Studies on the biochemical basis of distal axonopathies - I. Inhibition of glycolysis by neurotoxic hexacarbon compounds.
Sabri-MI; Moore-CL; Spencer-PS
J Neurochem 1979 Jan; 32(3):683-689
The effect of neurotoxic and nonneurotoxic solvents on glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) was examined. The effects were studied using both the crystalline enzyme and the endogenous enzyme present in nerve tissue. The rate of reduction of NAD in the presence of GAPDH, measured at 340 nanometers, was used to assay enzyme activity. The neurotoxic compounds 2,5-hexanedione (110134) (2,5-HD) and methyl-n-butyl-ketone (591786) (MBK) inhibited crystalline and endogenous central nervous and peripheral nervous system GAPDH when the enzyme was preincubated with the toxin. The degree of inhibition was a function of both the concentration of the toxin and the length of the incubation. The concentration of the substrate had no effect on the degree of inhibition. The enzyme activity was preserved by the addition of dithiothreitol in the presence of either neurotoxin. Lactate-dehydrogenase (LDH) activity was not inhibited by these neurotoxic chemicals. The neurologically inactive compounds, 1,6-hexanediol (629118) and acetone (67641), did not inhibit GAPDH. Studies with nerve homogenates showed that the activity of GAPDH was lowered by 2,5-HD and that LDH was not affected. In rat brain homogenates, both MBK and 2,5-HD effectively blocked GAPDH activity; MKB was more inhibitory than 2,5-HD. The results indicate that 2,5-HD and MBK block energy metabolism by inhibiting glycolysis at the site of GAPDH. These findings may account for the known failure of GAPDH dependent axonal transport and the axonal degeneration which occurs in hexacarbon neuropathy.
NIOSH-Publication; NIOSH-Grant; Neurotoxic-effects; Organic-solvents; Biochemistry; Nervous-system-disorders; Enzyme-activity
Neuroscience Albert Einstein College 1410 Pelham Parkway Bronx, N Y 10461
110-13-4; 591-78-6; 629-11-8; 67-64-1
Journal of Neurochemistry
Yeshiva University, New York, New York