![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Rowett Research Institute, Aberdeen, United Kingdom
3To whom correspondence should be addressed. E-mail: sd{at}rri.sari.ac.uk.
 |
ABSTRACT |
|---|
 TOP ABSTRACT Folate and cancerFolate deficiency and mechanisms...DISCUSSIONLITERATURE CITED |
|---|
KEY WORDS: • folate • DNA stability • methylation • nutrition
|
Folate and cancer |
|---|
|
TOPABSTRACTFolate and cancerFolate deficiency and mechanisms...DISCUSSIONLITERATURE CITED |
|---|
,2
). Although there is little real consensus as to the positive dietary risk factors for cancer (e.g., meat, fat and alcohol intake) in >80% of epidemiological case-control studies, consumption of fruits and vegetables is associated with a decreased risk (2
). Folate is one of many compounds or components of fruits and vegetables that could be acting as a cytoprotective agent. Folate deficiency is common in developed countries and may affect a substantial percentage of the population, especially in low socioeconomic groups (3
,4
).
Folate deficiency has been implicated in the etiology of lung, cervical, breast and brain cancer. Convincing evidence links folate deficiency with colorectal cancer incidence. Colorectal cancer incidence is inversely associated with both dietary folate intake and blood cell folate concentrations (5
). Moreover, the use of folate supplements has been reported to reduce cancer risk (6
).
|
Folate deficiency and mechanisms of DNA instability |
|---|
|
TOPABSTRACTFolate and cancerFolate deficiency and mechanisms...DISCUSSIONLITERATURE CITED |
|---|
). The first is through altered DNA methylation. Folate, in the form of 5-methyltetrahydrofolate (5-methyl THF)4
, serves as methyl donor in the remethylation of homocysteine to methionine, which in turn is converted to S-adenosylmethionine (SAM).SAM methylates specific cytosines in DNA, and this regulates gene transcription. As a consequence of folate deficiency, cellular SAM is depleted, which in turn induces DNA hypomethylation and potentially induces proto-oncogene expression leading to cancer (7
). The second pathway through which folate may alter DNA stability has received less attention. Folate, as 5,10 methylene THF, donates a methyl group to uracil converting it to thymine, which is used for DNA synthesis and repair. However, if folate is limiting, uracil misincorporation into DNA may occur. This in itself is mutagenic, but DNA instability also may occur via a different mechanism. As the cell attempts to repair itself, it breaks the DNA molecule to excise the uracil. If folate is continually limited, imbalances in deoxynucleotide triphosphates in the precursor pool occur. Uracil is misincorporated and repaired in what is termed "a catastrophic repair cycle," which may lead to double-strand breaks, chromosomal damage and cancer (8
). Evidence from several in vitro and animal and human studies in vivo support the hypothesis that folates maintain DNA stability and prevent cancer. Selected areas will be reviewed here, with emphasis on work from our laboratory.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTFolate and cancerFolate deficiency and mechanisms...DISCUSSIONLITERATURE CITED |
|---|
Cell culture models provide a well defined, relatively simple and easily manipulated experimental system in which to investigate the ability of folate to modulate DNA stability and gene expression. DNA strand breakage, chromosomal aberrations (breaks, gaps and fragments) and apoptosis are induced in Chinese hamster ovary (CHO) cells cultured in folate-deficient media (9
–11
). The cellular deoxyuridine monophosphate (dUTP):deoxythymidine triphosphate (dTTP) DNA precursor pool ratio is altered significantly in folate-deficient CHO cells, whereas spontaneous and chemically induced hypoxanthine-guanine phosphoribosyltransferase gene mutation frequency is increased (10
,11
). Uracil is increased in DNA from human lymphoid HL60 cells, normal human lymphocytes and repair-deficient CHO cells (CHO-UV5) grown in folate-deficient medium (12
,13
). Folate-deficient CHO-UV5 cells, subsequently repleted with vitamin B, undergo malignant transformation (13
). Folate deficiency in vitro alters normal DNA replication, progressively inhibiting both normal human colonocyte and stimulated lymphocyte growth (14
,15
). More importantly, folate deficiency increases uracil misincorporation (measured using single-cell gel electrophoresis) two- to threefold in these cells (Fig. 2
). This negative effect of folate deficiency on DNA stability is concentration dependent, with decreasing levels of folate both inhibiting cell proliferation and inducing uracil misincorporation progressively. DNA instability is induced at concentrations of folate (1–10 µ g/L) found in human plasma, suggesting that levels of folate that are adequate to prevent overt deficiency may not be optimal in maintaining DNA stability. Folate deficiency also impairs DNA repair processes, thus reducing the capacity of the cell to repair its DNA in response to oxidative or alkylation damage (15
,16
). Folate-deficient human colonocytes exposed to hydrogen peroxide or methyl methanesulfonate, an alkylating agent, are unable to repair DNA strand breakage as efficiently as folate-sufficient cells (Fig. 3
). Initial damage is similar for both groups, only subsequent nucleotide excision repair is negatively affected. This inefficient repair of oxidative and alkylation damage is meaningful considering that folate-deficient diets probably also are poor in antioxidants and other micronutrients that protect against oxidative and alkylation damage.
