PMID- 8240252
OWN - NLM
STAT- MEDLINE
DCOM- 19931203
LR  - 20191210
IS  - 0264-6021 (Print)
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 295 ( Pt 2)
IP  - Pt 2
DP  - 1993 Oct 15
TI  - Econazole inhibits thapsigargin-induced platelet calcium influx by mechanisms 
      other than cytochrome P-450 inhibition.
PG  - 525-9
AB  - Cytochrome P-450 has been suggested as a mediator of the signal between depleted 
      platelet calcium stores and an increase in plasma membrane permeability to 
      calcium which follows depletion of the stores. This hypothesis is based on the 
      observations that inhibitors of cytochrome P-450, such as the imidazole 
      antifungal agents, also inhibit influx of a calcium surrogate (manganese) into 
      calcium-depleted platelets. We tested the effects of econazole and of a 
      cytochrome P-450 inhibitor, carbon monoxide (CO), on thapsigargin (TG)-induced 
      platelet 45Ca2+ influx. TG specifically depletes internal calcium stores and 
      activates store-regulated calcium influx. Econazole blocked 45Ca2+ influx when it 
      was added before TG (IC50 11 microM). Econazole at a concentration (20 microM) 
      that inhibited 83% of TG-induced calcium influx was not inhibitory to TG-induced 
      calcium efflux from 45Ca(2+)-loaded platelets, and did not affect calcium fluxes 
      in resting platelets. This econazole concentration was also inhibitory to calcium 
      influx even when it was added after the stores had been calcium-depleted by EGTA 
      and TG for 15 min and the signal to increase calcium influx had already been 
      generated. Inhibition of cytochrome P-450 with CO bubbled through platelet 
      suspensions did not change calcium influx in resting cells and potentiated 
      TG-induced calcium influx (160% of control calcium accumulation at 20 min). This 
      effect appeared to be concentration-dependent, such that a 5 min exposure to CO 
      produced a greater influx potentiation than a 3 min exposure. These observations 
      indicate that (1) cytochrome P-450 does not mediate store-regulated calcium 
      influx, and (2) econazole probably inhibits store-regulated calcium influx by an 
      alternative mechanism, such as interaction with plasma membrane calcium channels.
FAU - Vostal, J G
AU  - Vostal JG
AD  - Hematology Division, Food and Drug Administration, Bethesda, MD 20892.
FAU - Fratantoni, J C
AU  - Fratantoni JC
LA  - eng
PT  - Journal Article
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Cytochrome P-450 Enzyme Inhibitors)
RN  - 0 (Terpenes)
RN  - 67526-95-8 (Thapsigargin)
RN  - 6Z1Y2V4A7M (Econazole)
RN  - 7U1EE4V452 (Carbon Monoxide)
RN  - EC 7.2.2.10 (Calcium-Transporting ATPases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Biological Transport
MH  - Blood Platelets/*drug effects/enzymology/metabolism
MH  - Calcium/*metabolism
MH  - Calcium-Transporting ATPases/antagonists & inhibitors
MH  - Carbon Monoxide/pharmacology
MH  - *Cytochrome P-450 Enzyme Inhibitors
MH  - Econazole/*pharmacology
MH  - Humans
MH  - In Vitro Techniques
MH  - Terpenes/*antagonists & inhibitors
MH  - Thapsigargin
PMC - PMC1134911
EDAT- 1993/10/15 00:00
MHDA- 1993/10/15 00:01
PMCR- 1993/10/15
CRDT- 1993/10/15 00:00
PHST- 1993/10/15 00:00 [pubmed]
PHST- 1993/10/15 00:01 [medline]
PHST- 1993/10/15 00:00 [entrez]
PHST- 1993/10/15 00:00 [pmc-release]
AID - 10.1042/bj2950525 [doi]
PST - ppublish
SO  - Biochem J. 1993 Oct 15;295 ( Pt 2)(Pt 2):525-9. doi: 10.1042/bj2950525.