Mitigation of gamma-radiation induced abasic sites in genomic DNA by dietary nicotinamide supplementation: Metabolic up-regulation of NAD+ biosynthesis

Abstract

The search for non-toxic radio-protective drugs has yielded many potential agents but most of these compounds have certain amount of toxicity. The objective of the present study was to investigate dietary nicotinamide enrichment dependent adaptive response to potential cytotoxic effect of 60Co γ-radiation. To elucidate the possible underlying mechanism(s), male Swiss mice were maintained on control diet (CD) and nicotinamide supplemented diet (NSD). After 6 weeks of CD and NSD dietary regimen, we exposed the animals to γ-radiation (2, 4 and 6Gy) and investigated the profile of downstream metabolites and activities of enzymes involved in NAD+ biosynthesis. Increased activities of nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase (NMNAT) were observed up to 48h post-irradiation in NSD fed irradiated mice. Concomitant with increase in liver NAMPT and NMNAT activities, NAD+ levels were replenished in NSD fed and irradiated animals. However, NAMPT and NMNAT-mediated NAD+ biosynthesis and ATP levels were severely compromised in liver of CD fed irradiated mice. Another major finding of these studies revealed that under γ-radiation stress, dietary nicotinamide supplementation might induce higher and long-lasting poly(ADP)-ribose polymerase 1 (PARP1) and poly(ADP-ribose) glycohydrolase (PARG) activities in NSD fed animals compared to CD fed animals. To investigate liver DNA damage, number of apurinic/apyrimidinic sites (AP sites) and level of 8-hydroxy-2′-deoxyguanosine (8-oxo-dG) residues were quantified. A significant increase in liver DNA AP sites and 8-oxo-dG levels with concomitant increase in caspase-3 was observed in CD fed and irradiated animals compared to NSD fed and irradiated mice. In conclusion present studies show that under γ-radiation stress conditions, dietary nicotinamide supplementation restores DNA excision repair activity via prolonged activation of PARP1 and PARG activities. Present results clearly indicated that hepatic NAD+ replenishment might be a novel and potent approach to reduce radiation injury.