Interaction of chelerythrine with inositol phosphate metabolism.
Chelerythrine, a potent inhibitor of protein kinase C (PKC), was evaluated for its effect on inositol phosphate (IP) metabolism in newborn rat cardiomyocytes in culture. In a first step, we evaluated the effect of chelerythrine on IP accumulation in basal conditions. For a 10(-4) M dose, 5-phosphatase activity (which dephosphorylates IP3 into IP2) was completely blocked and we observed a large increase in IP accumulation limited to IP2 without any increase in IP3, strongly suggesting that chelerythrine at this dose modifies IP metabolism. At a lower dose (10(-5) M) of chelerythrine, which did not modify IP accumulation and 5-phosphatase activity in basal conditions, the response to angiotensin II stimulation was completely abolished by the addition of chelerythrine. We conclude thus that chelerythrine, even at 10(-5) M, interacts markedly with IP metabolism, and caution should be exerted when interpreting the results obtained with this drug, which is still currently used at this dose.
Le Corvoisier
Philippe
P
Unité INSERM U400 Faculté de Médecine, 8 rue du Général Sarrail 94000 Créteil France.
Lacotte
Jérôme
J
Laplace
Monique
M
Crozatier
Bertrand
B
D000470:Alkaloids; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D053119:Benzophenanthridines; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism*; D000072181:Inositol Polyphosphate 5-Phosphatases; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D010738:Type C Phospholipases / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D010617:Phenanthridines; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C016299:chelerythrine; D011493:Protein Kinase C; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D010738:Type C Phospholipases