Cellular toxicity of nicotinamide metabolites

Area of Science:

• Biochemistry
• Nephrology
• Toxicology

Background:

• Uremic toxins contribute to oxidative stress and impaired cellular repair in chronic kidney disease (CKD).
• Nicotinamide derivatives represent a newly identified family of uremic toxins.
• These toxins inhibit poly (ADP-ribose) polymerase activity, affecting cellular processes.

Purpose of the Study:

• To evaluate the concentrations of 4-pyridone-3-carboxamid-1-β-ribonucleoside-triphosphate (4PYTP) and 4-pyridone-3-carboxamid-1-β-ribonucleoside-monophosphate (4PYMP) in erythrocytes of CKD patients.
• To investigate the changes in these metabolite levels across different stages of CKD treatment, including conservative management, hemodialysis, and post-kidney transplantation.
• To explore the metabolic relationship between 4PYR, 4PYMP, and 4PYTP within erythrocytes.

Main Methods:

• Serum and red blood cells were collected from CKD patients (conservative, hemodialysis, post-transplant) and healthy controls.
• Nicotinamide metabolites were quantified using a validated liquid chromatography-mass spectrometry method.
• Erythrocytes were incubated with 4PYR to study metabolite formation in vitro.

Main Results:

• Three novel nicotinamide metabolites were identified: 4-pyridone-3-carboxamid-1-β-ribonucleoside (4PYR), 4PYMP, and 4PYTP.
• Elevated serum 4PYR and erythrocyte 4PYMP/4PYTP were observed in dialysis patients.
• Erythrocyte 4PYTP levels remained elevated post-transplantation, while 4PYR and 4PYMP normalized with graft function.

Conclusions:

• 4PYR is absorbed by erythrocytes and metabolized to 4PYMP and 4PYTP, potentially contributing to cellular dysfunction in CKD.
• These findings highlight the role of specific nicotinamide metabolites in CKD pathogenesis and erythrocyte toxicity.
• Further research is warranted to elucidate the precise mechanisms and clinical implications of these novel uremic toxins.