin and its metabolites to compete with direct inhibitors of dihydrofolate reductase and other metabolically important folate-dependent enzymes appears to be associated with leucovorin rescue.

Breast Neoplasms↗
PubMed1991

The biochemical pharmacology of the thymidylate synthase inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583).

2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) is a more water-soluble analogue of the quinazoline-based thymidylate synthase (TS) inhibitor, N10-propargyl-5,8-dideazafolic acid (CB3717). A 3-fold loss in TS inhibitory activity (murine and human TS, Ki = 10 nM) was accompanied by a 40-fold increase in growth inhibitory potency against L1210 and W1L2 cells in vitro (IC50 = 0.085 and 0.05 microM, respectively) when compared with CB3717. In L1210 cells a concentrative uptake mechanism was demonstrated for [3H]ICI 198583 (Kt = 2.9 microM). The L1210:1565 cell line, with an impaired ability to transport reduced folates or methotrexate (MTX), was resistant (100-fold relative to the wild-type L1210 line) to ICI 198583 (but not CB3717) and did not take up [3H]ICI 198583 significantly. The measurement of folylpolyglutamate synthetase (FPGS) substrate activity demonstrated a Km of 40 microM for ICI 198583 and a Vmax/Km (relative to folic acid) of 3.5. The formation of intracellular polyglutamate derivatives was demonstrated in both L1210 (mouse) and WIL2 (human) cells grown in vitro after exposure to 1 microM [3H]ICI 198583. In L1210 cells, by 4 hr, approximately 50% of the intracellular 3H(approximately 1 microM) was found as polyglutamate forms of ICI 198583, principally as tri- and tetraglutamates. After 24 hr the ICI 198583 polyglutamate pool had expanded, the tetraglutamate metabolite predominated and there was significant formation of the pentaglutamate. Upon resuspension of L1210 cells in drug free medium, ICI 198583 was largely lost from the cells but the polyglutamates were preferentially retained, after 24 hr approximately 70% remained. Synthetic ICI 198583 polyglutamates were shown to be up to 100-fold more potent as inhibitors of isolated TS than the parent compound. Following in vivo administration (500 mg/kg i.v.) ICI 198583 was cleared rapidly from the plasma of mice (T1/2 beta = 16 min, clearance = 42 mL/min/kg). Despite this clearance there was prolonged, dose-dependent inhibition of TS in L1210:NCI cells in vivo. Thus, following 500 mg/kg i.v. the flux through TS was inhibited by greater than 80% for at least 24 hr. Administration of five doses at 5 mg/kg daily of ICI 198583 to L1210:ICR tumour-bearing mice resulted in greater than 60% of the mice being cured, a 10-fold improvement in potency over CB3717. The maximum tolerated dose (MTD) for ICI 198583 using this schedule was greater than 500 mg/kg/day compared with 200 mg/kg/day of CB3717.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Inhibition of glycine N-methyltransferase activity by folate derivatives: implications for regulation of methyl group metabolism.

Glycine N-methyltransferase, an enzyme that uses S-adenosylmethionine to methylate glycine with the production of sarcosine, was recently shown to be identical with a major folate binding protein of rat liver (Cook, R.J. and Wagner, C. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 3631-3634). We now present evidence that 5-methyltetrahydropteroylpentaglutamate (5-CH3-H4PteGlu5) is bound with high specificity, and is a powerful inhibitor of the enzyme. It is proposed that this information may be used to modify the "methyl trap" hypothesis which describes how the availability of one-carbon units is regulated by folate, vitamin B12 and methionine.

Animals↗
PubMed1980

Vitamin B12 regulates folate metabolism by the supply of formate.

Nitrous oxide (N2O) inactivates the B12 coenzyme involved in methionine synthesis and interrupts formation of the folate coenzyme (folate polyglutamate). Normal synthesis of folate polyglutamate is restored in the N2O-treated rat when folate carrying a single carbon unit is supplied at the formate level of oxidation. The activity of the enzyme, formyl synthetase, which links formate to tetrahydrofolate, is increased after exposure to nitrous oxide. Formate is normally derived from the oxidation of methyl groups, methionine being an important source. It is suggested that failure of methionine synthesis leads to a paucity of formate and in turn to inadequate formylation of tetrahydrofolate. Formyltetrahydrofolate is the required substrate for the synthesis of folate polyglutamate, and impairment of this step in turn compromises general folate metabolism.

Animals↗
PubMed1984

Studies on the polyglutamate specificity of methylenetetrahydrofolate dehydrogenase from pig liver.

