N-methyl-2-pyridone-5-carboxamide: A novel uremic toxin?

Rutkowski, Bolesław; Słomińska, Ewa M.; Szołkiewicz, Marek; Smolenski, Ryszard T.; Striley, Cindy; Rutkowski, Przemysław; Świerczyński, Julian

doi:10.1046/j.1523-1755.63.s84.36.x

Cited by 80 publications

(66 citation statements)

References 12 publications

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“…The accumulation of nicotinamide endproducts may cause overinhibition of PARP1 and via this mechanism enhance the proliferation of oxidative stress processes (43). Interestingly, a correlation has already been reported between the serum concentration of 2-Py (as well as 4-Py and nicotinamide) and creatinine (44). An analysis of the urine metabolomic profile of healthy women and endometriosis patients at different MCPs was also performed, and statistical significant differences were observed during both phases.…”

Section: Discussionmentioning

confidence: 91%

“…The relationship between 2-Py and 4-Py and oxidative stress is still unclear. However, it is possible that inhibition of poly(ADP-ribose) polymerase (PARP1) by 2-Py and 4-Py could play a key role in this process (44). The accumulation of nicotinamide endproducts may cause overinhibition of PARP1 and via this mechanism enhance the proliferation of oxidative stress processes (43).…”

Section: Discussionmentioning

confidence: 99%

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Nuclear magnetic resonance metabolomic profiling of urine provides a noninvasive alternative to the identification of biomarkers associated with endometriosis

Vicente-Muñoz

Morcillo

Puchades‐Carrasco

et al. 2015

Fertility and Sterility

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Nuclear magnetic resonance metabolomic profiling of urine provides a noninvasive alternative to the identification of biomarkers associated with endometriosis

Vicente-Muñoz

Morcillo

Puchades‐Carrasco

et al. 2015

Fertility and Sterility

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“…Some other potential differences such as an increasing activity of xanthine oxidoreductase and aldehyde oxidase with age still need to be confirmed in humans [14]. Therefore it is important to find out whether nicotinamide metabolites accumulate in plasma of children with CRF and whether the pattern of this accumulation is similar to or different from adult patients [15]. Our objective was to clarify the relation between the inhibitory effects of nicotinamide metabolites on PARP-1 activity and the plasma concentrations of these compounds in children with CRF.…”

Section: Introductionmentioning

confidence: 99%

Accumulation of poly(ADP-ribose) polymerase inhibitors in children with chronic renal failure

et al. 2006

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Nicotinamide, N-methyl-2-pyridone-5-carboxamide (Met2PY) and N-methyl-4-pyridone-3-carboxamide (Met4PY) are biological metabolites of the intracellular coenzyme nicotinamide adenine dinucleotide (NAD) that can potentially inhibit poly(ADP-ribose) polymerase 1 (PARP-1; DNA repair enzyme). Our research was aimed at establishing whether chronic renal failure (CRF) in children leads to the elevation of plasma NAD metabolites sufficient to inhibit PARP-1 activity. Nicotinamide, Met2PY and Met4PY plasma and erythrocyte concentrations were measured in 25 children with CRF and in 19 healthy children. The effect of these NAD metabolites on PARP-1 activity was studied in vitro. We found that plasma concentration of all NAD metabolites (nicotinamide, Met2PY, Met4PY) in children with CRF could reach the concentration of 2, 30 and 10 microM as compared to 0.2, 1 and 0.5 microM, respectively, in healthy children. The concentration of nicotinamide metabolites correlated positively with plasma creatinine concentration and negatively with creatinine clearance in children with CRF. We found that Met2PY, Met4PY and nicotinamide inhibited in vitro PARP-1 activity with IC50 values of 2.1, 0.18 and 0.12 mM, respectively. Our data indicate that NAD metabolites accumulate in plasma of children with CRF and their combined effect could lead to the inhibition of PARP-1 activity. NAD metabolites could be particularly harmful in children due to higher DNA turnover than in adults.

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“…1). Two explanations for this observed increase could be reasoned as follows: the first, that the HD procedure removed inhibiting substances like heterocyclic amines and N-methyl-2-piridone-5-carboxamide [13, 14], and the second, that the HD procedure itself caused DNA damage, and in turn led to enhancement of the DNA repair reaction in order to overcome this newly produced DNA damage. The present study focused on the latter possibility.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous DNA Repair Increases during Hemodialysis

Herman

Ori²,

Chagnac³

et al. 2008

Nephron Clin Pract

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Background: Hemodialysis (HD) patients are subjected to increased oxidative stress. Oxidative stress causes DNA damage, which may be repaired by a DNA repair system. ‘Spontaneous DNA repair’ expresses DNA repair of in vitro unstimulated cells. The aim of the study was to evaluate the effect of one HD session on spontaneous DNA repair in peripheral blood mononuclear cells (PBMC). Methods: PBMC were separated from blood samples for the determination of spontaneous DNA repair, measured by ³H-thymidine incorporation, before and immediately after one HD session. Percent double-stranded DNA (ds-DNA) was measured by the fluorometric assay of DNA unwinding (FADU). Results: DNA repair increased significantly following HD. To examine if this increase was caused by newly produced DNA damage, we studied the effect of HD on percent ds-DNA in PBMC. HD significantly reduced percent ds-DNA, indicating increased DNA breakage. By repeating FADU in the presence of formamidopyrimidine-DNA glycosylase (Fpg), which nicks DNA at oxidized purine sites, we could show that the increased DNA damage was caused by oxidation. Conclusion: Spontaneous DNA repair increases during HD in response to an increase in DNA damage induced by oxidative stress.

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N-methyl-2-pyridone-5-carboxamide: A novel uremic toxin?

Abstract: Increased serum 2PY concentration, along with a deterioration of kidney function and its toxic properties (significant inhibition of PARP-1 by 2PY), suggest that it could be a novel uremic toxin.

Cited by 80 publications

References 12 publications

Nuclear magnetic resonance metabolomic profiling of urine provides a noninvasive alternative to the identification of biomarkers associated with endometriosis

Nuclear magnetic resonance metabolomic profiling of urine provides a noninvasive alternative to the identification of biomarkers associated with endometriosis

Accumulation of poly(ADP-ribose) polymerase inhibitors in children with chronic renal failure

Spontaneous DNA Repair Increases during Hemodialysis

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