Cleavage of folates during ethanol metabolism. Role of acetaldehyde/xanthine oxidase-generated superoxide

Shaw, Spencer; Jayatilleke, Elizabeth; Herbert, Victor; Colman, Neville

doi:10.1042/bj2570277

Cited by 162 publications

(65 citation statements)

References 23 publications

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“…Alcohol consumption leads to folate depletion, probably by decreasing intestinal absorption and hepatic uptake, 23) increasing renal excretion, 23) and cleaving folate. 25) The thymidylate synthesis pathway, rather than the process of DNA methylation, seems to be biologically linked with the protective association with the 677TT genotype. 11,12) Under a condition of sufficient folate, low activity of MTHFR leads to buildup of 5,10-methylentetrahydrofolate, which is required for conversion of uridylate to thymidylate.…”

Section: Discussionmentioning

confidence: 99%

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study

et al. 2004

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Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated the relation of MTHFR C677T and A1298C polymorphisms to colorectal cancer in a case-control study in Fukuoka, Japan. The subjects comprised 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly in the study area. The genotype was determined by the PCR-RFLP method using genomic DNA extracted from buffy coat. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for gender, age class, area, and alcohol use. The MTHFR 677TT genotype was associated with a statistically significant decrease in the risk with an adjusted odds ratio of 0.69 (95% confidence interval 0.51-0.93) compared with the 677CC and 677CT combined, and the decrease was most evident in individuals with no alcohol consumption. While the A1298C polymorphism showed no measurable association with the overall risk of colorectal cancer, the 1298CC genotype was associated with a statistically significant increase in the risk when alcohol consumption was high, and was also associated with an approximately 2-fold increase in the risk of each of proximal and distal colon cancer. The findings add to evidence that individuals with the MTHFR 677TT genotype have a decreased risk of colorectal cancer in the absence of folate depletion, suggesting a protective role of folate by ensuring a sufficient thymidylate pool for DNA synthesis. Because very few individuals had the 1298CC genotype, the findings regarding the A1298C polymorphism need careful interpretation and confirmation in larger studies. uch attention has recently been drawn to the role of folate metabolism in colorectal carcinogenesis.1, 2) Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism. It irreversibly converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is the major form of folate in blood.2) The substrate of MTHFR, 5,10-methylenetetrahydrofolate, is required for conversion of deoxyuridylate to thymidylate. Depletion of 5,10-methylenetetrahydrofolate results in uracil misincorporation into DNA, and removal of this abnormal base may lead to single and double strand breaks.3, 4) Furthermore, insufficient thymidylate can increase DNA misrepair, resulting in overall DNA damage in the cell.5) On the other hand, 5-methyltetrahydrofolate provides the methyl group for methylation of homocysteine to methionine. Imbalanced DNA methylation, i.e., global genomic hypomethylation and methylation of usually unmethylated CpG sites, has been implicated in colorectal carcinogenesis. [6][7][8] Two common functional polymorphisms are known in the MTHFR gene; one is the C677T polymorphism in exon 4, resulting in an alanine-to-valine substitution at codon 222, 9) and the other is the A1298C in exon 7, resulting in a substitution of glutamate with alanine at codon 429.10) Individuals who are homozygous for the vari...

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Section: Discussionmentioning

confidence: 99%

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study

et al. 2004

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“…The in¯uence of alcohol intake on tHcy has not yet been thoroughly studied. It has been proven that ethanol itself increases the blood tHcy levels because of inactivation of folate and slowing of remethylation of tHcy to methionine due to acetaldehyde oxidation (Shaw et al, 1989). The effects of alcohol may differ according to the prevailing type of alcoholic beverage consumed in the populations studied.…”

Section: Discussionmentioning

confidence: 99%

A population study of the influence of beer consumption on folate and homocysteine concentrations

2001

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Objective: Mild hyperhomocysteinemia is a signi®cant and independent risk factor for vascular diseases. Blood total homocysteine concentration (tHcy) is considered to be the product of an interaction between genetic and nutritional factors notably intake of folate, vitamin B 12 and pyridoxine. The aim of the study was to determine whether regular intake of beer containing large amount of folate and other vitamins in¯uences the tHcy blood concentrations. Design: Cross-sectional population-based survey. Setting: Adult population, residents of Pilsen (Czech Republic) and vicinity. Subjects: Population series included 292 males and 251 females aged 35 ± 65 y, mean age 53.4 y. All subjects were examined by a standard protocol for clinical, anthropometrical and laboratory estimations. Main outcome measures: tHcy was measured by high-pressure liquid chromatography with¯uorescent detection, blood folate and B 12 levels immunochemically using commercial kits. Results: Beer intake was associated with blood folate and vitamin B 12 concentrations positively and with tHcy concentration negatively. By categories of beer intake, subjects with intake of 1 l daily or more had signi®cantly lower tHcy and higher folate concentrations than those reporting lower daily beer intake. Conclusion: Moderate beer consumption may help to maintain the tHcy levels in the normal range due to high folate content. Folate from beer may thus contribute to the protective effect of alcohol consumption on cardiovascular disease in population with generally low folate intake from other nutrients.

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“…Ethanol and its metabolites can lower blood folate levels through several different mechanisms, such as promoting catabolism, inhibiting absorption and increasing excretion (Eichner and Hillman, 1971;Romero et Shaw et al, 1989). Methionine, an amino acid derived from protein, and folate are both essential for the production of S-adenosylmethionine (Cooper et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study

et al. 1999

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Summary 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 belowmedian 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.

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Cleavage of folates during ethanol metabolism. Role of acetaldehyde/xanthine oxidase-generated superoxide

Cited by 162 publications

References 23 publications

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study

A population study of the influence of beer consumption on folate and homocysteine concentrations

Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study

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