ALUMINUM INHIBITS HEMOGLOBIN-SYNTHESIS BUT ENHANCES IRON UPTAKE IN FRIEND-ERYTHROLEUKEMIA CELLS

Aluminum (Al) overload in dialysis patients and experimental animals is associated with the development of anemia. However, the precise mechanisms of erythrocyte Al uptake and toxicity are poorly understood. Al accumulation, hemoglobin (Hb) synthesis and cell growth were evaluated in dimethylsulfoxide (DMSO)-induced Friend erythroleukemia cells (FEC), a model system for erythroid differentiation. FEC were grown in media containing either Al citrate, transferrin-aluminum (Tf-Al), Tf or no additions. Al accumulation occurring only in cells grown in Tf-Al containing media was detected at 24 hours and increased linearly up to 96 hours after induction. By 96 hours, 200 ± 36 μg Al/liter lysed cells were detected in Tf-Al grown cells versus 5 ± 1 μg Al/liter lysed cells in cells grown in Al citrate (P < 0.001). Tf-Al inhibited Hb synthesis at 72 hours after induction. At 96 hours 50 ± 15% cells were benzidine positive when grown in Tf-Al compared to 76 ± 15% in Al citrate (P < 0.001). FEC grown in increasing concentrations of Tf-Al (100 to 500 μg/ml) showed inhibition of Hb synthesis at lower concentrations of Tf-Al at 100 μg/ml than for cell growth at 300 μg/ml. Higher concentrations of Tf-Al (>300 μg/ml) did not further inhibit Hb synthesis or cell growth. Iron (Fe) and Tf uptake were increased in Al loaded FEC compared to control cells. The increased Tf uptake was probably the result of increased Tf receptor expression on FEC since Tf cell cycling time was unchanged. These data indicate that Al utilizes the Tf uptake pathway for entry into erythrocyte precursors. Al is toxic at sites distal to Fe uptake, possibly at the heme and/or globin synthetic pathways, resulting in decreased Hb synthesis and cell growth.