Inhibition of brain glycolysis by aluminum.
Aluminum inhibited both the cytosolic and mitochondrial hexokinase activities in rat brain. The IC50 values were between 4 and 9 microM. Aluminum was effective at mildly acidic (pH 6.8) or slightly alkaline (pH 7.2-7.5) pH, in the presence of a physiological level of magnesium (0.5 mM). However, saturating (8 mM) magnesium antagonized the effect of aluminum on both forms of hexokinase activity. Other enzymes examined were considerably less sensitive to inhibition by aluminum. The IC50 of aluminum for phosphofructokinase was 1.8 mM and for lactate dehydrogenase 0.4 mM. At 10-600 microM, aluminum actually stimulated pyruvate kinase. Aluminum also inhibited lactate production by rat brain extracts: this effect was much more marked with glucose as substrate than with glucose-6-phosphate. However, the IC50 for inhibiting lactate production using glucose as substrate was 280 microM, higher than that required to inhibit hexokinase. This concentration of aluminum is comparable to those reportedly found in the brains of patients who had died with dialysis dementia and in the brains of some of the patients who had died with Alzheimer disease. Inhibition of carbohydrate utilization may be one of the mechanisms by which aluminum can act as a neurotoxin.
D000535:Aluminum / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D006019:Glycolysis / Q000187:drug effects*; D006593:Hexokinase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains
D007773:Lactates; D019344:Lactic Acid; D000535:Aluminum; D006593:Hexokinase; D010732:Phosphofructokinase-1; D008274:Magnesium