Related Experiment Videos
Modulation of human T-lymphocyte plasma membrane Ca2+ permeability by imidazole antimycotics
E H Hornstein1, D Vassilopoulos, D E Thomas
1Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, DC 20307-5001, USA.
Abstract:
The role of cytochrome P-450 in the regulation of plasma membrane Ca+2 permeability of human peripheral T-lymphocytes by intracellular Ca+2 was examined. We assessed the effect of imidazole inhibitors of cytochrome P-450 on the intracytoplasmic free Ca+2 ([Ca+2]i) response generated using the microsomal ATPase inhibitor thapsigargin (THG) to deplete the intracellular Ca+2 stores. Econazole, miconazole and clotrimazole dramatically inhibited the THG mediated increase in [Ca+2]i and induced an increase in [Ca+2]i themselves. This inhibitory effect was previously observed in other cell systems and was attributed to inhibition of cytochrome P-450 by these agents. However, we evaluated a variety of structurally dissimilar P-450 inhibitors and found that none affected [Ca+2]i, indicating that the mechanism of imidazole action does not involve P-450.
Insights
Imidazole compounds, like econazole, do not regulate calcium permeability in T-lymphocytes by inhibiting cytochrome P-450. This study found no evidence that cytochrome P-450 affects intracellular calcium levels in these cells.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Cytochrome P-450 enzymes are crucial in drug metabolism and cellular signaling.
- Intracellular calcium ([Ca+2]i) plays a vital role in T-lymphocyte activation and function.
- Imidazole antifungals are known to inhibit cytochrome P-450 in various cell types.
Purpose of the Study:
- To investigate the role of cytochrome P-450 in regulating plasma membrane calcium permeability in human peripheral T-lymphocytes.
- To determine if imidazole inhibitors of cytochrome P-450 influence intracellular calcium ([Ca+2]i) levels.
Main Methods:
- Human peripheral T-lymphocytes were treated with thapsigargin (THG) to deplete intracellular calcium stores.
- The effect of imidazole compounds (econazole, miconazole, clotrimazole) on THG-induced calcium responses was measured.
- Various structurally dissimilar cytochrome P-450 inhibitors were used to assess their impact on intracellular calcium.
Main Results:
- Imidazole compounds (econazole, miconazole, clotrimazole) significantly inhibited the THG-mediated increase in intracellular calcium ([Ca+2]i).
- These imidazole compounds also induced an increase in [Ca+2]i independently.
- However, a diverse range of other cytochrome P-450 inhibitors did not affect intracellular calcium levels in T-lymphocytes.
Conclusions:
- The observed effects of imidazole compounds on T-lymphocyte calcium are not mediated through the inhibition of cytochrome P-450.
- The mechanism underlying the action of imidazole compounds on intracellular calcium in T-lymphocytes requires further investigation and does not involve cytochrome P-450 inhibition.