Monochloroacetic acid inhibits liver gluconeogenesis by inactivating glyceraldehyde-3-phosphate dehydrogenase.
We previously reported that a lethal dose of monochloroacetate (MCA) causes severe hypoglycemia and lactic acidosis. MCA has been thought to inhibit mitochondrial aconitase; however, the exact effect of MCA on hepatic glucose metabolism is not clear. In this study, we investigated the effects of MCA on liver gluconeogenesis using an isolated perfused rat liver system. Gluconeogenesis from 2.5 mM lactate was inhibited by 1 mM MCA and was completely abolished after 2 h of perfusion. Levels of citric acid cycle intermediates such as citrate, isocitrate, and 2-oxoglutarate (2-OG) were significantly reduced by MCA. The finding that the levels of citrate and 2-OG were similarly reduced (to 31 and 36% of control, respectively) indicates that aconitase was not inhibited by MCA. On the contrary, gluconeogenesis from glycerol, which can be converted to glucose without glyceraldehyde-3-phosphate dehydrogenase (GAPDH), was not inhibited by MCA. GAPDH was inactivated by MCA in vitro, but enolase, phosphoglycerate mutase, and phosphoglycerate kinase were not inactivated at the same or higher concentrations of MCA. Furthermore, GAPDH activity in the MCA-perfused liver decreased to 33-42% of control and that in the liver of rats exposed to MCA was reduced to 19% of control. We concluded that MCA inactivates GAPDH, and this is the cause of the inhibition of liver gluconeogenesis.
Sakai
Akiko
A
Department of Chemistry, Osaka Medical College, 2-7 Daigakumachi, Takatsuki, Osaka 569-8686, Japan. asakai@art.osaka-med.ac.jp
Shimizu
Hiroyasu
H
Kono
Koichi
K
Furuya
Eisuke
E
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors*; D005990:Glycerol / Q000494:pharmacology; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000085:Acetates; D004791:Enzyme Inhibitors; D019344:Lactic Acid; C006972:chloroacetic acid; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005990:Glycerol