Impact of the gliotoxin l-serine-O-sulphate on cellular metabolism in cultured rat astrocytes

l-Serine-O-sulphate is a member of a group of amino acids collectively called gliotoxins and is a substrate for the high affinity sodium-dependent glutamate transporters. Previous studies have shown that it is toxic to primary cultures of astrocytes but the mode of toxicity is unknown. The current study demonstrates that l-serine-O-sulphate, at a sub-toxic concentration (400 μM), causes significant disruption to glucose and alanine metabolism in cultures of rat cortical astrocytes. More specifically, using 13C NMR spectroscopy a significant reduction in labelled end products from [1-13C]glucose and [3-13C]alanine was found in the presence of l-serine-O-sulphate. Additionally, using [2-13C]glycine a 27% reduction in de novo glutathione synthesis was observed in the presence of the gliotoxin. Incubation of the cells with l-serine-O-sulphate reduced the activity of alanine and aspartate aminotransferase by 53% and 67%, respectively. Collectively these results show that the gliotoxin, l-serine-O-sulphate, causes major disruptions to metabolic pathways in primary cultures of astrocytes.