Vitamin dificiencies and neural tube defects.
(17/4015)
Serum folate, red cell folate, white blood cell vitamin C, riboflavin saturation index, and serum vitamin A were determined during the first trimester of pregnancy in over 900 cases. For each of these there was a social classes I + II showed the highest levels which differed significantly from other classes, except for serum folate. In 6 mothers who gave birth to infants with neural tube defects, first trimester serum folate, red cell folate, white blood cell vitamin C, and riboflavin values were lower than in controls. In spite of small numbers the differences were significant for red cell folate (P less than 0-001) and white blood cell vitamin C (P less than 0-05). These findings are compatible with the hypothesis that nutritional deficiencies are significant in the causation of congenital defects of the neural tube in man. (+info)
Impaired membrane transport in methotrexate-resistant CCRF-CEM cells involves early translation termination and increased turnover of a mutant reduced folate carrier.
(18/4015)
The basis for impaired reduced folate carrier (RFC) activity in methotrexate-resistant CCRF-CEM (CEM/Mtx-1) cells was examined. Parental and CEM/Mtx-1 cells expressed identical levels of the 3. 1-kilobase RFC transcript. A approximately 85-kDa RFC protein was detected in parental cells by photoaffinity labeling and on Western blots with RFC-specific antiserum. In CEM/Mtx-1 cells, RFC protein was undetectable. By reverse transcriptase-polymerase chain reaction and sequence analysis, G to A point mutations were identified in CEM/Mtx-1 transcripts at positions 130 (P1; changes glycine 44 --> arginine) and 380 (P2; changes serine 127 --> asparagine). A 4-base pair (CATG) insertion detected at position 191 (in 19-30% of cDNA clones) resulted in a frameshift and early translation termination. Wild-type RFC was also detected (0-9% of clones). Wild-type RFC and double-mutated RFC (RFCP1+P2) cDNAs were transfected into transport-impaired K562 and Chinese hamster ovary cells. Although RFC transcripts paralleled wild-type protein, for the RFCP1+P2 transfectants, disproportionately low RFCP1+P2 protein was detected. This reflected an increased turnover of RFCP1+P2 over wild-type RFC. RFCP1+P2 did not restore methotrexate transport; however, uptake was partially restored by constructs with single mutations at the P1 or P2 loci. Cumulatively, our results show that loss of transport function in CEM/Mtx-1 cells results from complete loss of RFC protein due to early translation termination and increased turnover of a mutant RFC protein. (+info)
Prevalence and determinants of hyperhomocysteinemia in hemodialysis and peritoneal dialysis.
(19/4015)
BACKGROUND: Hyperhomocysteinemia is an independent risk factor for atherosclerotic complications in patients with end-stage renal disease, although the mechanisms remain unclear. The major determinants of plasma homocysteine concentration are usually folate, vitamin B12, pyridoxal 5'-phosphate (vitamin B6), and glomerular filtration rate. METHODS: We measured factors, including plasma folate, vitamin B12, vitamin B6, creatinine, as well as the dose and duration of dialysis, that might affect plasma homocysteine concentrations in 130 patients on hemodialysis (HD) and compared these observations with those in 46 patients on peritoneal dialysis (PD). Independent determinants of total homocysteine were identified using a multiple logistical regression analysis. RESULTS: Total homocysteine values averaged 29.8 mumol/liter in HD patients, significantly higher than the mean value of 19.9 mumol/liter observed in patients on PD (P < 0.001). The prevalence of hyperhomocysteinemia was 90.8% among HD patients, significantly higher than the prevalence of 67.4% among PD patients. Folate values in HD patients averaged 45.5 nmol/liter and were significantly lower than in PD patients (104.2 nmol/liter, P < 0.001). For patients on HD, the only determinant of total homocysteine concentration was plasma folate (r = -0.31, P < 0.001). In contrast, for PD patients, total homocysteine did not correlate with plasma folate, vitamin B12, or vitamin B6. CONCLUSIONS: Hyperhomocysteinemia is more prevalent and intense in HD patients compared with those on PD. The homocysteine response may become refractory to excess folate supplementation in PD patients. (+info)
Folate metabolism and requirements.
(20/4015)
Folate functions in multiple coenzyme forms in acceptance, redox processing and transfer of one-carbon units, including nucleotides and certain amino acids. Folate-requiring metabolic processes are influenced by folate intake, intake of other essential nutrients, including vitamins B-12 and B-6, and at least one common genetic polymorphism. Estimates of folate requirements have been based on intakes associated with maintenance of normal plasma and erythrocyte folate concentrations and functional tests that reflect abnormalities in folate-dependent reactions. Dietary Reference Intakes for folate that have been developed recently are based primarily on metabolic studies in which erythrocyte folate concentration was considered the major indicator of adequacy. For adults >/=19 y, the Recommended Dietary Allowance (RDA) is 400 microg/d of dietary folate equivalents (DFE); for lactating and pregnant women, the RDAs include an additional 100 and 200 microg of DFE/d, respectively. (+info)
Availability of food folate in humans.
(21/4015)
The aim of our study was to determine whether the area-under-the-plasma-response-curve method with the positive area (AUC+) as primary analysis variable is suitable to evaluate the availability of food folate in humans. Healthy volunteers (n = 20) received four test meals in a randomized, four-period cross-over design as follows: meal A, 600 g spinach; meal B, 300 g spinach; meal C, 0.4 mg folic acid in water; meal D, folate-free control meal. Blood samples were drawn before administration of the test meals and up to 10 h postprandially. Plasma folate was significantly increased for up to 6 h after uptake of spinach and folic acid (P < 0.007), whereas the response curve after the control meal decreased slightly but significantly (P < 0.007). To calculate the net increase of plasma folate, the values were corrected by the individual predose concentrations. The AUC+ was calculated with these corrected values. The mean AUC+ was highest after consumption of meal A (71.2 +/- 24.0 h x nmol/L) followed by meal C (61.8 +/- 23. 8 h x nmol/L) and meal B (41.4 +/- 19.4 h x nmol/L). The AUC+ after meal B was significantly lower than after the other two meals (P < 0. 05). The results suggest that the AUC method with multiple blood sampling is useful for assessing the availability of food folate in humans. (+info)
A novel class of lipophilic quinazoline-based folic acid analogues: cytotoxic agents with a folate-independent locus.
