Cellular neurotoxicity of trivalent manganese bound to transferrin or pyrophosphate studied in human neuroblastoma (SH-SY5Y) cell cultures.
Previous studies have shown that cellular uptake of manganese is related to its binding to transferrin. However, it is not known how transferrin binding influences manganese toxicity. Therefore, the cytotoxic activity of manganese bound as manganic ion to either transferrin or pyrophosphate was investigated in the cloned human neuroblastoma cell line SH-SY5Y. The toxicity of the two compounds was studied as changes in cell growth and survival by lipid and protein determinations. There was a significant difference in the toxicity between the two complexes after 72 hr of exposure. The toxicity of the manganic-pyrophosphate (MnPPi) complex differed from that of the manganic-transferrin (MnTf) complex by a factor of 2 (IC(50): 26 +/- 2.6 and 65 +/- 2.4 mum, respectively). After 3 days of exposure to MnPPi and MnTf, the mitochondrial integrity was monitored by the mitochondrial dehydrogenase activity. The two manganese complexes reduced the enzyme activity to the same extent. Measurements of membrane integrity, using (3)[H]-2-deoxy-d-glucose as a probe, showed an increase in the membrane permeability of cells exposed to MnPPi for 60 min. Exposure to MnTf did not result in any significant change in membrane permeability. These findings suggest that transferrin not only mediates manganese transport into the neurone, but also protects the cell from damage caused by the manganic ion. The increase in cell membrane permeability after MnPPi exposure indicates that this complex may enter the cell. Furthermore, the results show that inhibited mitochondrial function is part of the mechanism of manganese neurotoxicity.
Suarez
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Department of Neurochemistry and Neurotoxicology, Stockholm University, S-10691 Stockholm, Sweden; IIBCE, Instituto de Investigacions, Biologicas Clemente Estable, Montevideo, Uruguay.
Walum
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Eriksson
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