Mechanism of aluminum-induced inhibition of hepatic glycolysis: inactivation of phosphofructokinase.
Aluminum, an abundant element in the earth's crust, has been implicated in various pathological disorders and low concentrations of this element have recently been shown to inhibit brain glycolysis. However, despite the fact that aluminum accumulates in high concentrations in the liver, potential effects of this metal on hepatic intermediary metabolism have not been explored. In perfused livers from untreated rats, maximal rates of production of lactate plus pyruvate (glycolysis) were 93 +/- 15 mumols/g/hr. Glycolysis was severely inhibited in livers from aluminum-treated rats (0.5 mg/kg, 6 hr before experiment) with maximal rates of only 23 +/- 4 mumols/g/hr. In contrast, glucose production (glycogenolysis) and hepatic oxygen uptake were not altered significantly by prior treatment with aluminum. In livers from fasted rats, pretreatment with aluminum did not influence gluconeogenesis or production of lactate and pyruvate from fructose (5 mM). This finding indicates that pyruvate kinase is not inhibited by aluminum and implicates phosphofructokinase, hexokinase and/or glucokinase as sites for the inhibitory effect of aluminum on glycolysis. In liver homogenates from untreated rats, increasing concentrations of aluminum did not show any appreciable effect on hexokinase or glucokinase activity but did cause progressive decreases in phosphofructokinase activity. Therefore, aluminum-induced inhibition of liver phosphofructokinase, an important control site in the glycolytic pathway, is most likely responsible for aluminum-induced inhibition of hepatic glycolysis.
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School of Pharmacy, University of Missouri-Kansas City.
Fox
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Melethil
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Winberg
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Badr
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000535:Aluminum / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D006019:Glycolysis / Q000187:drug effects*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D010732:Phosphofructokinase-1 / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains
D000255:Adenosine Triphosphate; D000535:Aluminum; D010732:Phosphofructokinase-1