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[Effects of tamoxifen on the voltage-dependent ionic currents in mouse colonic smooth muscle cells]
Dong Min Lee1, Sung Jong Chang, Chan Guk Park
1Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Korea.
Background/Aims:
Tamoxifen is a widely used anticancer drug for breast cancer with frequent gastrointestinal side effects. Changes in gastrointestinal motility is associated with altered activities of membrane ion channels. Ion channels have important role in regulating membrane potential and cell excitability. This study was performed to investigate the effects of tamoxifen on the membrane ionic currents in colonic smooth muscle cells.
Methods:
Murine colonic smooth muscle cells were isolated from the proximal colon using collagenase, and the membrane currents were recorded using a whole-cell patch clamp technique.
Results:
Two types of voltage-dependent K(+) currents were recorded (A-type and delayed rectifier K(+) currents). Tamoxifen inhibited both types of voltage-dependent K(+) currents in a dose-dependent manner. However, tamoxifen did not change the half-inactivation potential and the recovery time of voltage-dependent K(+) currents. Chelerythrine, a protein kinase C inhibitor or phorbol 12, 13-dibutyrate, a protein kinase C activator did not affect the voltage-dependent K(+) currents. Guanosine 5'-O-(2-thio-diphosphate) did not affect the tamoxifen-induced inhibition of voltage-dependent K(+) currents. Tamoxifen inhibited voltage-dependent Ca(2+) currents completely in whole-test ranges.
Conclusions:
These results suggest that tamoxifen can alter various membrane ionic currents in smooth muscle cells and cause some adverse effects on the gastrointestinal motility.
Insights
Tamoxifen, an anticancer drug, inhibits key potassium and calcium ion currents in colonic smooth muscle cells. This action may explain the gastrointestinal side effects associated with tamoxifen treatment.
Area of Science:
- Pharmacology
- Physiology
- Gastroenterology
Context:
- Tamoxifen is a vital breast cancer therapeutic.
- Gastrointestinal (GI) dysfunction is a common side effect of tamoxifen.
- GI motility is regulated by ion channel activity in smooth muscle cells.
Purpose:
- To investigate the direct effects of tamoxifen on membrane ionic currents in colonic smooth muscle cells.
- To elucidate the ion channel mechanisms underlying tamoxifen-induced GI side effects.
Summary:
- Tamoxifen was found to inhibit both A-type and delayed rectifier potassium currents in a dose-dependent manner in murine colonic smooth muscle cells.
- Furthermore, tamoxifen completely inhibited voltage-dependent calcium currents.
- These effects were independent of protein kinase C signaling pathways.
Impact:
- The study reveals that tamoxifen alters membrane ionic currents in colonic smooth muscle.
- These alterations provide a potential cellular mechanism for tamoxifen's adverse effects on gastrointestinal motility.
- Understanding these mechanisms may aid in mitigating tamoxifen's GI side effects.
