Gliotoxins are a group of
amino acids that are toxic to astrocytes, and are substrates of high-affinity
sodium-dependent
glutamate transporters. In the present study, C6
glioma cells were preincubated for 20 h in the presence of 400 microM L-alpha-aminoadipate,
L-serine-O-sulphate,
D-aspartate or L-
cysteate, as well as in the presence of the poorly transported
L-glutamate uptake inhibitor, L-anti-endo-methanopyrrolidine dicarboxylate. In experiments following [3-13C]
alanine metabolism, all toxins caused a decreased incorporation of label into
glutamate. Production of labelled
lactate changed only when cells were incubated in the presence of L-alpha-aminoadipate or
L-serine-O-sulphate. Incubation with L-anti-endo-methanopyrrolidine dicarboxylate caused no change in the amount of label incorporated into either
glutamate or
lactate. When
glutathione production was followed using 1 mM [2-13C]
glycine, differential effects of the
gliotoxins were revealed. Most notably, both
L-serine-O-sulphate and L-alpha-aminoadipate caused significant increases in labelling of
glutathione. Once again, L-anti-endo-methanopyrrolidine dicarboxylate was without effect. Overall, we have shown that the
gliotoxins cause disruption to
alanine metabolism and
glutathione production in C6
glioma cells, but that there are notable differences in their mechanisms of action. In the absence of any disruption to metabolism by L-anti-endo-methanopyrrolidine dicarboxylate, it is concluded that their mode of action involves more than inhibition of
glutamate transport.