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Activation of glycogen phosphorylase in rat pheochromocytoma PC12 cells and isolated hepatocytes by organophosphates.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 1990 Jan 15; Vol. 39 (2), pp. 347-54. - Publication Year :
- 1990
-
Abstract
- Several organophosphates including diisopropylfluorophosphonate (DPF) and a variety of compounds used as chemical warfare agents produced dose- and time-dependent increases in phosphorylase-a, the phosphorylated form of glycogen phosphorylase in rat pheochromocytoma cells, PC12, and isolated hepatocytes. Increases in phosphorylase-a did not occur in cells exposed to the carbamates, physostigmine or pyridostigmine, or to O-ethyl S-2-diisopropylaminoethylmethyl-phosphonathiolate (VX), an organophosphate which is protonated at physiological pH. When extracellular pH was increased to pH 8, VX acted like the other organophosphates and increased phosphorylase-a activity. The possibility that organophosphates increase phosphorylase-a in intact cells by releasing Ca2+ from intracellular binding sites is supported by the following findings: organophosphate-induced increases in phosphorylase-a did not correlate with changes in cyclic AMP in the two cell types studied; in PC12 cells, increases in this activity occurred in the absence of extracellular calcium and were not inhibited by the calcium channel blocker, verapamil; fluorescence of the calcium sensitive dye, Quin-2, in PC12 cells preloaded with the acetoxymethyl ester of the dye was increased by soman; finally, addition of the calcium ionophore, A23187, to PC12 cells maintained in calcium-free medium caused sarin-stimulated phosphorylase-a activity to return rapidly to basal levels. Collectively, these data argue strongly that organophosphates increase phosphorylase-a activity in intact cells via a novel mechanism involving release of calcium from intracellular binding sites.
- Subjects :
- Adenine Nucleotides analysis
Animals
Calcium analysis
Cells, Cultured drug effects
Cytosol analysis
Dose-Response Relationship, Drug
Drug Interactions
Enzyme Activation drug effects
Hydrogen-Ion Concentration
Liver enzymology
Male
Physostigmine pharmacology
Pyridostigmine Bromide pharmacology
Rats
Tumor Cells, Cultured drug effects
Verapamil pharmacology
Liver drug effects
Organophosphorus Compounds pharmacology
Pheochromocytoma enzymology
Phosphorylase a metabolism
Phosphorylases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2952
- Volume :
- 39
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 2302257
- Full Text :
- https://doi.org/10.1016/0006-2952(90)90034-i