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Methionine, folate, vitamin B(6), vitamin B(12), niacin, and riboflavin intakes may be related to breast carcinogenesis. These associations may vary by breast cancer type. Using the prospective cohort Shanghai Women's Health Study (1997-2008) including 718 Chinese breast cancer cases, the authors evaluated baseline dietary intake of these factors and breast cancer risk and whether the associations varied by menopausal status and estrogen receptor (ER) and progesterone receptor (PR) status. They estimated associations using hazard ratios and 95% confidence intervals from Cox proportional hazards regression models and stratified analyses by menopausal status and ER/PR status. Lowest quantile of intake was used as the comparison group. For postmenopausal women, dietary intakes of methionine and B vitamins were not associated with breast cancer risk. For premenopausal women, higher intake of folate was associated with decreased breast cancer risk (hazard ratio = 0.58, 95% confidence interval: 0.34, 0.99 for the highest vs. lowest quintile of intake). Only niacin intake was associated with ER+/PR+ breast cancer risk (hazard ratio = 1.62, 95% confidence interval: 1.07, 2.46; P for trend = 0.04 for the highest vs. lowest quartile of intake). Findings support the hypothesis that high folate intake may reduce breast cancer risk and that the association may vary by menopausal and ER/PR status.
The effects of folate status and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism on the kinetics of homocysteine metabolism are unclear. We measured the effects of dietary folate restriction on the kinetics of homocysteine remethylation and synthesis in healthy women (20-30 y old) with the MTHFR 677 C/C or T/T genotypes (n = 9/genotype) using i.v. primed, constant infusions of [(13)C(5)]methionine, [3-(13)C]serine, and [(2)H(3)]leucine before and after 7 wk of dietary folate restriction (115 mug dietary folate equivalents/d). Dietary folate restriction significantly reduced folate status ( approximately 65% reduction in serum folate) in both genotypes. Total remethylation flux was not affected by dietary folate restriction, the MTHFR 677C-->T polymorphism, or their combination. However, the percentage of remethylation from serine was reduced approximately 15% (P = 0.031) by folate restriction in C/C subjects. Further, homocysteine synthesis rates of T/T subjects and folate-restricted C/C subjects were twice that of C/C subjects at baseline. In conclusion, elevated homocysteine synthesis is a cause of mild hyperhomocysteinemia in women with marginal folate status, particularly those with the MTHFR 677 T/T genotype.
Whether folate status and the methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism interact to affect methionine-cycle metabolite concentrations is uncertain. We evaluated the effects of dietary folate restriction on relations among folate status indices and plasma concentrations of methionine cycle metabolites in women with the MTHFR 677 C/C and T/T genotypes. Healthy, normohomocysteinemic women (n = 18; 20-30 y old) of adequate B vitamin status, and equally divided according to MTHFR 677C-->T genotype (9 C/C and 9 T/T) were recruited. Folate status indices and methionine cycle metabolites were measured in blood samples collected at baseline and after 7 wk of dietary folate restriction (115 microg dietary folate equivalents/d). Significant negative correlations between plasma total homocysteine concentrations and total or 5-methyl folate concentrations (P = 0.041 and 0.023, respectively) in RBCs were found only in T/T subjects. Formylated folates were detected in RBCs of T/T subjects only, and their abundance was predictive of plasma total homocysteine concentration despite no significant alteration by folate restriction. Plasma concentrations of S-adenosylmethionine and S-adenosylhomocysteine were not significantly affected by dietary folate restriction and the MTHFR 677 T/T genotype. In conclusion, plasma total homocysteine concentrations in subjects with the MTHFR 677 T/T genotype were inversely related to 5-methyl folate concentrations and directly related to formylated folate concentrations in RBCs, even though the latter were not significantly affected by moderate folate restriction.
An in vitro model of folate-deficient erythropoiesis has been developed using proerythroblasts isolated from the spleens of Friend virus-infected mice fed an amino acid-based, folate-free diet. Control proerythroblasts were obtained from Friend virus-infected mice fed the same diet plus 2 mg folic acid/kg diet. Our previous studies showed that, after 20 to 32 hours of culture in folate-deficient medium with 4 U/mL of erythropoietin, the folate-deficient proerythroblasts underwent apoptosis, whereas control erythroblasts survived and differentiated into reticulocytes over a period of 48 hours. The addition of folic acid or thymidine to the folate-deficient medium prevented the apoptosis of the folate-deficient erythroblasts, thereby implicating decreased thymidylate synthesis as the main cause of apoptosis in the folate-deficient erythroblasts. In the study reported here, we examined intracellular folate levels, uracil misincorporation into DNA, p53 and p21 proteins, and reticulocyte formation in erythroblasts cultured in folate-deficient or control medium. In all experiments, the folate-deficient erythroblasts cultured in folate-deficient medium gave results that varied significantly from folate-deficient erythroblasts cultured in control medium or control erythroblasts cultured in either folate-deficient or control media. Folate-deficient erythroblasts cultured in folate-deficient medium had marked decreases in all coenzyme forms of folate that persisted throughout culture, increased uracil misincorporation into DNA, persistent accumulations of p53 and p21, and decreased reticulocyte production but increased size of individual reticulocytes. A model of folate-deficient erythropoiesis based on apoptosis of late stage erythroblasts is presented. This model provides explanations for the clinical findings in megaloblastic anemia.
