Cellular Toxicity of Nicotinamide Metabolites

Rutkowski, Bolesław; Rutkowski, Przemysław; Słomińska, Ewa M.; Smolenski, Ryszard T.; Świerczyński, Julian

doi:10.1053/j.jrn.2011.10.033

Cited by 21 publications

(17 citation statements)

References 12 publications

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“…Although the accumulation of 2PY in CKD patients might have toxic effects, the clinical consequences remain inconclusive. Some data suggest that an accumulation of 2PY could be harmful because the compound is known to inhibit the activity of poly(ADP-ribose) polymerase-1 (PARP-1) [28,29,30]. PARP-1 (the most active poly (ADP-ribose) polymerase) is an abundant nuclear enzyme that appears to be involved in the cellular response to DNA injury, since the latter triggers an increase in levels of this enzyme.…”

Section: Toxicological Profilementioning

confidence: 99%

N-methyl-2-pyridone-5-carboxamide (2PY)—Major Metabolite of Nicotinamide: An Update on an Old Uremic Toxin

Lenglet

Liabeuf

Bodeau

et al. 2016

Toxins

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N-methyl-2-pyridone-5-carboxamide (2PY, a major metabolite of nicotinamide, NAM) was recently identified as a uremic toxin. Recent interventional trials using NAM to treat high levels of phosphorus in end-stage renal disease have highlighted new potential uremic toxicities of 2PY. In the context of uremia, the accumulation of 2PY could be harmful—perhaps by inhibiting poly (ADP-ribose) polymerase-1 activity. Here, we review recently published data on 2PY’s metabolism and toxicological profile.

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Section: Toxicological Profilementioning

confidence: 99%

N-methyl-2-pyridone-5-carboxamide (2PY)—Major Metabolite of Nicotinamide: An Update on an Old Uremic Toxin

Lenglet

Liabeuf

Bodeau

et al. 2016

Toxins

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“…These two studies 21,22 thus suggest that PARP1 and PDE4 act in tandem to exert the metabolic benefits of resveratrol. Because both PARP1 and SIRTuins use NAD + , they antagonistically regulate each other, i.e; PARP1 activation inhibits SIRTuins through generation of nicotinamide 22,27,28 and vice versa the metabolic byproducts of nicotinamide (1-Methylnicotinamide) 29,30 or treatment with nicotinamide riboside (NR) result in the inhibition of PARP1 28,30 through SIRT1 activation 28,29,31 . Most significantly, inhibition of PARP1 leads to induction of DNA damage and cytotoxicity 32,33 and mitochondrial dysfunction 34 , which are implicated in the etiology of various metabolic disorders.…”

mentioning

confidence: 99%

Nicotinamide Augments the Anti-Inflammatory Properties of Resveratrol through PARP1 Activation

Yanez

Jhanji

Murphy

et al. 2019

Sci Rep

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Resveratrol (RSV) and nicotinamide (NAM) have garnered considerable attention due to their anti-inflammatory and anti-aging properties. NAM is a transient inhibitor of class III histone deacetylase SIRTs (silent mating type information regulation 2 homologs) and SIRT1 is an inhibitor of poly-ADP-ribose polymerase-1 (PARP1). The debate on the relationship between RSV and SIRT1 has precluded the use of RSV as a therapeutic drug. Recent work demonstrated that RSV facilitates tyrosyl-tRNA synthetase (TyrRS)-dependent activation of PARP1. Moreover, treatment with NAM is sufficient to facilitate the nuclear localization of TyrRS that activates PARP1. RSV and NAM have emerged as potent agonists of PARP1 through inhibition of SIRT1. In this study, we evaluated the effects of RSV and NAM on pro-inflammatory macrophages. Our results demonstrate that treatment with either RSV or NAM attenuates the expression of pro-inflammatory markers. Strikingly, the combination of RSV with NAM, exerts additive effects on PARP1 activation. Consistently, treatment with PARP1 inhibitor antagonized the anti-inflammatory effect of both RSV and NAM. For the first time, we report the ability of NAM to augment PARP1 activation, induced by RSV, and its associated anti-inflammatory effects mediated through the induction of BCL6 with the concomitant down regulation of COX-2.

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“…1. These molecules exhibit low-toxicity 33 and play a role in biological processes such as NADH synthesis. 34 Furthermore, their derivatives also feature in various antibiotics.…”

Section: Introductionmentioning

confidence: 99%