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

N-methyl-2-pyridone-5-carboxamide (2PY) is one of the end products of nicotinamide-adenine dinucleotide (NAD) degradation. We recently found that serum 2PY concentrations in chronic renal failure (CRF) patients were enhanced to the values, which are potentially toxic. The aim of this study was to determine whether 2PY is an inhibitor of poly(ADP-ribose) polymerase, the nuclear enzyme that is highly involved in variety of physiologic events, including regulation of DNA replication and DNA repair. High-performance liquid chromatography (HPLC) was used to determine 2PY and other NAD catabolite concentrations in serum of: nondialyzed patients; patients chronically hemodialyzed; patients after kidney transplantation; and healthy individuals (control group). Moreover, the effect of nicotinamide and 2PY on poly(ADP-ribose) polymerase (PARP-1) in vitro was studied. The serum nicotinamide, 2PY, and 4PY (N-methyl-4-pyridone-3-carboxamide) concentrations are many times elevated in nondialyzed CRF patients when compared with controls. The direct correlations were found between serum 2PY (as well as 4PY and nicotinamide) concentrations and serum creatinine concentration, and negative correlations between serum concentrations of these compounds and creatinine clearance. The concentration of 2PY decreases considerably after hemodialysis (HD) session, but elevates back 48 hours later. It permanently declines after kidney transplantation. Nicotinamide and 2PY significantly inhibit PARP-1 activity in vitro. 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.