|
|
). It remains to be established whether gene expression or even malignant transformation is altered in these model systems. Animal models
Does folate deficiency in vivo have the same effects as in cultured cells? Obviously, the model systems employed here are more complex, and the conclusions that can be drawn from the literature are less clear.
Red blood cell micronuclei levels are increased in mice made folate deficient over a period of several weeks (17
). Methyl donor deficiency in rats increases the hepatic ratio of dUTP to dTTP threefold, induces DNA strand breakage in hepatic p53 and in genomic DNA from splenic lymphocytes and liver and upregulates apoptosis (18
–20
). Uracil misincorporation is increased in the liver of methyl-deficient or combined hepatectomized and methotrexate-treated rats (21
). In a recent experiment in our laboratory (22
), rats were fed a control diet (group A) or a diet deficient in folate alone (group B) or deficient in the methyl donors choline and methionine (group C). Animals in group D were deficient in all three compounds. Feeding the rats a folate-free diet for 10 wk caused a 50% decrease in plasma folate and an 
25% decrease both in red blood cell and liver folate, both regarded as folate stores. DNA strand breakage was increased progressively from 0 to 4 to 8 wks in rats fed any of the experimental diets. The greatest effect was observed in the combined deficiency group indicating that, at least for DNA strand breaks, the effect of methyl donor deficiency may be relatively nonspecific (22
). This is in direct contrast with the effect of methyl donor deficiency on uracil misincorporation, where only the rats made folate deficient (groups B and D) showed a progressive increase in lymphocyte uracil concentrations (Fig. 4
). Strangely, the increase in uracil misincorporation in the combined deficiency group lagged behind the purely folate-deficient group. Possibly the combined deficiency was so severe in this group that apoptosis was induced in the lymphocytes. Circulating lymphocyte numbers were halved in this group compared with controls (193 ± 5.5 x 104/mL in folate-deficient rats compared with 288 ± 14.3 x 104/mL in control animals). In the same study, methyl deficiency in general increased DNA strand breakage in rat colonocytes isolated by enzyme digestion. Conversely, uracil misincorporation in colonocytes was not altered by either folate or methyl donor deficiency (Fig. 5
). Why this should be the case remains to be established. Endogenous levels of uracil DNA glycosylase are highest in actively proliferating cells (23
), raising questions of differential repair and tissue susceptibility and, most importantly, of whether lymphocytes really can be used as a surrogate for target tissues in biomonitoring.
