Effects of vitamin B12 and folate deficiencies on DNA methylation and carcinogenesis in rat liver.
Deficiencies of the major dietary sources of methyl groups, methionine and choline, lead to the formation of liver cancer in rodents. The most widely investigated hypothesis has been that dietary methyl insufficiency results in abnormal DNA methylation. Vitamin B12 and folate also play important roles in DNA methylation since these two coenzymes are required for the synthesis of methionine and S-adenosyl methionine, the common methyl donor required for the maintenance of methylation patterns in DNA. The aim of this study was to review the effects of methyl-deficient diets on DNA methylation and liver carcinogenesis in rats, and to evaluate the role of vitamin B12 status in defining carcinogenicity of a methyl-deficient diet. Several studies have shown that a methyl-deficient diet influences global DNA methylation. Evidence from in vivo studies has not clearly established a link between vitamin B12 and DNA methylation. We reported that vitamin B12 and low methionine synthase activity were the two determinants of DNA hypomethylation. Choline- or choline/methionine-deficient diets have been shown to cause hepatocellular carcinoma in 20-50% of animals after 12-24 months. In contrast, the effect of vitamin B12 withdrawal, in addition to choline, methionine and folate, induced hepatocellular carcinoma in less than 5% of rats.
Brunaud
Laurent
L
Laboratory of Cell and Molecular Pathology in Nutrition, INSERM EMI 0014 Medical Faculty, University of Nancy I, Vandoeuvre lès Nancy, France. lbrunaud@planete.net
Alberto
Jean-Marc
JM
Ayav
Ahmet
A
Gérard
Philippe
P
Namour
Farès
F
Antunes
Laurent
L
Braun
Marc
M
Bronowicki
Jean-Pierre
JP
Bresler
Laurent
L
Guéant
Jean-Louis
JL
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage; D002794:Choline / Q000008:administration & dosage; D002796:Choline Deficiency / Q000378:metabolism / Q000503:physiopathology; D019175:DNA Methylation; D004032:Diet; D005494:Folic Acid Deficiency / Q000378:metabolism / Q000503:physiopathology*; D005743:Gastrectomy; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008715:Methionine / Q000008:administration & dosage / Q000172:deficiency / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D014806:Vitamin B 12 Deficiency / Q000378:metabolism / Q000503:physiopathology*
D002273:Carcinogens; D008715:Methionine; D002794:Choline