The selective neurotoxicity produced by 3-chloropropanediol in the rat is not a result of energy deprivation.

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Skamarauskas J, Carter W, Fowler M, Madjd A, Lister T, Mavroudis G, Ray DE

The selective neurotoxicity produced by 3-chloropropanediol in the rat is not a result of energy deprivation.

Toxicology. 2007 Apr 11;232(3):268-76. Epub 2007 Jan 21.

PubMed ID

17321661 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Glutathione	Glutathione S-transferase A2	Protein	Humans	Unknown	Not Available	Details