title: Fluvastatin inhibits mast cell degranulation without changing the cytoplasmic Ca2+ level.
abstract: We evaluated the pharmacological effect of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) on mast cell degranulation in RBL-2H3 cells. A hydrophilic statin (pravastatin) did not inhibit degranulation induced by dinitrophenol-human serum albumin (DNP-HSA); in contrast, lipophilic statins (simvastatin, fluvastatin and atorvastatin) inhibited DNP-HSA-induced degranulation in that order. The inhibitory effects were completely attenuated by simultaneous treatment with 100-1000 microM mevalonic acid for 4 h. We used fluvastatin to clarify the mechanism of the statin-mediated inhibitory action of mast cell degranulation. Fluvastatin (3 microM) had no effect on Ca(2+) release from the endoplasmic reticulum or Ca(2+) influx in the DNP-HSA- or thapsigargin-stimulated cells. Fluvastatin treatment also had no effect on the total granule content of the cell or sensitivity to DNP-HSA and IgE. Fluvastatin (3 microM, 24 h treatment) also failed to affect the morphology, proliferation, and viability of RBL-2H3 cells. Geranylgeranyl transferase inhibitor, GGTI-286 (20 microM), but not farnesyl transferase inhibitor, FPTIII (20 microM), inhibited the DNP-HSA-induced degranulation. The GGTI-286-induced inhibitory action was not associated with a decrease in the cytoplasmic Ca(2+) level. In conclusion, fluvastatin at a lower concentration range inhibited DNP-HSA-induced degranulation without affecting the cytoplasmic Ca(2+) response and also without changing the amount of granule content and proliferation of the mast cells. The statin-induced inhibitory action may be mediated by the suppression of geranylgeranyl transferase via the depletion of intracellular mevalonic acid.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Oka
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism*; D015550:Cell Degranulation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D003593:Cytoplasm / Q000187:drug effects* / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism; D004140:Dinitrophenols / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008798:Mevalonic Acid / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D012709:Serum Albumin / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: C436083:2-(2-oxo-2-((3,7,11-trimethyl-2,6,10-dodecatrienyl)oxy)aminoethyl)phosphonic acid, (2,2-dimethyl-1-oxopropoxy)methyl ester sodium; D004140:Dinitrophenols; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; C437105:GGTI 286; D007211:Indoles; D063065:Organophosphonates; D011106:Polyisoprenyl Phosphates; D012709:Serum Albumin; C058064:dinitrophenyl-human serum albumin conjugate; C502746:farnesyl thiopyrophosphate; D000077340:Fluvastatin; D019284:Thapsigargin; D002784:Cholesterol; D019883:Alkyl and Aryl Transferases; D007930:Leucine; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid; D002118:Calcium