Inhibition by 2,5-anhydromannitol of glycolysis in isolated rat hepatocytes and in Ehrlich ascites cells.
2,5-Anhydromannitol decreases lactate formation and 3H2O formation from [5-3H]glucose in isolated rat hepatocytes metabolizing high concentrations of glucose. The inhibition of glycolysis is accompanied by a slight decrease in the cellular content of fructose-6-P and a more substantial decrease in the cellular content of fructose-1,6-P2, with no change in the content of glucose-6-P. The 3H2O release data and changes in hexosephosphate distribution indicate possible inhibitions at phosphofructokinase-1 and phosphoglucose isomerase. 2,5-Anhydromannitol also inhibits glycolysis in Ehrlich ascites cells, but the tumor cells, unlike hepatocytes, must be treated with 2,5-anhydromannitol prior to exposure to glucose to obtain the inhibition. The decrease in 3H2O formation from [5-3H]glucose and the metabolite pattern that results from the addition of low concentrations (less than or equal to 0.25 mM) of 2,5-anhydromannitol indicate an inhibition at phosphofructokinase-1 that cannot be attributed to a decrease in the cellular content of fructose-2,6-P2. Higher concentrations (greater than or equal to 0.5 mM) of 2,5-anhydromannitol cause a substantial decrease in the cellular content of ATP that is accompanied by decreases in the content of glucose-6-P and fructose-6-P and transient increases in fructose-1,6-P2. In Ehrlich ascites cells, 2,5-anhydromannitol is metabolized to 2,5-anhydromannitol mono- and bisphosphate. The inhibition of glycolysis caused by 2,5-anhydromanitol decreases with time, because the phosphorylated metabolites formed during the preliminary incubation in the absence of glucose are rapidly dephosphorylated during the incubation in the presence of glucose.
Riquelme
P T
PT
Kneer
N M
NM
Wernette-Hammond
M E
ME
Lardy
H A
HA
D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism; D005636:Fructosephosphates / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006600:Hexosephosphates / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008353:Mannitol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D010732:Phosphofructokinase-1 / Q000378:metabolism; D051381:Rats
D005636:Fructosephosphates; D006600:Hexosephosphates; D007773:Lactates; D019344:Lactic Acid; D008353:Mannitol; C031765:2,5-anhydromannitol; D010732:Phosphofructokinase-1; D005947:Glucose