MALE-RATS FED METHYL-DEFICIENT AND FOLATE-DEFICIENT DIETS WITH OR WITHOUT NIACIN DEVELOP HEPATIC CARCINOMAS ASSOCIATED WITH DECREASED TISSUE NAD CONCENTRATIONS AND ALTERED POLY(ADP-RIBOSE) POLYMERASE-ACTIVITY

Folate is an essential cofactor in the generation of endogenous methio nine, and there is evidence that folate deficiency exacerbates the eff ects of a diet low in choline and methionine, including alterations in poly(ADP-ribose) polymerase (PARP) activity, an enzyme associated wit h DNA replication and repair. Because PARR requires NAD as its substra te, we postulated that a deficiency of both folate and niacin would en hance the development of liver cancer in rats fed a diet deficient in methionine and choline. In two experiments, rats were fed choline- and folate-deficient, low methionine diets containing either 12 or 8% cas ein (12% MCFD, 8% MCFD) or 6% casein and 6% gelatin with niacin (MCFD) or without niacin (MCFND) and were compared with folate-supplemented controls. Liver NAD concentrations were lower in all methyl-deficient rats after 2-17 mo. At 17 mo, NAD concentrations in other tissues of r ats fed these diets were also lower than in controls. Compared with co ntrol values, liver PARP activity was enhanced in rats fed the 12% MCF D diet but was lower in MCFND-fed rats following a further reduction i n liver NAD concentration. These changes in PARR activity associated w ith lower NAD concentrations may slow DNA repair and enhance DNA damag e. Only rats fed the MCFD and MCFND diets developed hepatocarcinomas a fter 12-17 mo. In Experiment 2, hepatocarcinomas were found in 100% of rats fed the MCFD and MCFND diets. These preliminary results indicate that folic acid deficiency enhances tumor development. Because tumors developed in 100% of the MCFD-fed rats and because tissue concentrati ons of NAD in these animals were also low, further studies are needed to clearly define the role of niacin in methyl-deficient rats.