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Biochemical and Molecular Actions of Nutrients

Vitamin B-12 Deficiency Induces Anomalies of Base Substitution and Methylation in the DNA of Rat Colonic Epithelium¹

Sang-Woon Choi^*,2, Simonetta Friso, Haifa Ghandour, Pamela J. Bagley, Jacob Selhub and Joel B. Mason^*,**3

^* Vitamins and Carcinogenesis Laboratory and Vitamin Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston MA 02111; ^** Divisions of Clinical Nutrition and Gastroenterology, Tufts University School of Medicine, Boston, MA 02111; and Department of Clinical and Experimental Medicine, Policlinico G.B. Rossi, University of Verona, 37134 Verona, Italy

²To whom correspondence should be addressed. E-mail: sang.choi{at}tufts.edu.

Derangements of one-carbon metabolism can directly affect the integrity of the genome by producing inappropriate uracil insertion into DNA and by altering patterns of DNA methylation. Vitamin B-12, a one-carbon nutrient, serves as a cofactor in the synthesis of precursors of biological methylation and in nucleotide synthesis. We therefore examined whether vitamin B-12 deficiency can induce these molecular anomalies in the colonic mucosa of rats. Weanling male Sprague-Dawley rats (n = 30) were divided into 2 groups and fed either a vitamin B-12–deficient diet or a similar diet containing adequate amounts of the vitamin. Rats from each group were killed at 6 and 10 wk. Uracil misincorporation into DNA was measured by GC/MS and genomic DNA methylation was measured by LC/MS. Plasma vitamin B-12 concentrations in deficient rats were below detectable limits at 6 and 10 wk; in control rats, concentrations were 0.46 ± 0.07 and 0.42 ± 0.10 nmol/L at those times. Although the colon total folate concentration did not differ between the groups, the proportion that was methylfolate was marginally greater in the deficient rats at 10 wk (P = 0.05) compared with control, consistent with the "methylfolate trap" that develops during vitamin B-12 deficiency. After 10 wk, the colonic DNA of the deficient rats displayed a 35% decrease in genomic methylation and a 105% increase in uracil incorporation (P < 0.05). This vitamin B-12–deficient diet, which was of insufficient severity to cause anemia or illness, created aberrations in both base substitution and methylation of colonic DNA, which might increase susceptibility to carcinogenesis.

KEY WORDS: • vitamin B-12 • DNA methylation • uracil misincorporation • rats • colon

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