Econazole inhibits thapsigargin-induced platelet calcium influx by mechanisms other than cytochrome P-450 inhibition.

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  • Author(s): Vostal JG;Vostal JG; Fratantoni JC
  • Source:
    The Biochemical journal [Biochem J] 1993 Oct 15; Vol. 295 ( Pt 2), pp. 525-9.
  • Publication Type:
    Journal Article
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Published by Portland Press on behalf of the Biochemical Society Country of Publication: England NLM ID: 2984726R Publication Model: Print Cited Medium: Print ISSN: 0264-6021 (Print) Linking ISSN: 02646021 NLM ISO Abbreviation: Biochem J Subsets: MEDLINE
    • Publication Information:
      Original Publication: London, UK : Published by Portland Press on behalf of the Biochemical Society
    • Subject Terms:
      Cytochrome P-450 Enzyme Inhibitors*; Blood Platelets/*drug effects ; Calcium/*metabolism ; Econazole/*pharmacology ; Terpenes/*antagonists & inhibitors; Biological Transport ; Blood Platelets/enzymology ; Blood Platelets/metabolism ; Calcium-Transporting ATPases/antagonists & inhibitors ; Carbon Monoxide/pharmacology ; Humans ; In Vitro Techniques ; Thapsigargin
    • Abstract:
      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.
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    • Accession Number:
      0 (Cytochrome P-450 Enzyme Inhibitors)
      0 (Terpenes)
      67526-95-8 (Thapsigargin)
      6Z1Y2V4A7M (Econazole)
      7U1EE4V452 (Carbon Monoxide)
      EC 7.2.2.10 (Calcium-Transporting ATPases)
      SY7Q814VUP (Calcium)
    • Publication Date:
      Date Created: 19931015 Date Completed: 19931203 Latest Revision: 20191210
    • Publication Date:
      20250114
    • Accession Number:
      PMC1134911
    • Accession Number:
      10.1042/bj2950525
    • Accession Number:
      8240252