|
|
,25
). Conversely, a moderate folate deficiency either produces no effect on global DNA methylation (liver or colon) or only very specific changes in particular proto-oncogenes (26
,27
). We have found that colonocyte global DNA methylation status is unaffected by folate and/or methyl deficiency (28
). This was the same for liver and lymphocyte DNA. Studies with human subjects
The crucial question, however, is, "Can folate alter DNA stability in humans?" Certain studies have reported that blood cell micronuclei levels are elevated in subjects with low blood folate and vitamin B-12 levels (29
) but can be reduced following supplementation with folic acid (29
,30
). However, in subjects with normal blood levels, micronuclei frequency appears to be unrelated to folate status (31
). Small but detectable levels of uracil are found in leukocyte DNA from subjects with normal plasma and erythrocyte folate levels (14
,30
), whereas uracil misincorporation is elevated in patients with megaloblastic anemia (32
) and in folate-deficient individuals (30
). As in rats, the effect of folate on DNA methylation in humans is unclear. Jacob et al. (33
) reported that dietary folate depletion caused global DNA methylation in lymphocytes isolated from postmenopausal women. This was reversible upon folate repletion (33
). Conversely, there was no significant association between blood folate and DNA methylation status prior to or following supplementation with folic acid in other human studies (31
,34
). The scenario becomes even more complex when the influence of human genetic polymorphisms in folate-metabolizing enzymes is taken into consideration. 5,10-Methylenetetrahydrofolate is converted to 5-methyltetrahydrofolate by the enzyme methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20). This enzyme is polymorphic with 10–15% of the population homozygous for a mutation termed C677T (a cytosine-to-thymine transition at position 677), which decreases the efficiency of the enzyme (35
). The extent to which uracil misincorporation and/or DNA methylation influence colorectal cancer risk may be established by investigating DNA stability in individuals with these various polymorphisms. It might be expected that, for homozygous variants with reduced enzyme activity, 5-methyltetrahydrofolate and SAM levels would be decreased and DNA hypomethylation would increase cancer risk. Alternatively, the homozygous mutation might cause accumulation of 5,10-methylenetetrahydrofolate, which would drive the reaction toward thymidine synthesis. This would suggest a decreased risk of colorectal cancer in this group (Fig. 6
). Individuals homozygous for the C677T mutation appear to be at reduced risk of colorectal cancer compared with homozygous wild-type or heterozygote individuals (35
), suggesting that chemoprotection occurs via decreased uracil misincorporation into DNA. Surprisingly, uracil misincorporation into human lymphocyte DNA following folate depletion (at least in vitro) is similar for all genotypes (36
). Moreover, mice deficient in MTHFR (homozygous variants and heterozygotes) exhibit tissue-specific decreased methylation capacity (37
), whereas peripheral leukocytes from human subjects homozygous for the C677T polymorphism have a significantly higher methyl group acceptance capacity compared with homozygous wild types (38
).
|
Moreover, there may be other ways, in addition to the two mechanisms described here, through which folate may prevent human cancers. Recent studies suggest that several folates can act directly as strong antiproliferative agents inhibiting gastric mucosal cell hyperproliferation and malignant transformation (39
,40
). Tyrosine kinase activity, epidermal growth factor receptor expression and colon cancer cell growth are all inhibited in vitro following exposure to specific folates (39
,40
). Also, folate has antioxidant properties, scavenging several reactive oxygen species in vitro and inhibiting lipid peroxidation in rat microsomes (41
). Thus, folate could modulate heart disease by inhibiting low density lipoprotein oxidation in humans. Could folate similarly protect the genome by inhibiting free radical attack against DNA oxidative damage, for example by reducing 8-hydroxydeoxyguanosine levels and decreasing mutagenesis? Certainly in the experimental systems that we have used this does not appear to be the case. Oxidized pyrimidine levels were unaffected in human lymphocytes made folate deficient in vitro (14
). Similarly, in the rat model described earlier, folate deficiency did not alter the extent of either oxidized purines or pyrimidines (22
).
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
2 This work was supported by to the Scottish Executive Environment and Rural Affairs Department and the World Cancer Research Fund.
4 Abbreviations used: C677T, cytosine-to-thymine transition at position 677; CHO cells, Chinese hamster ovary cells; CHO-UV5, repair deficient CHO cells; dTTP; deoxythymidine triphosphate; dUMP, deoxyuridine monophosphate; MTHFR, methylene+tetrahydrofolate reductase; 5,10-methylene THF, 5,10-methylenetetrahydrofolate; SAM, S-adenosylmethionine.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTFolate and cancerFolate deficiency and mechanisms...DISCUSSIONLITERATURE CITED |
|---|
1. Doll, R. & Peto, R. (1981) The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl. Cancer Inst. 66:1191-1308.
2. World Cancer Research Fund (1997) Food, Nutrition and the Prevention of Cancer: a Global Perspective 1997 American Institute of Cancer Research Washington, DC. .
3. Senti, R. F. & Pilch, S. M. (1985) Analysis of folate data from the 2nd National Health and Nutritional Examination Survey (NHANES-II). J. Nutr. 115:1398-1402.
