title: Nicotinamide megadosing increases hepatic poly(ADP-ribose) levels in choline-deficient rats.
abstract: Previous work in our laboratory has shown that dietary megadoses of nicotinamide, used in the prevention of diabetes, cause increases in hepatic poly(ADP-ribose). Poly(ADP-ribose) is synthesized from NAD+ by a nuclear enzyme, poly(ADP-ribose)polymerase, which is activated by DNA strand breaks. The nicotinamide-induced increase in poly(ADP-ribose) could result from an increase in substrate, NAD+, or the induction of strand breaks in DNA. Strand breaks may result from the depletion of single carbon groups, through the excretion of methylated derivatives of nicotinamide. To differentiate between these mechanisms, a 3 x 3 factorial experiment was conducted in which rats were fed diets containing various supplements of choline bitartrate (0, 2, 20 g/kg diet) and nicotinamide (0, 1, 2 g/kg diet). At the conclusion of treatments, blood NAD+ and liver lipid, NAD+ and poly(ADP-ribose) levels were determined. Choline deficiency caused the characteristic accumulation of fat in the liver at all levels of nicotinamide. In choline deficient rats, nicotinamide supplements further increased liver lipid concentration. Blood and liver NAD+ concentrations were increased by nicotinamide supplementation, irrespective of choline status. In contrast, liver poly(ADP-ribose) levels were increased by nicotinamide supplementation only in choline deficient rats. These results show that nicotinamide-induced increases in poly(ADP-ribose) levels appear to be dependent on decreased methyl donor status and suggest that adequate choline status is important for preventing some deleterious effects of nicotinamide treatment.
authors.affiliation: Department of Nutritional Sciences, University of Guelph, Ontario, Canada.
authors.forename: M M
authors.initials: MM
authors.lastname: ApSimon
authors.forename: J M
authors.initials: JM
authors.lastname: Rawling
authors.forename: J B
authors.initials: JB
authors.lastname: Kirkland
mesh_terms: D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D002794:Choline / Q000008:administration & dosage / Q000494:pharmacology; D002796:Choline Deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005527:Food, Fortified; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000494:pharmacology; D009243:NAD / Q000032:analysis / Q000097:blood / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000494:pharmacology*; D011064:Poly Adenosine Diphosphate Ribose / Q000032:analysis / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D009243:NAD; D009536:Niacinamide; D011064:Poly Adenosine Diphosphate Ribose; D008715:Methionine; D002794:Choline