Inhibition of glyceraldehyde-3-phosphate dehydrogenase in tissues of the rat by acrylamide and related compounds.

In previous investigations acrylamide was found to inhibit several enzymes of glycolysis both in vitro and in vivo. The present study examines the characteristics of the in vitro inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and compares the in vivo effects of acrylamide on GAPDH activity to other analogs. Inhibition of GAPDH produced by acrylamide was characteristic of an irreversible or slowly reversible mechanism. In vivo, GAPDH activity was determined in sciatic nerve, brain, skeletal muscle and liver after cumulative doses of 250, 350 or 500 mg/kg of acrylamide. Specific activities were significantly lower in extensor muscle and liver after the 250 mg/kg dose. Activities in brain and sciatic nerve tended to be decreased but the differences were not statistically significant. Specific activity of GAPDH was decreased in medulla pons, cerebellum and the rest of the brain after a 350 mg/kg cumulative dose of acrylamide, although protein concentrations were not different from those in controls. The maximum decrease was about 20%. Treatment with acrylamide, methylene-bis-acrylamide (non-neurotoxic), or N-isopropylacrylamide (neurotoxic) significantly decreased the weight of the cortex and associated brain areas as well as general body weights. No signs of developing neuropathy were observed during treatment with methylene-bis-acrylamide to a cumulative dose (8.1 mmoles/kg) equivalent to that of acrylamide causing frank paralysis. Although the compound exhibited some ability to inhibit GAPDH in vitro, no decrease in GAPDH activity was found in rat brain. Treatment with N-isopropylacrylamide resulted in progressive neurologic impairment. After treatment to a cumulative dose of the compound causing a severe hind-limb paralysis (9.2 mmoles/kg), a small but significant decrease in GAPDH was found in the three areas of brain examined.