Albumin has been considered a "sacrificial plasma antioxidant" due to the high reactivity of the protein sulfhydryl groups with oxidants such as hydrogen peroxide (H2O2) and hypochlorous acid (HOCl). Based on its large quantity and high turnover. It is considered as one of the most important plasma antioxidants for protecting key cellular and regulatory proteins. Since hemodialysis patients have lower overall levels of albumin and possible protein modifications due to uremic toxins, we investigated whether modifications by various uremic toxins would affect the susceptibility of albumin to an oxidative challenge. We incubated bovine serum albumin in the presence of carboxymethyllysine (CML) (10 micromol/L(-1) mmol/L), methyl glyoxal (50 micromol/L(-5) mmol/L), p-cresol (100 micromol/L-10 mmol/L) or hippuric acid (200 micromol/L-20 mmol/L) for 16 hours at 37 degrees C and then subsequently added 0.5 mmol/L(-1) mmol of H2O2/HOCl. We measured the extent of protein modification by the loss of protein sulfhydryl groups, dityrosine formation and the formation of advanced oxidation protein products (AOPP). Incubation of albumin with the uremic toxins caused a loss of protein sulfhydryl groups and an increase in dityrosines and AOPP. The presence of uremic toxins had no effect on the loss of protein sulfhydryl groups after addition of H2O2/HOCl; however, low levels of CML, p-cresol and methyl glyoxal inhibited the formation of AOPP and dityrosines. We suggest that uremic toxins may possibly play a role in mediating free radical initiated protein damage.