Participation of tyrosine kinase and phospholipase Cgamma in isradipine-induced proliferation of cultured human gingival fibroblasts.
Some kinds of drugs such as calcium (Ca(2+)) channel antagonists, antiepileptics and immunosuppressants cause gingival overgrowth as a side effect, the mechanism of which is still unclear. We have examined the effects of isradipine, one of the dihydropyridine-derivative Ca(2+) channel antagonists, on cultured human gingival fibroblast Gin-1 cells. In the present study, to elucidate the mechanism by which isradipine causes gingival overgrowth, we examined whether tyrosine kinase (TK) and phopholipase Cgamma (PLCgamma) are involved in the isradipine-induced proliferation of gingival fibroblasts. Herbimycin A (1 microM) remarkably inhibited the isradipime (10 microM)-induced proliferation. Both U73122 (5 microM), a PLCgamma inhibitor, and xestospongin C (5 microM), an antagonist of a receptor of inositol 1,4,5-trisphosphate in Ca(2+) stores, significantly reduced the [Ca(2+)]i raised by isradipine (10 microM). Thus, the findings obtained here indicate that TK and PLCgamma are closely involved in the isradipine-induced [Ca(2+)]i rise to elicit gingival overgrowth.
Hattori
Toshimi
T
Department of Dental Pharmacology, Matsumoto Dental University, Shiojiri, Japan. hattori@po.mdu.ac.jp
Ara
T
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Wang
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D016227:Benzoquinones; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005881:Gingiva / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D017275:Isradipine / Q000494:pharmacology*; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D010080:Oxazoles / Q000494:pharmacology; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives
D016227:Benzoquinones; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D004963:Estrenes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D010080:Oxazoles; D011760:Pyrrolidinones; D011809:Quinones; C108644:xestospongin A; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D051966:Phospholipase C gamma; D017275:Isradipine