The etiology of toxic peripheral neuropathies: in vitro effects of acrylamide and 2,5-hexanedione on brain enolase and other glycolytic enzymes.
The in vitro effects of the neurotoxic compounds, acrylamide and 2,5-hexanedione, on several glycolytic enzymes including enolase, phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and lactic dehydrogenase (LDH) were studied in rat brain. A differential sensitivity of the enzymes to the inhibitory effects of the neurotoxins was observed. The order of increasing sensitivity to 2,5-hexanedione was enolase -- GAPDH -- PFK and to acrylamide the order was PFK -- enolase -- GAPDH. Neither neurotoxin inhibited LDH. The inhibition of enolase by acrylamide exhibited a mixed type pattern in double reciprocal plots. The inhibition could be completely reversed by dialysis indicating that it did not involve covalent bond formation. In the presence of dithiothreitol (DTT) or glutathione the inhibition of enolase by either acrylamide or 2,5-hexanedione was potentiated. Activity of enolase inhibited by both acrylamide and DTT could not be restored to pre-inhibition rates following dialysis indicating that an irreversible interaction between acrylamide and enolase had taken place. The results suggest that neurotoxic compounds which produce distal axonopathies have a common pattern of attack on glycolytic enzymes and that interruption of glycolysis is the underlying biochemical basis for both the physiological and morphological damage caused by these compounds.
D000178:Acrylamides / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors; D006019:Glycolysis / Q000187:drug effects*; D006588:Hexanones / Q000633:toxicity*; D007659:Ketones / Q000633:toxicity*; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors; D008297:Male; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors; D010751:Phosphopyruvate Hydratase / Q000037:antagonists & inhibitors*; D051381:Rats
D000178:Acrylamides; D006588:Hexanones; D007659:Ketones; C011269:2,5-hexanedione; D007770:L-Lactate Dehydrogenase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D010732:Phosphofructokinase-1; D010751:Phosphopyruvate Hydratase