(22/4015)
Three lipophilic quinazoline-based aminomethyl pyridine compounds, which differ only in the position of the nitrogen in their pyridine ring, are described. CB300179 (2-pyridine), CB300189 (4-pyridine) and CB30865 (3-pyridine) all inhibited isolated mammalian TS with IC50 values of 508, 250 and 156 nM respectively. CB30865 was the most potent growth inhibitory agent (IC50 values in the range 1-100 nM for several mouse and human cell types). CB300179 and CB300189 were active in the micromolar range. Against W1L2 cells, CB300179 and CB300189 demonstrated reduced potency in the presence of exogenous thymidine (dThd), and against a W1L2:C1 TS overproducing cell line. In contrast, CB30865 retained activity in these systems. Furthermore, combinations of precursors and end products of folate metabolism, e.g. dThd/hypoxanthine (HX) or leucovorin (LV), did not prevent activity. CB30865 did not interfere with the incorporation of tritiated dThd, uridine or leucine after 4 h. A cell line was raised with acquired resistance to CB30865 (W1L2:R865; > 200-fold), which was not cross-resistant to CB300179 or CB300189. In addition, W1L2:R865 cells were as sensitive as parental cells to agents from all the major chemotherapeutic drug classes. CB300179 and CB300189 induced an S phase accumulation (preventable by co-administration of dThd). No cell cycle redistribution was observed following exposure (4-48 h) to an equitoxic concentration of CB30865. In the NCI anticancer drug-discovery screen, CB30865 displayed a pattern of activity which was not consistent with known anti-tumour agents. These data suggest that CB30865 represents a class of potent potential anti-tumour agents with a novel mechanism of action. (+info)
Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study.
(23/4015)
Accumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case-control study including 105 cases and 523 matched controls from the New York University Women's Health Study cohort. In univariate analyses, the cases had lower serum folate and higher serum homocysteine levels than controls. The difference was more significant for folate (P < 0.001) than for homocysteine (P = 0.04). After adjusting for potential confounders, the risk of colorectal cancer in the subjects in the highest quartile of serum folate was half that of those in the lowest quartile (odds ratio, OR = 0.52, 95% confidence interval, CI = 0.27-0.97, P-value for trend = 0.04). The OR for the highest quartile of homocysteine, relative to the lowest quartile, was 1.72 (95% CI = 0.83-3.65, P-value for trend = 0.09). In addition, the risk of colorectal cancer was almost twice as high in subjects with below-median serum folate and above-median total alcohol intake compared with those with above-median serum folate and below-median alcohol consumption (OR = 1.99, 95% CI = 0.92-4.29). The potentially protective effects of folate need to be confirmed in clinical trials. (+info)
Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery disease in a population with low plasma folate.
(24/4015)
OBJECTIVE: To determine the effects of the thermolabile methylene tetrahydrofolate reductase (MTHFR) mutation on the presence and extent of coronary atherosclerosis in a population with low plasma folate. METHODS: 242 consecutive patients undergoing coronary angiography were prospectively evaluated for conventional risk factors, plasma homocysteine, vitamin B-12, and folate, and MTHFR genotype. The severity of coronary atherosclerosis was determined by the Leaman score. RESULTS: Mean (SD) plasma homocysteine was 15.6 (10) micromol/l in controls and 18.5 (11) micromol/l in patients with coronary artery disease (p > 0.05). Plasma homocysteine concentrations above 15 micromol/l were a risk factor for coronary artery disease (p = 0.03, risk ratio 2.1, 95% confidence interval (CI) 1.07 to 4.4). Homocysteine remained an independent risk factor on multivariate analysis when conventional risk factors were taken into account (p = 0.04). Homocysteine concentrations above 15 micromol/l were correlated with the extent of atherosclerosis (p = 0. 04, risk ratio 3.2, 95% CI 1.3 to 8.2). Homocysteine had no effect on other lipid variables (p > 0.05). Plasma folate was 15.8 (7.2) nmol/l in controls and 11.5 (2.9) nmol/l in patients with coronary artery disease. Plasma folate concentrations below 12.9 nmol/l (5.7 ng/ml) conferred a risk for coronary artery disease (p = 0.03, risk ratio 2.42, 95% CI 1.05 to 5.59). When the MTHFR genotype was determined, the TT genotype was present in 7.4% of patients and 5.2% of controls (p > 0.05). The prevalence of alleles was within the Hardy-Weinberg equilibrium (TT 7, CT 40, CC 53, chi2 = 2.3, p = 0.3). The highest homocysteine concentrations were found in patients with the TT genotype and folate below the median of the population (p = 0. 01). The extent of coronary atherosclerosis judged by the Leaman score was significantly higher in patients with the TT genotype (p = 0.03). CONCLUSIONS: Plasma homocysteine over 15 micromol/l was a significant risk factor for the presence and extent of coronary artery disease. The mean plasma folate of the population was low and correlated negatively with homocysteine. Although TT genotype was not an independent predictor of coronary artery disease, it was an important predictor of the extent of coronary atherosclerosis and plasma homocysteine, especially in the presence of plasma folate values below the median of the population. These findings may have important implications for folate replacement in patients with the TT genotype. (+info)