Interactions between folate and aging for carcinogenesis

2005 ◽  
Vol 43 (10) ◽  
Author(s):  
Sang-Woon Choi ◽  
Simonetta Friso
Keyword(s):  
Carbon Metabolism ◽  
Genomic Dna ◽  
Folate Intake ◽  
Dna Hypomethylation ◽  
Folate Supplementation ◽  
Nucleotide Synthesis ◽  
Dietary Folate ◽  
One Carbon Metabolism ◽  
Molecular Aberrations ◽  
Folate Depletion

AbstractInadequate folate intake and aging are each strongly implicated as important risk factors for certain cancers. Since both folate depletion and aging are strongly associated with hyperhomocysteinemia, genomic DNA hypomethylation, and increased uracil misincorporation into DNA, it appears that each of them enhances carcinogenesis by inducing a derangement of one-carbon metabolism that supplies one-carbons to biological methylation reactions and nucleotide synthesis. Recent studies have demonstrated that inadequate dietary folate and aging may interact and synergistically disturb the normal homeostasis of one-carbon metabolism, thereby provoking subsequent biochemical and molecular aberrations, including alterations in critical gene expression related to carcinogenesis. These studies have further indicated that modest folate supplementation may reverse or partially ameliorate those adverse effects induced by folate depletion and aging.

scholarly journals A candidate gene study of one-carbon metabolism pathway genes and colorectal cancer risk

2012 ◽  
Vol 109 (6) ◽  
pp. 984-989 ◽  
Author(s):  
Marcella Martinelli ◽  
Luca Scapoli ◽  
Gabriella Mattei ◽  
Giampaolo Ugolini ◽  
Isacco Montroni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Carbon Metabolism ◽  
Protein Function ◽  
Restriction Analysis ◽  
Likelihood Ratio Statistic ◽  
Folate Intake ◽  
Nucleotide Synthesis ◽  
Preliminary Results ◽  
Increased Risk ◽  
One Carbon Metabolism

The risk of colorectal cancer (CRC) may be influenced by aberrant DNA methylation and altered nucleotide synthesis and repair, possibly caused by impaired dietary folate intake as well as by polymorphic variants in one-carbon metabolism genes. A case–control study using seventy-one CRC patients and eighty unrelated healthy controls was carried out to assess the genetic association of fifteen SNP and one insertion in nine genes belonging to the folate pathway. Polymorphism selection was based on literature data, and included those which have a known or suspected functional impact on cancer and missense polymorphisms that are most likely to alter protein function. Genotyping was performed by real-time PCR and PCR followed by restriction analysis. The likelihood ratio statistic indicated that most of the polymorphisms were not associated with the risk of CRC. However, an increased risk of CRC was observed for two variant alleles of SNP mapping on the transcobalamin 2 gene (TCN2): C776G (rs1801198) and c.1026-394T>G (rs7286680). Considering the crucial biological function played by one-carbon metabolism genes, further investigations with larger cohorts of CRC patients are needed in order to confirm our preliminary results. These preliminary results indicate that TCN2 polymorphisms can be a susceptibility factor for CRC.

scholarly journals Folate, vitamin B6, vitamin B12 and methionine intakes and risk for nasopharyngeal carcinoma in Chinese adults: a matched case–control study

2015 ◽  
Vol 115 (1) ◽  
pp. 121-128 ◽  
Author(s):  
Fang-fang Zeng ◽  
Yuan-ting Liu ◽  
Xiao-ling Lin ◽  
Yu-ying Fan ◽  
Xing-lan Zhang ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Carbon Metabolism ◽  
Folate Intake ◽  
Dietary Vitamin ◽  
High Risk Population ◽  
Vitamin B ◽  
Toxic Substances ◽  
Chinese Adults ◽  
Dietary Folate ◽  
One Carbon Metabolism

