Niacin, poly(ADP-ribose) polymerase-1 and genomic stability

Nicotinic acid (NA) and nicotinamide (NAM), commonly called niacin, are the dietary precursors for NAD(+) (nicotinamide adenine dinucleotide), which i s required for DNA synthesis, as well as for the activity of the enzyme pol y(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) for which NAD(+) is the so le substrate. The enzyme PARP-1 is highly activated by DNA strand breaks du ring the cellular genotoxic stress response, is involved in base excision r epair, plays a role in p53 expression and activation, and hence, is thought to be important for genomic stability. In this review, first the absorption, metabolism of niacin to NAD(+), as we ll as the assessment of niacin status are discussed. Since NAD(+) is import ant for PARP-1 activity, various aspects of PARP-1 in relation to DNA synth esis and repair, and regulation of gene expression am addressed. This is fo llowed by a discussion on interactions between dietary methyl donor deficie ncy, niacin status, PARP-1 activity and genomic stability. In vitro studies show that PARP-1 function is impaired and genomic stabilit y decreased when cells are either depleted from NAD(+) or incubated with hi gh concentrations of NAM which is a PARP-1 inhibitor. In vitro as well as a nimal studies indicate that niacin deficiency increases,genomic instability especially in combination with genotoxic and oxidative stress. Niacin defi ciency may also increase the risk for certain tumors. Preliminary data sugg est that niacin supplementation may protect against UV-induced tumors of th e skin in mice, but data on similar preventive effects in humans are not av ailable. NAM has been shown in vitro to have an autioxidant activity compar able to that of ascorbic acid. Data on niacin status and genomic stability in vivo in humans are limited a nd yield ambiguous results. Therefore, no firm conclusions vith respect to optimal niacin intake are possible. As a consequence of oral niacin supplem entation, however, NAM levels in the body may increase, which may result in inhibition of PARP-1 and increased genomic instability. More studies are n eeded to define an optimal level of niacin nutriture in relation to genomic stability and tumorigenesis. (C) 2001 Elsevier Science B.V. All rights res erved.