P-Cresol, a uremic compound, enhances the uptake of aluminum in hepatocytes

In the end-stage renal disease patient, certain uremic compounds could influence the cellular accumulation of aluminum (Al). In this study, we examined the effect of 15 uremic ultrafiltrate fractions obtained by HPLC on the uptake and toxicity of Al in mouse hepatocytes (MH) in culture, a model system in which Al is taken up bound to transferrin (Tf). Uremic fractions 4 to 8, 12, 14, and 15 increased cellular Al uptake and aspartate aminotransferase release and decreased cell growth when Tf-Al, not Al citrate, was added to culture media. Compounds that have been extracted previously from these ultrafiltrate fractions (p-cresol, xanthine, tryptophan, hippuric acid, and o-hydroxyhippuric acid) were then tested for their effect on Al uptake and toxicity in MH at concentrations found in uremic serum. Significant Al uptake by MH was observed only when p-cresol was added together with Tf-Al. Time-response curves showed increased Al uptake and toxicity at p-cresol concentrations of 3 mg/dl in culture media. Dose-response curves confirmed that Al uptake and cell toxicity were proportional to p-cresol from 1.5 mg/dl to 3 mg/dl in culture media. p-Cresol was not toxic to MH in the absence of Tf-Al in media. p-Cresol increased Tf-associated Al uptake only because there was no effect on Al uptake when Al citrate was substituted, and studies with Tf-I125-Al in the presence of this compound showed increased Tf-I125 taken up by MH. p-Cresol did not increase Tf saturation with Al. p-Cresol also increased Tf-Al uptake in Friend erythroleukemia and neuroblastoma cells in culture. Our studies suggest that p-cresol and uremic fractions 4 to 8, 12, 14, and 15 increase the uptake and toxicity of Al in cultured MH. These compounds may play a role in the accumulation and toxicity of Al in the liver of end-stage renal disease patients and possibly in all cells that express Tf receptors.