AbstractMany studies have suggested that folate-related one-carbon metabolism-related nutrients may play a role in certain cancer risks, but few studies have assessed their associations with the risk for nasopharyngeal carcinoma (NPC). In this study, we investigated the association between four folate-related one-carbon metabolism-related nutrients (folate, vitamin B6, vitamin B12 and methionine) and NPC risk in Chinese adults. A total of 600 patients newly diagnosed (within 3 months) with NPC were individually matched with 600 hospital-based controls by age, sex and household type (urban v. rural). Folate, vitamin B6, vitamin B12 and methionine intakes were measured using a validated seventy-eight-item FFQ. A higher dietary folate or vitamin B6 intake was associated with a lower NPC risk after adjusting for potential confounders. The adjusted OR of NPC for quartiles 2–4 (v. 1) were 0·66 (95 % CI 0·48, 0·91), 0·52 (95 % CI 0·37, 0·74) and 0·34 (95 % CI 0·23, 0·50) (Ptrend<0·001) for folate and 0·72 (95 % CI 0·52, 1·00), 0·55 (95 % CI 0·39, 0·78) and 0·44 (95 % CI 0·30, 0·63) (Ptrend<0·001) for vitamin B6. No significant association with NPC risk was observed for dietary vitamin B12 or methionine intake. The risk for NPC with dietary folate intake was more evident in the participants who were not exposed to toxic substances than in those who were exposed (Pinteraction=0·014). This study suggests that dietary folate and vitamin B6 may be protective for NPC in a high-risk population.

Genetic Variation: Impact on Folate (and Choline) Bioefficacy

2010 ◽  
Vol 80 (45) ◽  
pp. 319-329 ◽  
Author(s):  
Allyson A. West ◽  
Marie A. Caudill
Keyword(s):  
Carbon Metabolism ◽  
Genetic Variants ◽  
Plasma Homocysteine ◽  
Water Soluble ◽  
Gene Interactions ◽  
Dietary Folate ◽  
Methyl Donors ◽  
Common Genetic Variants ◽  
One Carbon Metabolism ◽  
The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

scholarly journals Folate, DNA methylation and colo-rectal cancer

2003 ◽  
Vol 62 (2) ◽  
pp. 437-445 ◽  
Author(s):  
Maria Pufulete ◽  
Peter W. Emery ◽  
Thomas A. B. Sanders
Keyword(s):  
Dna Methylation ◽  
Rectal Cancer ◽  
Rectal Mucosa ◽  
Case Control ◽  
Folate Intake ◽  
Controlled Study ◽  
Rectal Adenoma ◽  
Dna Hypomethylation ◽  
Folate Supplementation ◽  
Rectal Neoplasia

Prospective cohort and case-control studies suggest an association between low folate intake and increased risk of colo-rectal adenoma and cancer. Some, but not all, animal studies indicate that folate supplementation protects against the development of colo-rectal neoplasms, although supraphysiological folate doses have been shown to enhance tumour growth. Folate is a methyl donor for nucleotide synthesis and biological methylation reactions, including DNA methylation. A low dietary folate intake may increase the risk of colo-rectal neoplasia by inducing genomic DNA hypomethylation, which can affect the expression of proto-oncogenes and tumour suppressor genes associated with the development of cancer. Common polymorphisms in genes involved in the methylation pathway, such as methylenetetrahydrofolate reductase and methionine synthase, have been shown to influence risk of colo-rectal neoplasia, with interactions dependent on folate status and/or alcohol intake, which is known to antagonise methyl group availability. There is some evidence to show that DNA from normal-appearing colo-rectal mucosa in individuals with colo-rectal cancer is hypomethylated. In a case-control study DNA methylation in normal-appearing colo-rectal mucosa has been shown to be lower in individuals with colo-rectal cancer (P=0.08) and colo-rectal adenoma (P=0.009) than in controls free of colo-rectal abnormalities. Human intervention trials to date suggest that supraphysiological doses of folate can reverse DNA hypomethylation in colo-rectal mucosa of individuals with colo-rectal neoplasia. In a double-blind randomised placebo-controlled study folate supplementation at physiological doses has been shown to increase DNA methylation in leucocytes (P=0.05) and colonic mucosa (P=0.09). Further studies are required to confirm these findings in larger populations and to define abnormal ranges of DNA methylation.

scholarly journals Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, intakes of folate and related B vitamins and colorectal cancer: a case–control study in a population with relatively low folate intake