4. Bailey, L. B, Wagner, P. A, Christakis, G. J, Davis, C. G, Appledorf, H, Araujo, P. E, Dorsey, E & Dinning, J. S () Folacin and iron status and haematological findings in black and Spanish-American adolescents from urban low-income households. Am. J. Clin. Nutr. 35:1023-1032.
5. Kim, Y. & Mason, J. B. (1995) Folate, epithelial dysplasia and colon cancer. Proc. Assoc. Am. Physicians 107:218-227.[Medline]
6. Lashner, B. A., Heidenrich, P. A., Su, G. L., Kane, S. V. & Hanauer, S. B. (1989) Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. Gastroenterology 97:255-259.[Medline]
7. Fang, J. Y., Zhu, S. S., Xiao, S. D., Jiang, S. J., Shi, Y., Chen, X. Y., Zhou, X. M. & Qian, L. F. (1996) Studies on the hypomethylation of c-myc, c-Ha-ras oncogenes and histopathological changes in human gastric carcinoma. J. Gastroenterol. Hepatol. 11:1079-1082.[Medline]
8. Reidy, J. A. (1988) Role of deoxyuridine incorporation and DNA repair in the expression of human chromosomal fragile sites. Mutat. Res. 211:215-220.
9. Branda, R. F. & Blickensderfer, D. B. (1993) Folate deficiency increases genetic damage by alkylating agents and 
-irradiation in Chinese hamster ovary cells. Cancer Res. 53:5401-5408.
10. Libbus, B. L., Borman, L. S., Ventrone, C. H. & Branda, R. F. (1990) Nutritional folate-deficiency in Chinese hamster ovary cells: chromosomal abnormalities associated with perturbations in nucleic acid precursors. Cancer Genet. Cytogenet. 46:231-242.[Medline]
11. James, S. J., Basnakian, A. G. & Miller, B. J. (1994) In vitro folate deficiency induces deoxynucleotide pool imbalances, apoptosis and mutagenesis in Chinese hamster ovary cells. Cancer Res. 54:5075-5080.
12. Wickramasinghe, S. N. & Fida, S. (1993) Misincorporation of uracil into the DNA of folate and B12-deficient HL60 cells. Eur. J. Haematol. 50:127-132.[Medline]
13. Melnyk, S., Pogribna, M., Miller, B. J., Basnakian, A. G., Pogribny, I. P. & James, S. J. (1999) Uracil misincorporation, DNA strand breaks and gene amplification are associated with tumorigenic cell transformation in folate deficient/repleted Chinese hamster ovary cells. Cancer Lett. 146:35-44.[Medline]
14. Duthie, S. J. & Hawdon, A. (1998) DNA stability (strand breakage, uracil misincorporation and defective repair) is increased by folic acid depletion in human lymphocytes in vitro. FASEB J. 12:1491-1497.
15. Duthie, S. J., Narayanan, S., Blum, S., Pirie, L. & Brand, G. (2000) Folate deficiency in vitro induces uracil misincorporation and DNA hypomethylation and inhibits DNA excision repair in immortalised normal human colon epithelial cells. Nutr. Cancer 37:245-251.[Medline]
16. Choi, S. W., Kim, Y. I., Weitzel, J. N. & Mason, J. B. (1998) Folate depletion impairs DNA excision repair in the colon of the rat. Gut 43:93-99.
17. MacGregor, J. T., Schlegel, R., Wehr, C. M., Alperin, P. & Ames, B. N. (1990) Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine. Proc. Natl. Acad. Sci. USA 87:9962-9965.
18. Pogribny, I. P., Basnakian, A. G., Miller, B. J., Lopatina, N. G., Poirier, L. A. & James, S. J. (1995) Breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl-deficient rats. Cancer Res. 55:1894-1901.
19. James, S. J. & Yin, L. (1989) Diet-induced DNA damage and altered nucleotide metabolism in lymphocytes from methyl-deficient rats. Carcinogenesis 10:1209-1214.
20. James, J. S., Miller, B. J., Basnakian, A. G., Pogribny, I. P., Pogribna, M. & Muskhelishvili, L. (1997) Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats. Carcinogenesis 18:287-293.