Glycine N-methyltransferase (GNMT) is inhibited by 5-methyltetrahydrofolate polyglutamate in vitro. It is believed to play a regulatory role in the synthesis de novo of methyl groups. We have used the amino-acid-defined diet of Walzem and Clifford [(1988) J. Nutr. 118, 1089-1096] to determine whether folate deficiency in vivo would affect GNMT activity, as predicted by the studies in vitro. Weanling male rats were fed on the folate-deficient diet or a folate-supplemented diet pair-fed to the deficient group. A third group was fed on the folate-supplemented diet ad libitum. Development of folate deficiency rapidly resulted in decreased levels of S-adenosylmethionine (SAM) and elevation of S-adenosylhomocysteine (SAH). The ratios of SAM to SAH were 1.8, 2.7 and 1.5 in the deficient group for weeks 2, 3 and 4 of the experiment, and the values were 9.7, 7.1 and 8.9 for the pair-fed control group and 10.3, 8.8 and 8.0 for the control group ad libitum fed. The activity of GNMT was significantly higher in the deficient group than in either of the two control groups at each time period. This was not due to increased amounts of GNMT protein, but reflected an increase in specific enzyme activity. Levels of folate in both the cytosol and mitochondria were severely lowered after only 2 weeks on the diet. The distribution of folate coenzymes was also affected by the deficiency, which resulted in a marked increase in the percentage of tetrahydrofolate polyglutamates in both cytosol and mitochondria and a very large decrease in cytosolic 5-methyltetrahydrofolate. The increased GNMT activity is therefore consistent with decreased folate levels and decreased inhibition of enzyme activity.
An amino acid-defined, folate-deficient diet was used to investigate the regulation of pancreatic glycine N-methyltransferase in vivo. This enzyme modulates the ratio of S-adenosylmethionine to S-adenosylhomocysteine and is inhibited by bound folate in vitro. Rats were fed either a folate-deficient diet, a folate-supplemented diet (pair-fed to the deficient group), or a folate supplemented diet ad libitum and measurements were made after 2, 3, and 4 wk. Folate concentrations were greatly reduced in the folate-deficient pancreas after only 2 wk and pancreatic glycine N-methyltransferase activity was elevated but the amount of immunologically measured enzyme protein was the same. The ratio of S-adenosylmethionine to S-adenosylhomocysteine was rapidly reduced in the deficient pancreas. This ratio was also reduced with age in the ad libitum control rats. The pancreas of deficient rats had more immature secretory granules and the ducts were devoid of secreted material.
Folate deficiency produces a marked decrease in the ratio of S-adenosylmethionine to S-adenosylhomocysteine. This ratio regulates the activity of many cellular methylation reactions including that of DNA. We used bacterial CpG methylase to evaluate the effect of folate deficiency on methylation of DNA from livers of weanling rats fed an amino acid-defined folate deficient diet. After 4 weeks, liver DNA from deficient animals was undermethylated compared with DNA from pair-fed control animals.
Previous studies have suggested that the metabolism of methyl groups is an important factor in the function of the exocrine pancreas. Ethionine, an inhibitor of cellular methylation reactions, produces hemorrhagic pancreatitis when administered to mice fed a choline-deficient diet. Glycine N-methyltransferase, an enzyme which regulates the ratio of S-adenosylmethionine to S-adenosylhomocysteine, is particularly abundant in the exocrine pancreas. Since de novo synthesis of methyl groups requires the participation of folate coenzymes, we investigated the effect of folate deficiency on pancreatic exocrine function. Rats were fed an amino acid-defined folate-deficient diet or the same diet supplemented with folate ad libitum. A third group received the folate supplemented diet pair-fed to the deficient group. After 3 and 5 wk, pancreatic amylase secretion was measured in perfused duodenal segments of anesthetized animals before and after cholecystokinin injection. Pancreatic secretion was significantly reduced in the deficient group compared with the pair-fed control group after 5 wk. These results indicate that severe folate deficiency impairs pancreatic exocrine function.