Hyperuricemia is associated with
hypertension,
metabolic syndrome,
preeclampsia, cardio-
vascular disease and renal disease, all conditions associated with oxidative stress. We hypothesized that
uric acid, a known
antioxidant, might become prooxidative following its reaction with
oxidants; and, thereby contribute to the pathogenesis of these diseases.
Uric acid and 1,3-(15)N(2)-uric
acid were reacted with
peroxynitrite in different
buffers and in the presence of
alcohols,
antioxidants and in human plasma. The reaction products were identified using liquid chromatography-mass spectrometry (LC-MS) analyses. The reactions generate reactive intermediates that yielded
triuret as their final product. We also found that the
antioxidant, ascorbate, could partially prevent this reaction. Whereas
triuret was preferentially generated by the reactions in aqueous
buffers, when
uric acid or 1,3-(15)N(2)-uric
acid was reacted with
peroxynitrite in the presence of
alcohols, it yielded alkylated
alcohols as the final product. By extension, this reaction can alkylate other biomolecules containing
OH groups and others containing labile hydrogens.
Triuret was also found to be elevated in the urine of subjects with
preeclampsia, a pregnancy-specific hypertensive syndrome that is associated with oxidative stress, whereas very little
triuret is produced in normal healthy volunteers. We conclude that under conditions of oxidative stress,
uric acid can form reactive intermediates, including potential alkylating species, by reacting with
peroxynitrite. These reactive intermediates could possibly explain how
uric acid contributes to the pathogenesis of diseases such as the
metabolic syndrome and
hypertension.