Dexfenfluramine modulates hepatic glycogen metabolism by a calcium-dependent pathway.
In this study, the mechanism of action of dexfenfluramine (DEXF) at the hepatic level was investigated. The drug is shown to bind to the alpha 1-adrenergic receptor and to increase intracellular calcium in isolated rat hepatocytes, thereby activating phosphorylase via a calcium-dependent mechanism. Moreover, phosphorylase activation by DEXF was inhibited by different agents that interfere with the alpha 1-adrenergic signalling system: prazosin, phorbol 12 alpha-myristate 13 beta-acetate (PMA), and DEXF itself. We also show that phosphorylase activation induced by catecholamines and analogues (epinephrine, phenylephrine), whose actions are mediated by a calcium-dependent mechanism, was counteracted by the drug in the submillimolar range (0.1-1 mM). The activation of glycogenolysis by the drug is accompanied by a stimulation of the glycolytic flux (54% increase in lactate plus pyruvate accumulation), consistent with an increase in fructose-2,6-bisphosphate (F-2,6-BP) levels (36%). These results indicate that the interaction of DEXF with the alpha 1-adrenergic receptor channels glucose 6-phosphate derived from glycogen away from glucose production into the glycolytic pathway.
Comte
B
B
Département de nutrition, Université de Montréal, QC, Canada.
Romanelli
A
A
Haddad
P
P
van de Werve
G
G
D000322:Adrenergic Agonists / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D005277:Fenfluramine / Q000494:pharmacology*; D005635:Fructosediphosphates / Q000378:metabolism; D005947:Glucose / Q000096:biosynthesis; D019344:Lactic Acid / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D006005:Phosphorylases / Q000187:drug effects / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects
D000322:Adrenergic Agonists; D000316:Adrenergic alpha-Agonists; D005635:Fructosediphosphates; D008112:Liver Glycogen; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D005277:Fenfluramine; D019344:Lactic Acid; C027652:fructose 2,6-diphosphate; D019289:Pyruvic Acid; D006005:Phosphorylases; D005947:Glucose; D002118:Calcium; D004837:Epinephrine