Methylenetetrahydrofolate dehydrogenase, which is one of the activities of a trifunctional folate-dependent enzyme isolated from pig liver, displays an ordered bi-bi kinetic mechanism when methylenetetrahydropteroylmonoglutamate is used as the folate substrate [Cohen, L., & MacKenzie, R. E. (1978) Biochim. Biophys. Acta 522, 311-317]. We have studied the inhibition of this activity by a series of pteroylglutamates containing one to seven glutamyl residues. Inhibitors with one to four glutamyl residues exhibit a kinetically determined KD of about 56 microM for binding at the folate site of the enzyme, while inhibitors with five to seven glutamyl residues exhibit a KD of about 16 microM. These results suggest that folylpolyglutamates are bound to the trifunctional enzyme relatively weakly, with the major interaction involving the fifth glutamyl residue of the polyglutamate "tail". A free energy decrease of about 0.74 kcal (3.1 kJ) is associated with this interaction. The possibility of a swinging arm mechanism for the trifunctional enzyme is discussed. We have also measured the kinetic parameters Vmax and the Km values for NADP+ and the folate substrate associated with catalysis using a series of methylenetetrahydropteroylpolyglutamate substrates. The variation in these parameters with the length of the polyglutamate tail is small.

Animals↗
PubMed1982

Folate pentaglutamate and folate hexaglutamate mediated one-carbon metabolism.

The proposal that folate polyglutamate cofactors of different chain lengths function differently in metabolism was investigated. We identified the one-carbon units present in rat liver folates within each of the liver folate polyglutamate groups, the folate penta-, hexa-, and heptaglutamates. This identification revealed that at the pentaglutamate level, 5-methyl-H4folate was the major form, accounting for 18% of the total liver folates, with small amounts of H4folate. At the hexaglutamate level, 5-methyl-H4folate and H4folate were major forms, accounting for 17% and 22% of the liver folates, respectively. At the heptaglutamate level, 5-methyl-H4folate occurred in small amounts while H4folate predominated. The rats used here had been fed a diet low in methionine and were exposed to N2O gas. These results are qualitatively similar to those from rat brain [Brody, T., Shin, Y. S., & Stokstad, E. L. R. (1976) J. Neurochem. 27, 409--413] where 5-methyl-H4folate was a major fraction of the folate pentaglutamates but a minor, if detectable, part of the hexa- and heptaglutamates. The folates 5-methyl-H4PteGlu5-7 were metabolically active in the liver, as illustrated by the severe contraction in the amounts of these folates following an injection of methionine. This indicates that "folate-binding proteins" do not prevent 5-methyl-H4folates from entering into one-carbon metabolism.

Animals↗
PubMed2000

Folate absorption in women with a history of neural tube defect-affected pregnancy.

BACKGROUND: The risk of neural tube defects (NTDs) is significantly reduced by supplemental folic acid. NTD risk may be associated with impaired absorption of polyglutamyl folate, the primary form of naturally occurring food folate, and of folic acid in supplements or fortified food. Stable-isotope methods provide the specificity needed to test this hypothesis. OBJECTIVE: We determined whether women who had an NTD-affected pregnancy had a reduced ability compared with control women to absorb polyglutamyl folate relative to folic acid. DESIGN: Healthy, nonpregnant women with a history of an NTD-affected pregnancy (cases; n = 11) and control women (n = 11) were administered an oral dose containing a mixture of [(2)H]pteroylpentaglutamate ([(2)H(2)]PteGlu(5); 233 nmol) and [(13)C]pteroylmonoglutamate ([(13)C(5)]PteGlu(1); 567 nmol) after a 30-d saturation protocol (2 mg unlabeled folic acid/d). Relative extents of absorption were evaluated by urinary excretion of (2)H(2)- and (13)C(5)-labeled folates 48 h postdose. RESULTS: During the first 24 h postdose, cases excreted less (f1.gif" BORDER="0"> +/- SD) [(2)H(2)]PteGlu(5) (21 +/- 12% compared with 37 +/- 19%; P = 0.01) and [(13)C(5)]PteGlu(1) (17 +/- 8% compared with 31 +/- 14%; P = 0.007) than did controls. No significant differences between cases and controls were detected in the percentage of [(2)H(2)]PteGlu(5) or [(13)C(5)]PteGlu(1) excreted during the second 24 h postdose or when the data were averaged over 48 h. However, excretion of the [(2)H(2)]folates tended to be lower in cases than in controls over the 48-h period (33 +/- 13% compared with 45 +/- 26%; P = 0.21). A similar trend (P = 0.29) for lower excretion of [(13)C(5)]folates in cases was also observed (31 +/- 16% compared with 39 +/- 17%). The ratio of urinary [(2)H(2)]folates to [(13)C(5)]folates did not differ significantly between cases and controls. CONCLUSION: These data suggest the need for a larger-scale study using stable-isotope methods to further investigate this hypothesis.

