Cell-type specificity of inhibition of glycolysis by 5-amino-4-imidazolecarboxamide riboside. Lack of effect in rabbit cardiomyocytes and human erythrocytes, and inhibition in FTO-2B rat hepatoma cells.
The nucleoside AICAriboside (5-amino-4-imidazolecarboxamide riboside) has been shown to inhibit glycolysis in isolated rat hepatocytes [Vincent, Bontemps and Van den Berghe (1992) Biochem. J. 281, 267-272]. The effect is mediated by AICA-ribotide (ZMP), the product of the phosphorylation of AICA-riboside by adenosine kinase. To assess the cell-type specificity of the effect, studies were conducted in rabbit cardiomyocytes, human erythrocytes and rat hepatoma FTO-2B cells. AICA-riboside had no effect on glycolysis in cardiomyocytes, and a slight stimulatory effect in erythrocytes, but inhibited glycolysis by 65% at 250 microM concentration in FTO-2B cells, although only when tissue-culture medium was replaced by Krebs-Ringer bicarbonate buffer. At 500 microM AICAriboside, ZMP remained undetectable in cardiomyocytes, but reached 0.65 mM in erythrocytes and 5 mM in FTO-2B cells. In the latter, AICAriboside provoked up to 2-fold elevations of glucose 6-phosphate and fructose 6-phosphate, accompanied by a decrease in fructose 1,6-bisphosphate. This indicated inhibition of 6-phosphofructo-1-kinase (PFK-1). Accordingly, in FTO-2B cell-free extracts, the activity of PFK-1, measured under physiological conditions, was inhibited by approx. 70% by 5 mM ZMP. ZMP had a less pronounced effect on the activity of PFK-1 in normal rat liver; it did not influence the activity of PFK-1 in rat muscle, rabbit heart and human erythrocytes. It is concluded that the inhibitory effect of AICAriboside on glycolysis is dependent on both (1) the capacity of the cells to accumulate ZMP and (2) the presence of target enzymes which are sensitive to ZMP.
Javaux
F
F
Laboratory of Physiological Chemistry, International Institute of Cellular and Molecular Pathology, Brussels, Belgium.
Vincent
M F
MF
Wagner
D R
DR
van den Berghe
G
G
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004098:Dihydroxyacetone / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005636:Fructosephosphates / Q000378:metabolism; D019298:Glucose-6-Phosphate; D005958:Glucosephosphates / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D007773:Lactates / Q000096:biosynthesis; D019344:Lactic Acid; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D012263:Ribonucleosides / Q000494:pharmacology*; D012265:Ribonucleotides / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D005636:Fructosephosphates; D005958:Glucosephosphates; D007773:Lactates; D012263:Ribonucleosides; D012265:Ribonucleotides; D019344:Lactic Acid; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D019298:Glucose-6-Phosphate; C027618:fructose-6-phosphate; D000248:Adenosine Kinase; C031143:AICA ribonucleotide; D004098:Dihydroxyacetone