Hageman G J, Stierum R H
Department of Health Risk Analysis and Toxicology, University of Maastricht, 6200 MD, Maastricht, The Netherlands. ghageman@
Mutat Res. 2001 Apr 18;475(1-2):45-56. doi: 10.1016/s0027-5107(01)00078-1.
Nicotinic acid (NA) and nicotinamide (NAM), commonly called niacin, are the dietary precursors for NAD(+) (nicotinamide adenine dinucleotide), which is required for DNA synthesis, as well as for the activity of the enzyme poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) for which NAD(+) is the sole substrate. The enzyme PARP-1 is highly activated by DNA strand breaks during the cellular genotoxic stress response, is involved in base excision repair, 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 well as the assessment of niacin status are discussed. Since NAD(+) is important for PARP-1 activity, various aspects of PARP-1 in relation to DNA synthesis and repair, and regulation of gene expression are addressed. This is followed by a discussion on interactions between dietary methyl donor deficiency, niacin status, PARP-1 activity and genomic stability. In vitro studies show that PARP-1 function is impaired and genomic stability decreased when cells are either depleted from NAD(+) or incubated with high concentrations of NAM which is a PARP-1 inhibitor. In vitro as well as animal studies indicate that niacin deficiency increases genomic instability especially in combination with genotoxic and oxidative stress. Niacin deficiency may also increase the risk for certain tumors. Preliminary data suggest that niacin supplementation may protect against UV-induced tumors of the skin in mice, but data on similar preventive effects in humans are not available. NAM has been shown in vitro to have an antioxidant activity comparable to that of ascorbic acid. Data on niacin status and genomic stability in vivo in humans are limited and yield ambiguous results. Therefore, no firm conclusions with respect to optimal niacin intake are possible. As a consequence of oral niacin supplementation, however, NAM levels in the body may increase, which may result in inhibition of PARP-1 and increased genomic instability. More studies are needed to define an optimal level of niacin nutriture in relation to genomic stability and tumorigenesis.
烟酸（NA）和烟酰胺（NAM），通常称为尼克酸，是烟酰胺腺嘌呤二核苷酸（NAD(+)）的膳食前体，DNA合成以及聚（ADP - 核糖）聚合酶 - 1（PARP - 1；EC 2.4.2.30）的活性都需要NAD(+)，而NAD(+)是PARP - 1的唯一底物。在细胞遗传毒性应激反应期间，PARP - 1酶被DNA链断裂高度激活，参与碱基切除修复，在p53表达和激活中发挥作用，因此，被认为对基因组稳定性很重要。在这篇综述中，首先讨论了烟酸向NAD(+)的吸收、代谢以及烟酸状态的评估。由于NAD(+)对PARP - 1活性很重要，因此探讨了PARP - 1与DNA合成和修复以及基因表达调控相关的各个方面。接下来讨论膳食甲基供体缺乏、烟酸状态、PARP - 1活性和基因组稳定性之间的相互作用。体外研究表明，当细胞从NAD(+)中耗尽或与作为PARP - 1抑制剂的高浓度NAM一起孵育时，PARP - 1功能受损，基因组稳定性降低。体外以及动物研究表明，烟酸缺乏会增加基因组不稳定性，特别是在与遗传毒性和氧化应激相结合时。烟酸缺乏也可能增加某些肿瘤的风险。初步数据表明，烟酸补充剂可能预防小鼠紫外线诱导的皮肤肿瘤，但关于对人类有类似预防作用的数据尚无。体外研究表明，NAM具有与抗坏血酸相当的抗氧化活性。关于人体体内烟酸状态和基因组稳定性的数据有限，结果也不明确。因此，关于最佳烟酸摄入量无法得出确凿结论。然而，口服烟酸补充剂的结果可能会使体内NAM水平升高，这可能导致PARP - 1受到抑制并增加基因组不稳定性。需要更多研究来确定与基因组稳定性和肿瘤发生相关的最佳烟酸营养水平。