2008 ◽  
Vol 99 (2) ◽  
pp. 379-389 ◽  
Author(s):  
Linda Sharp ◽  
Julian Little ◽  
Nigel T. Brockton ◽  
Seonaidh C. Cotton ◽  
Lindsey F. Masson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Carbon Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Case Control Study ◽  
Case Control ◽  
B Vitamins ◽  
Folate Intake ◽  
Vitamin B ◽  
One Carbon Metabolism ◽  
Control Study

Folate is key in one-carbon metabolism, disruption of which can interfere with DNA synthesis, repair, and methylation. Efficient one-carbon metabolism requires other B vitamins and the optimal activity of enzymes including 5,10-methylenetetrahydrofolate reductase (MTHFR). We report a population-based case–control study of folate intake, related dietary factors andMTHFRpolymorphisms (C677T, A1298C) and colorectal cancer in a population with relatively high colorectal cancer incidence and relatively low folate intake. A total of 264 cases with histologically confirmed incident colorectal cancer and 408 controls participated. There was no clear trend in risk with reported intakes of total, or dietary, folate, riboflavin, vitamin B12or vitamin B6, nor were there interactions between folate intake and the other B vitamins or alcohol. For C677T, risk decreased with increasing variant alleles (multivariate OR for CTv.CC = 0·77 (95 % CI 0·52, 1·16); OR for TTv.CC = 0·62 (95 % CI 0·31, 1·24)), which, although not statistically significant, was consistent with previous studies. For A1298C, compared with AA subjects, CC subjects had modest, non-significant, reduced risk (multivariate OR = 0·81 (95 % CI 0·45, 1·49)). There were significant interactions between total folate and C677T (P = 0·029) and A1298C (P = 0·025), and total vitamin B6and both polymorphisms (C677T,P = 0·016; A1298C,P = 0·033), although the patterns observed differed from previous studies. Seen against the setting of low folate intake, the results suggest that the role of folate metabolism in colorectal cancer aetiology may be more complex than previously thought. Investigation of particular folate vitamers (for example, tetrahydrofolate, 5,10-methylenetetrahydrofolate) may help clarify carcinogenesis pathways.

scholarly journals Formate metabolism in fetal and neonatal sheep

2015 ◽  
Vol 308 (10) ◽  
pp. E921-E927 ◽  
Author(s):  
Shannon E. Washburn ◽  
Marie A. Caudill ◽  
Olga Malysheva ◽  
Amanda J. MacFarlane ◽  
Nathalie A. Behan ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
Carbon Metabolism ◽  
Maternal Plasma ◽  
Nucleotide Synthesis ◽  
Fetal Sheep ◽  
Vitamin Deficiencies ◽  
Cellular Events ◽  
High Concentrations ◽  
One Carbon Metabolism ◽  
Formate Metabolism

By virtue of its role in nucleotide synthesis, as well as the provision of methyl groups for vital methylation reactions, one-carbon metabolism plays a crucial role in growth and development. Formate, a critical albeit neglected component of one-carbon metabolism, occurs extracellularly and may provide insights into cellular events. We examined formate metabolism in chronically cannulated fetal sheep (gestation days 119–121, equivalent to mid-third trimester in humans) and in their mothers as well as in normal full-term lambs. Plasma formate levels were much higher in fetal lamb plasma and in amniotic fluid (191 ± 62 and 296 ± 154 μM, respectively) than in maternal plasma (33 ± 13 μM). Measurements of folate, vitamin B12, and homocysteine showed that these high formate levels could not be due to vitamin deficiencies. Elevated formate levels were also found in newborn lambs and persisted to about 8 wk of age. Formate was also found in sheep milk. Potential precursors of one-carbon groups were also measured in fetal and maternal plasma and in amniotic fluid. There were very high concentrations of serine in the fetus (∼1.6 mM in plasma and 3.5 mM in the amniotic fluid) compared with maternal plasma (0.19 mM), suggesting increased production of formate; however, we cannot rule out decreased formate utilization. Dimethylglycine, a choline metabolite, was also 30 times higher in the fetus than in the mother.

scholarly journals Folate supplementation differently affects uracil content in DNA in the mouse colon and liver

