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United States Department of Agriculture

Agricultural Research Service

Research Project: ONE-CARBON NUTRIENTS IN THE PREVENTION OF CANCER

Location: Human Nutrition Research Center on Aging

Title: Folate supplementation differently affects uracil content in DNA in the mouse colon and liver

Authors
item Kim, K.C. -
item Jang, H. -
item Zimmerly, E.H. -
item Liu, Z. -
item Chason, A. -
item Smith, D.E. -
item Frisco, S. -
item Choi, S.W. -

Submitted to: British Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: September 24, 2010
Publication Date: March 15, 2011
Citation: Kim, K., Jang, H., Zimmerly, E., Liu, Z., Chason, A., Smith, D., Frisco, S., Choi, S. 2011. Folate supplementation differently affects uracil content in DNA in the mouse colon and liver. British Journal of Nutrition. 105(5):688-693.

Interpretive Summary: High folate intake may increase the cancer risk especially in the elderly. This study examined the effects of aging and dietary folate on uracil misincorporation into DNA. Uracil is a precursor of thymidylate, which is a building block of DNA. Folate deficiency reduces the conversion of thymidylate from uracil, resulting in misincorporation of uracil into DNA where thymidylate should be. Misincorporated uracil causes the instability of DNA, which may induce cancer. In our young and old rodent study, in which animals were treated with three different dietary folate levels (folate deplete, folate replete and folate supplemented), the mean values of uracil in liver DNA decreased with increasing dietary folate among old mice but it did not reach a statistically significant level. In contrast, uracil content in colonic DNA was paradoxically increased in parallel with increasing dietary folate among young mice, but differences were not observed in the old mice. This study suggests that effects of folate and aging 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.

Technical Abstract: 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/kgdiet). Thymidylate synthesis from uracil requires folate, but synthesis from thymidine is folate independent. Liver folate concentrationswere 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 1/4 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 1/4 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 1/4 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.

Last Modified: 7/23/2014
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