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 microM), causes significant disruption to glucose and alanine metabolism in cultures of rat cortical astrocytes. More specifically, using (13)C NMR spectroscopy a significant reduction in labelled end products from [1-(13)C]glucose and [3-(13)C]alanine was found in the presence of L-serine-O-sulphate. Additionally, using [2-(13)C]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.
Brennan
Lorraine
L
UCD School of Biomolecular and Biomedical Sciences, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Alves
Paula M
PM
Hewage
Chandralal
C
Malthouse
J Paul G
JP
McBean
Gethin J
GJ
D000409:Alanine / Q000378:metabolism; D000410:Alanine Transaminase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001219:Aspartate Aminotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007842:Lathyrism / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009498:Neurotoxins / Q000633:toxicity; D019906:Nuclear Magnetic Resonance, Biomolecular; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000031:analogs & derivatives* / Q000633:toxicity
D002250:Carbon Radioisotopes; D009498:Neurotoxins; D012694:Serine; C036040:serine O-sulfate; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D005947:Glucose; D000409:Alanine