2011 ◽  
Vol 105 (5) ◽  
pp. 688-693 ◽  
Author(s):  
Kyong-Chol Kim ◽  
Hyeran Jang ◽  
Julia Sauer ◽  
Ella M. Zimmerly ◽  
Zhenhua Liu ◽  
...  
Keyword(s):  
Mutagenic Effect ◽  
Folate Intake ◽  
Folate Supplementation ◽  
Mean Values ◽  
Dietary Folate ◽  
Mouse Colon ◽  
Risk Of Cancer ◽  
Old Mice ◽  
Liver Folate ◽  
Young Mice

High folate intake may increase the risk of cancer, especially in the elderly. The present study examined the effects of ageing and dietary folate on uracil misincorporation into DNA, which has a mutagenic effect, in the mouse colon and liver. Old (18 months; n 42) and young (4 months; n 42) male C57BL/6 mice were pair-fed with four different amino acid-defined diets for 20 weeks: folate deplete (0 mg/kg diet); folate replete (2 mg/kg diet); folate supplemented (8 mg/kg diet); folate deplete (0 mg/kg diet) with thymidine supplementation (1·8 g/kg diet). Thymidylate synthesis from uracil requires folate, but synthesis from thymidine is folate independent. Liver folate concentrations were determined by the Lactobacillus casei assay. Uracil misincorporation into DNA was measured by a GC/MS method. Liver folate concentrations demonstrated a stepwise increase across the spectrum of dietary folate levels in both old (P = 0·003) and young (P < 0·001) mice. Uracil content in colonic DNA was paradoxically increased in parallel with increasing dietary folate among the young mice (P trend = 0·033), but differences were not observed in the old mice. The mean values of uracil in liver DNA, in contrast, decreased with increasing dietary folate among the old mice, but it did not reach a statistically significant level (P < 0·1). Compared with the folate-deplete group, thymidine supplementation reduced uracil misincorporation into the liver DNA of aged mice (P = 0·026). The present study suggests that the effects of folate and thymidine supplementation on uracil misincorporation into DNA differ depending on age and tissue. Further studies are needed to clarify the significance of increased uracil misincorporation into colonic DNA of folate-supplemented young mice.

scholarly journals Folate supplementation increases genomic DNA methylation in the liver of elder rats

2005 ◽  
Vol 93 (1) ◽  
pp. 31-35 ◽  
Author(s):  
Sang-Woon Choi ◽  
Simonetta Friso ◽  
Mary K. Keyes ◽  
Joel B. Mason
Keyword(s):  
Dna Methylation ◽  
Animal Model ◽  
Genomic Dna ◽  
Folate Supplementation ◽  
Dietary Folate ◽  
Time Points ◽  
Wide Range ◽  
Old Rats ◽  
The Relationship ◽  
Liver Folate

The availability of folate is implicated as a determinant of DNA methylation, a functionally important feature of DNA. Nevertheless, when this phenomenon has been examined in the rodent model, the effect has not always been observed. Several reasons have been postulated for the inconsistency between studies: the rodent is less dependent on folate as a methyl source than man; juvenile animals, which most studies use, are more resistant to folate depletion than old animals; methods to measure genomic DNA methylation might not be sensitive enough to detect differences. We therefore examined the relationship between folate and genomic DNA methylation in an elder rat model with a newly developed method that can measure genomic DNA methylation sensitively and precisely. Thirty-nine 1-year-old rats were divided into three groups and fed a diet containing 0, 4·5 or 18 μmol folate/kg (folate-deplete, -replete and -supplemented groups, respectively). Rats were killed at 8 and 20 weeks. At both time points, mean liver folate concentrations increased incrementally between the folate-deplete, -replete and -supplemented rats (Pfor trend <0·001) and by 20 weeks hepatic DNA methylation also increased incrementally between the folate-deplete, -replete and -supplemented rats (Pfor trend=0·025). At both time points folate-supplemented rats had significantly increased levels of DNA methylation compared with folate-deplete\ rats (P<0·05). There was a strong correlation between hepatic folate concentration and genomic DNA methylation in the liver (r0·48,P=0·004). In the liver of this animal model, dietary folate over a wide range of intakes modulates genomic DNA methylation.

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