21. Blount, B. C. & Ames, B. N. (1994) Analysis of uracil in DNA by gas chromatography-mass spectrometry. Anal. Biochem. 219:195-200.[Medline]
22. Duthie, S. J., Grant, G. & Narayanan, S. (2000) Increased uracil misincorporation in lymphocytes from folate-deficient rats. Br. J. Cancer 83:1532-1537.[Medline]
23. Vilpo, J. A. & Autio-Harmainen, H. (1983) Uracil DNA glycosylase and deoxyuridine triphosphatase: studies of activity and subcellular location in human normal and malignant lymphocytes. Scand. J. Clin. Invest. 43:583-590.[Medline]
24. Wainfain, E. & Poirier, L. A. (1992) Methyl groups in carcinogenesis: effects on DNA methylation and gene expression. Cancer Res. 52:2071s-2077s.[Medline]
25. Balaghi, M. & Wagner, C. (1993) DNA methylation in folate deficiency: use of CpG methylase. Biochem. Biophys. Res. Commun. 193:1184-1190.[Medline]
26. Kim, Y. I., Christman, J. K., Fleet, J. C., Cravo, M. L., Salomon, R. N., Smith, D., Ordovas, J., Selhub, J. & Mason, J. B. (1995) Moderate folate deficiency does not cause global hypomethylation of hepatic and colonic DNA or c-myc-specific hypomethylation of colonic DNA in rats. Am. J. Clin. Nutr. 61:1083-1090.
27. Kim, Y. I., Pogribny, L. P., Salomon, R. N., Choi, S. W., Smith, D. E., James, S. J. & Mason, J. B. (1996) Exon-specific DNA hypomethylation of the p53 gene of rat colon induced by dimethylhydrazine: modulation by dietary folate. Am. J. Pathol. 149:1129-1137.[Abstract]
28. Duthie, S. J., Narayanan, S., Brand, G. M. & Grant, G. (2000) DNA stability and genomic methylation status in colonocytes isolated from methyl-donor-deficient rats. Eur. J. Nutr. 39:106-111.[Medline]
29. Everson, R. B., Wehr, C. M., Erexson, G. L. & MacGregor, J. T. (1988) Association of marginal folate depletion with increased human chromosomal damage in vivo: demonstration by analysis of micronucleated erythrocytes. J. Natl. Cancer Inst. 80:525-529.
30. Blount, B. C., Mack, M. M., Wehr, C. M., MacGregor, J. T., Hiatt, R. A., Wang, G., Wickramasinghe, S. N., Everson, R. B. & Ames, B. N. (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc. Natl. Acad. Sci. USA 94:3290-3295.
31. Fenech, M., Aitken, C. & Rinaldi, J. (1998) Folate vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis 19:1163-1171.
32. Wickramasinghe, S. N. & Fida, S. (1994) Bone marrow cells from vitamin B12- and folate-deficient patients misincorporate uracil into DNA. Blood 83:1656-1661.
33. Jacob, R. A., Gretz, D. M., Taylor, P. C., James, S. J., Pogribny, I. P., Miller, B. J., Henning, S. M. & Swendseid, M. E. (1998) Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J. Nutr. 128:1204-1212.
34. Cravo, M., Gloria, L., Salazar de Sousa, L., Chaves, P., Dias Pereira, A., Quina, M., Nobre Leitao, C. & Costa Mira, F. (1995) Folate status, DNA methylation and colon cancer risk in inflammatory bowel disease. Clin. Nutr. 14:50-53.
35. Ma, J., Stampfer, M. J., Giovannucci, E., Artigas, C., Hunter, D. J., Fuchs, C., Willett, W. C., Selhub, J., Hennekens, C. H. & Rozen, R. (1997) Methylenetetrahydrofolate reductase polymorphisms, dietary interactions, and risk of colorectal cancer. Cancer Res. 57:1098-1102.
36. Crott, J. W., Mashiyama, S. T., Ames, B. N. & Fenech, M. (2001) Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into human lymphocyte DNA in vitro. Carcinogenesis 22:1019-1025.
37. Chen, Z., Karaplis, A. C., Ackerman, S. L., Pogribny, I. P., Melnyk, S., Lussier-Cacan, S., Chen, M. F., Pai, A., John, S. W. & Smith, R. S. et al. (2001) Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum. Mol. Genet. 10:433-443.