Administration, Oral↗
PubMed2006

A dual-isotope-labeling method of studying the bioavailability of hexaglutamyl folic acid relative to that of monoglutamyl folic acid in humans by using multiple orally administered low doses.

BACKGROUND: The bioavailability of dietary folate may be hampered by the need of the glutamate moieties to be deconjugated before absorption. Previous studies comparing the bioavailabilities of polyglutamyl and monoglutamyl folic acid had inconsistent results. OBJECTIVE: The objective was to estimate the bioavailability of polyglutamyl relative to that of monoglutamyl folic acid by using a sensitive stable-isotope approach that allowed for the administration of multiple low doses in humans. DESIGN: Twenty subjects aged 20-50 y ingested 2 capsules daily for 28 d; each capsule contained approximately 50 nmol [(13)C(6)]hexaglutamyl and approximately 50 nmol [(13)C(11)]monoglutamyl folic acid. Amounts of the isotopically labeled compounds in the capsules were verified by various methods. The degrees of isotopic enrichment of plasma 5-methyltetrahydrofolate with (13)C(6) and (13)C(11) were measured by using liquid chromatography tandem mass spectrometry, and the ratio of (13)C(6) to (13)C(11) ((13)C(6):(13)C(11)) in plasma on day 28 was used as a measure of their relative bioavailability. RESULTS: The (13)C(11):(13)C(6) in plasma 5-methyltetrahydrofolate reached equilibrium on day 4 and was 0.66 (95% CI: 0.58, 0.74) on day 28. The (13)C(11):(13)C(6) content in the capsules varied between 1.18 and 1.96. After correction for this ratio, the estimated bioavailability of hexaglutamyl relative to that of monoglutamyl folic acid was >/=78%. CONCLUSION: Multiple dosing of low amounts of labeled folic acid is a sensitive, accurate, and efficient method of measuring the relative bioavailability of folic acid compounds, provided that the administered doses can be reliably assessed.

Administration, Oral↗
PubMed1982

Folate derivatives in human cells: studies on normal and 5,10-methylenetetrahydrofolate reductase-deficient fibroblasts.

The distribution of folylpolyglutamates in normal and methylenetetrahydrofolate reductase-deficient human fibroblasts cultured in medium containing folic acid or 5-methyltetrahydrofolic acid has been determined. Human fibroblasts concentrated these folates to higher levels than in the medium, an effect that was more pronounced with methyltetrahydrofolate as the folate source. Over 95% of the intracellular vitamin derivatives were polyglutamates of chain length 2 to 10. The major derivatives were hexaglutamates in cells cultured with folic acid and heptaglutamates in cells cultured with methyltetrahydrofolic acid. No significant differences were detected in the polyglutamate distribution between normal and methylenetetrahydrofolate reductase-deficient fibroblast. Excess medium methionine reduced cell growth rates and intracellular vitamin levels and changed the predominant polyglutamate in cells cultured with methyltetrahydrofolate from hepta- to hexaglutamate. No significant differences were seen between the overall folate polyglutamate distributions of different one-carbon folate pools of normal fibroblasts, although slight changes in the proportions of individual polyglutamate forms were detected in the different pools.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1990

Nitrous oxide provokes changes in folylpenta- and hexaglutamates.

Liver folates isolated from rats fed a control diet consisted of H4PteGlu5 (44% of total) and 5-methyl-H4PteGlu5 (19%) with smaller amounts of 10-formyl-H4PteGlu5 (13%), H4PteGlu6 (13%), 10-formyl-H4PteGlu6 (4%) and 5-methyl-H4PteGlu6 (2%). Folates from methionine-deficient rats contained more nearly equal amounts, on a molar basis, of folylpenta- and hexaglutamates, and hence these were more suitable subjects for comparing the metabolism of these compounds in vivo. Livers from methionine-deficient rats contained H4PteGlu5 (30%), 5-methyl-H4PteGlu5 (13%), 10-formyl-H4PteGlu5 (10%), H4PteGlu6 (22%), 5-methyl-H4PteGlu6 (9%) and 10-formyl-H4PteGlu6 (11%). With exposure to N2O, 5-methyl-H4PteGlu5 and 6 increased to 27% and 13%, respectively, whereas H4PteGlu5 and 6 decreased to 20% and 17%, respectively. Nitrous oxide (N2O) perturbed both the penta- and hexaglutamates; the effect was somewhat more pronounced with the pentaglutamates. The partial depletion in tissue H4PteGlun with N2O treatment helps explain the concomitant inhibition of the oxidation of [ring-14C]histidine, an event dependent on tetrahydrofolates.

Animals↗