We have identified a novel
nucleotide,
4-pyridone 3/5-carboxamide ribonucleoside
triphosphate (4PyTP), which accumulates in human erythrocytes during
renal failure. Using plasma and erythrocyte extracts obtained from children with
chronic renal failure we show that the concentration of 4PyTP is increased, as well as other soluble
NAD(+) metabolites (
nicotinamide, N(1)-methylnicotinamide and 4Py-riboside) and the major
nicotinamide metabolite N(1)-methyl-2-pyridone-5-carboxamide (2PY), with increasing degrees of
renal failure. We noted that 2PY concentration was highest in the plasma of haemodialysis patients, while 4PyTP was highest in erythrocytes of children undergoing
peritoneal dialysis: its concentration correlated closely with 4Py-riboside, an authentic precursor of 4PyTP, in the plasma. In the dialysis patients,
GTP concentration was elevated: similar accumulation was noted previously, as a paradoxical effect in erythrocytes during treatment with
immunosuppressants such as
ribavirin and
mycophenolate mofetil, which deplete
GTP through inhibition of
IMP dehydrogenase in nucleated cells such as lymphocytes. We predict that 4Py-riboside and 4Py-nucleotides bind to this
enzyme and alter its activity. The
enzymes that regenerate
NAD(+) from
nicotinamide riboside also convert the drugs
tiazofurin and
benzamide riboside into
NAD(+) analogues that inhibit
IMP dehydrogenase more effectively than the related ribosides: we therefore propose that the accumulation of 4PyTP in erythrocytes during
renal failure is a marker for the accumulation of a related toxic
NAD(+) analogue that inhibits
IMP dehydrogenase in other cells.