38. Stern, L. L., Mason, J. B., Selhub, J. & Choi, S. W. (2000) Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol. Biomarkers Prev. 9:849-853.
39. Jaszewski, R., Khan, A., Sarkar, F. H., Kucuk, O., Tobi, M., Sagnoon, A., Dhar, R., Kinzie, J. & Majumdar, A. P. (1999) Folic acid inhibition of EGFR-mediated proliferation in human colon cancer cell lines. Am. J. Physiol. 277:C1142-C1148.
40. Akoglu, B., Faust, D., Milovic, V. & Stein, J. (2001) Folate and chemoprevention of colorectal cancer: is methyl-THF an active antiproliferative agent in folate-treated colon cancer cells?. Nutrition 17:652-653.[Medline]
41. Joshi, R., Adhikari, S., Patro, B. S., Chattopadhyay, S. & Mukherjee, T. (2001) Free radical scavenging behavior of folic acid: evidence for possible antioxidant activity. Free Radical Biol. Med. 30:1390-1399.[Medline]
42. Duthie, S. J. (1999) Folic acid and DNA stability. Br. Med. Bull. 55:578-592.
This article has been cited by other articles:
|
|
 |
|
  J. Lin, I-M. Lee, N. R Cook, J. Selhub, J. E Manson, J. E Buring, and S. M Zhang Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women Am. J. Clinical Nutrition, March 1, 2008; 87(3): 734 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-Y. Huang, B. Caballero, S. Chang, A. J. Alberg, R. D. Semba, C. R. Schneyer, R. F. Wilson, T.-Y. Cheng, J. Vassy, G. Prokopowicz, et al. The Efficacy and Safety of Multivitamin and Mineral Supplement Use To Prevent Cancer and Chronic Disease in Adults: A Systematic Review for a National Institutes of Health State-of-the-Science Conference Ann Intern Med, September 5, 2006; 145(5): 372 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Leopardi, F. Marcon, S. Caiola, A. Cafolla, E. Siniscalchi, A. Zijno, and R. Crebelli Effects of folic acid deficiency and MTHFR C677T polymorphism on spontaneous and radiation-induced micronuclei in human lymphocytes Mutagenesis, September 1, 2006; 21(5): 327 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Ulrich Nutrigenetics in Cancer Research--Folate Metabolism and Colorectal Cancer J. Nutr., November 1, 2005; 135(11): 2698 - 2702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Gori, A. M. Corsi, S. Fedi, A. Gazzini, F. Sofi, B. Bartali, S. Bandinelli, G. F. Gensini, R. Abbate, and L. Ferrucci A proinflammatory state is associated with hyperhomocysteinemia in the elderly Am. J. Clinical Nutrition, August 1, 2005; 82(2): 335 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J C Mathers Reversal of DNA hypomethylation by folic acid supplements: possible role in colorectal cancer prevention Gut, May 1, 2005; 54(5): 579 - 581. [Full Text] [PDF]
|
|
|
|
 |
|
 N. Di Simone, P. Riccardi, N. Maggiano, A. Piacentani, M. D'Asta, A. Capelli, and A. Caruso Effect of folic acid on homocysteine-induced trophoblast apoptosis Mol. Hum. Reprod., September 1, 2004; 10(9): 665 - 669. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Townsend, S. R. Davis, A. D. Mackey, and J. F. Gregory III Folate deprivation reduces homocysteine remethylation in a human intestinal epithelial cell culture model: role of serine in one-carbon donation Am J Physiol Gastrointest Liver Physiol, April 1, 2004; 286(4): G588 - G595. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zijno, C. Andreoli, P. Leopardi, F. Marcon, S. Rossi, S. Caiola, A. Verdina, R. Galati, A. Cafolla, and R. Crebelli Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects Carcinogenesis, June 1, 2003; 24(6): 1097 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. B Fallon Commentary: Colon cancer, folate and genetic status Int. J. Epidemiol., February 1, 2003; 32(1): 67 - 70. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
) or absence (
) of folic acid (4 mg/L) for up to 14 d. Values are mean ± SEM; n > 8, * P < 0.05 vs. absence of folic acid. SEM, standard error of the mean. Reprinted from reference (15
