The selective neurotoxicity produced by 3-chloropropanediol in the rat is not a result of energy deprivation.
The biochemical mechanism of toxicity of the experimental astrocyte neurotoxicant and food contaminant S-3-chloro-1,2-propanediol (3-CPD) has been proposed to be via inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We have confirmed this action in liver, which shows inhibition to 6.0+/-0.7% control at the neuropathic dose of 140 mg/kg. However, GAPDH activity in brain only fell to a minimum of 54+/-24% control, and the concentrations of lactate and pyruvate (the downstream products of GAPDH), showed no pre-neuropathic decreases in 3-CPD susceptible brain tissue. There was no inhibition of GAPDH activity in primary astrocyte cultures at sub-cytotoxic exposures. We therefore sought alternative mechanisms to explain its toxicity to astrocytes. We were able to show that 3-CPD is a substrate for glutathione-S-transferase and also that, after bioactivation by alcohol dehydrogenase, it generates an irreversible inhibitor of glutathione reductase. In addition, incubation of brain slices from the 3-CPD-vulnerable inferior colliculus produces a depletion of glutathione and an inhibition of glutathione-S-transferase that is not seen in equivalent slices taken from the 3-CPD-resistant occipital neocortex. A smaller but significant and similarly regionally selective decrease in glutathione content is also seen in vivo. We conclude that 3-CPD does not produce its astrocytic toxicity via energy deprivation, and suggest that selective bioactivation and consequent disruption of redox state is a more likely mechanism.
Skamarauskas
J
J
School of Biomedical Sciences, University of Nottingham Medical School, Queens Medical Centre, Nottingham NG7 2UH, United Kingdom.
Carter
W
W
Fowler
M
M
Madjd
A
A
Lister
T
T
Mavroudis
G
G
Ray
D E
DE
D000818:Animals; D001253:Astrocytes; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D007245:Inferior Colliculi / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D021241:Spectrometry, Mass, Electrospray Ionization; D000517:alpha-Chlorohydrin / Q000633:toxicity*
D007773:Lactates; D009498:Neurotoxins; D011773:Pyruvates; D000517:alpha-Chlorohydrin; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005980:Glutathione Reductase; D005978:Glutathione