Inhibition of Ca2+ transport pathways in thymic lymphocytes by econazole, miconazole, and SKF 96365.
Cytochrome P-450 has been proposed to underlie the mechanism of regulation of the plasma membrane Ca2+ permeability by the Ca2+ content of the inositol 1,4,5-trisphosphate-sensitive Ca2+ pool. We have investigated the effects on divalent cation uptake in rat thymic lymphocytes of three structurally related imidazole reagents reported to inhibit redox mechanisms. Changes in intracellular Ca2+ concentration and intracellular Mn2+ concentration were measured fluorimetrically with indo-1 and/or quin-2. Econazole, miconazole, and SKF 96365 were found to be potent blockers of Ca2+ and Mn2+ uptake activated by release of Ca2+ from intracellular stores induced by thapsigargin. Additionally, we found that concentrations of these agents required to abolish divalent cation uptake also released Ca2+ from the thapsigargin-sensitive intracellular stores, consistent with inhibition of the endosomal Ca(2+)-ATPase. In agreement with this suggestion, we have found that all three of these agents are potent inhibitors of isolated sarcoplasmic reticulum Ca(2+)-ATPase. We conclude that econazole, miconazole, and SKF 96365 inhibit cytochrome P-450-independent filling of intracellular Ca2+ pools, as well as store-regulated Ca2+ entry, and caution against the use of these compounds as selective inhibitors of cytochrome P-450.
Mason
M J
MJ
Department of Physiology, Tulane University, New Orleans, Louisiana 70112.
Mayer
B
B
Hymel
L J
LJ
D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000493:pharmacokinetics*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000502:physiology; D002463:Cell Membrane Permeability / Q000502:physiology; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D004464:Econazole / Q000494:pharmacology*; D005453:Fluorescence; D007093:Imidazoles / Q000494:pharmacology*; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008825:Miconazole / Q000494:pharmacology*; D010084:Oxidation-Reduction; D054328:Proton Pump Inhibitors; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D054328:Proton Pump Inhibitors; D013729:Terpenes; D019284:Thapsigargin; D004464:Econazole; D008825:Miconazole; D000252:Calcium-Transporting ATPases; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium