Ep. Christian et al., EXTRACELLULAR SITE FOR ECONAZOLE-MEDIATED BLOCK OF CA2-ACTIVATED CA2+CURRENT (I-CRAC) IN T-LYMPHOCYTES( RELEASE), British Journal of Pharmacology, 119(4), 1996, pp. 647-654
1 Standard whole cell patch clamp recording techniques were used to st
udy the pharmacological characteristics and site of econazole-mediated
inhibition of calcium release-activated calcium current (I-crac) in t
he human leukaemic T cell line, Jurkat. 2 Extracellularly applied econ
azole blocked I-carc in a concentration-dependent manner (IC(50)approx
imate to 14 mu M). Block developed over a relatively slow timecourse o
f 30-60 s (10 mu M), and only partially reversed over minutes. 3 Econa
zole dialysed from the pipette into the cytosol at concentrations rang
ing from 0.1 to 30 mu M did not reduce I-carc, or quantitatively affec
t I-crac block by extracellularly applied econazole. 4 A less lipophil
ic quaternary iodide derivative of econazole was synthesized to retard
absorption through the cell membrane. When applied extracellularly, t
his compound blocked I-crac in a concentration-dependent manner with o
nset kinetics comparable to econazole. 5 Results with intracellularly
dialysed econazole and the quaternary econazole derivative provide con
vergent evidence that econazole blocks I-crac via an extracellular int
eraction. 6 The inability of intracellularly applied econazole to inhi
bit I-crac argues against the notion that econazole inhibits capacitat
ive Ca2+ entry pathways secondary to its known inhibitory effects on c
ytochrome P-450.