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

Lenglet, Aurélie; Liabeuf, Sophie; Bodeau, Sandra; Louvet, Loı̈c; Mary, Aurélien; Boullier, Agnès; Lemaire-Hurtel, Anne-Sophie; Jonet, Alexia; Sonnet, Pascal; Kamel, Saı̈d; Massy, Ziad A.

doi:10.3390/toxins8110339

Cited by 52 publications

(55 citation statements)

References 42 publications

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“…We recently used a sensitive, specific liquid chromatography–tandem mass spectrometry (LC-MS/MS) method to assay 2PY concentrations in healthy volunteers ( n = 65) and in patients with CKD (60 non-dialysed and 80 on haemodialysis). Our data confirmed that 2PY levels rise progressively with the CKD stage; the highest concentration was observed in patients on haemodialysis and greatly exceeded the value determined for healthy subjects [ 24 ]. This finding is important in view of the renewed interest in nicotinamide for the treatment of hyperphosphataemia in patients with advanced CKD [ 25 ].…”

Section: N -Methyl-2-pyridone-5-carboxamide: a Comeback By Asupporting

confidence: 85%

From old uraemic toxins to new uraemic toxins: place of ‘omics’

Massy

Liabeuf

2018

Nephrology Dialysis Transplantation

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Uraemic toxins seem to play an important role in the genesis of cardiovascular and renal damage in chronic kidney disease patients. This short article is divided into two thematic sections. The first part focuses on a selection of ‘old’ toxins for which recent data (published between 2016 and 2018) have provided a better understanding of the associated harmful mechanisms and which, in our opinion, nephrologists should be more aware of. The second part highlights new perspectives for identifying and quantifying these compounds using ‘omics’ techniques.

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Section: N -Methyl-2-pyridone-5-carboxamide: a Comeback By Asupporting

confidence: 85%

From old uraemic toxins to new uraemic toxins: place of ‘omics’

Massy

Liabeuf

2018

Nephrology Dialysis Transplantation

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“…However, at high concentrations NAM and MeNAM can have a toxic effect on neurons, as shown in Parkinson's and Huntington's disease models [39][40][41] . Similarly, NAM has been shown to be effective for management of hyperphosphatemia in patients with renal disease 42 ; however, it is also suggested to be a uremic toxin contributing to thrombocytopenia 43,44 . Whilst there have been studies showing NR safely elevates NAD + in human blood 16,17,45 it is important to consider that creating a state of NAD + excess and increasing clearance of NAM and MeNAM could potentially have unintended effects in the CNS and for kidney function.…”

Section: Discussionmentioning

confidence: 99%

Metabolic tracing reveals novel adaptations to skeletal muscle cell energy production pathways in response to NAD+ depletion

Oakey¹,

Fletcher²,

Elhassan³

et al. 2018

Wellcome Open Res

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Background: Skeletal muscle is central to whole body metabolic homeostasis, with age and disease impairing its ability to function appropriately to maintain health. Inadequate NAD+ availability is proposed to contribute to pathophysiology by impairing metabolic energy pathway use. Despite the importance of NAD+ as a vital redox cofactor in energy production pathways being well-established, the wider impact of disrupted NAD+ homeostasis on these pathways is unknown. Methods: We utilised skeletal muscle myotube models to induce NAD+ depletion, repletion and excess and conducted metabolic tracing to provide comprehensive and detailed analysis of the consequences of altered NAD+ metabolism on central carbon metabolic pathways. We used stable isotope tracers, [1,2-13C] D-glucose and [U-13C] glutamine, and conducted combined 2D-1H,13C-heteronuclear single quantum coherence (HSQC) NMR spectroscopy and GC-MS analysis. Results: NAD+ excess driven by nicotinamide riboside (NR) supplementation within skeletal muscle cells results in enhanced nicotinamide clearance, but had no effect on energy homeostasis or central carbon metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) inhibition induced NAD+ depletion and resulted in equilibration of metabolites upstream of glyceraldehyde phosphate dehydrogenase (GAPDH). Aspartate production through glycolysis and TCA cycle activity is increased in response to low NAD+, which is rapidly reversed with repletion of the NAD+ pool using NR. NAD+ depletion reversibly inhibits cytosolic GAPDH activity, but retains mitochondrial oxidative metabolism, suggesting differential effects of this treatment on sub-cellular pyridine pools. When supplemented, NR efficiently reverses these metabolic consequences. However, the functional relevance of increased aspartate levels after NAD+ depletion remains unclear, and requires further investigation. Conclusions: These data highlight the need to consider carbon metabolism and clearance pathways when investigating NAD+ precursor usage in models of skeletal muscle physiology.

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“…2Py has previously been classified as a uremic retention product by the European Uremic Toxin Working Group [32,33], though specific mechanisms of its renal clearance have yet not been characterized. Whereas plasma concentrations of 2Py are reported to increase progressively with chronic kidney disease stages [34], those of N 1 -MN are suggested to be less sensitive to kidney function because of the contribution of AOX1 to N 1 -MN clearance [13,14]. In view of this, we can speculate upon slower excretion of N 1 -MN, hence prolonged exposure to 2Py-forming AOX1 that is related to kidney function, rather than retention of 2Py primarily.…”

Section: Discussionmentioning

confidence: 88%

Urinary Excretion of N1-methyl-2-pyridone-5-carboxamide and N1-methylnicotinamide in Renal Transplant Recipients and Donors

Deen

Veen

Gomes-Neto

et al. 2020

JCM

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N1-methylnicotinamide (N1-MN) and N1-methyl-2-pyridone-5-carboxamide (2Py) are successive end products of NAD+ catabolism. N1-MN excretion in 24-h urine is the established biomarker of niacin nutritional status, and recently shown to be reduced in renal transplant recipients (RTR). However, it is unclear whether 2Py excretion is increased in this population, and, if so, whether a shift in excretion of N1-MN to 2Py can be attributed to kidney function. Hence, we assessed the 24-h urinary excretion of 2Py and N1-MN in RTR and kidney donors before and after kidney donation, and investigated associations of the urinary ratio of 2Py to N1-MN (2Py/N1-MN) with kidney function, and independent determinants of urinary 2Py/N1-MN in RTR. The urinary excretion of 2Py and N1-MN was measured in a cross-sectional cohort of 660 RTR and 275 healthy kidney donors with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Linear regression analyses were used to investigate associations and determinants of urinary 2Py/N1-MN. Median 2Py excretion was 178.1 (130.3–242.8) μmol/day in RTR, compared to 155.6 (119.6–217.6) μmol/day in kidney donors (p < 0.001). In kidney donors, urinary 2Py/N1-MN increased significantly after kidney donation (4.0 ± 1.4 to 5.2 ± 1.5, respectively; p < 0.001). Smoking, alcohol consumption, diabetes, high-density lipoprotein (HDL), high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) were identified as independent determinants of urinary 2Py/N1-MN in RTR. In conclusion, the 24-h urinary excretion of 2Py is higher in RTR than in kidney donors, and urinary 2Py/N1-MN increases after kidney donation. As our data furthermore reveal strong associations of urinary 2Py/N1-MN with kidney function, interpretation of both N1-MN and 2Py excretion may be recommended for assessment of niacin nutritional status in conditions of impaired kidney function.

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

Cited by 52 publications

References 42 publications

From old uraemic toxins to new uraemic toxins: place of ‘omics’

From old uraemic toxins to new uraemic toxins: place of ‘omics’

Metabolic tracing reveals novel adaptations to skeletal muscle cell energy production pathways in response to NAD+ depletion

Urinary Excretion of N1-methyl-2-pyridone-5-carboxamide and N1-methylnicotinamide in Renal Transplant Recipients and Donors

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