High ability of zileuton ((±)-1-(1-benzo[b]thien-2-ylethyl)-1-hydroxyurea) to stimulate IK(Ca) but suppress IK(DR) and IK(M) independently of 5-lipoxygenase inhibition

Eur J Pharmacol. 2020 Nov 15:887:173482. doi: 10.1016/j.ejphar.2020.173482. Epub 2020 Aug 12.


Zileuton (Zyflo®) is regarded to be an inhibitor of 5-lipoxygenase. Although its effect on Ca2+-activated K+ currents has been reported, its overall ionic effects on neurons are uncertain. In whole-cell current recordings, zileuton increased the amplitude of Ca2+-activated K+ currents with an EC50 of 3.2 μM in pituitary GH3 lactotrophs. Furthermore, zileuton decreased the amplitudes of both delayed-rectifier K+ current (IK(DR)) and M-type K+ current (IK(M)). Conversely, no modification of hyperpolarization-activated cation current (Ih) was demonstrated in its presence of zileuton, although the subsequent addition of cilobradine effectively suppressed the current. In inside-out current recordings, the addition of zileuton to the bath increased the probability of large-conductance Ca2+-activated K+ (BKCa) channels; however, the subsequent addition of GAL-021 effectively reversed the stimulation of channel activity. The kinetic analyses showed an evident shortening in the slow component of mean closed time of BKCa channels in the presence of zileuton, with minimal change in mean open time or that in the fast component of mean closed time. The elevation of BKCa channels caused by zileuton was also observed in hippocampal mHippoE-14 neurons, without any modification of single-channel amplitude. In conclusion, except for its suppression of 5-lipoxygenase, our results indicate that zileuton does not exclusively act on BKCa channels, and its inhibitory effects on IK(DR) and IK(M) may combine to exert strong influence on the functional activities of electrically excitable cells in vivo.

Keywords: Ca(2+)-activated K(+) current; Delayed-rectifier K(+) current; Electrically excitable cell; Hyperpolarization-activated cation current; Large-conductance Ca(2+)-activated K(+) channel; M-type K(+) current; Zileuton.

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / physiology
  • Cell Line
  • Delayed Rectifier Potassium Channels / antagonists & inhibitors*
  • Delayed Rectifier Potassium Channels / physiology
  • Dose-Response Relationship, Drug
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • Hydroxyurea / analogs & derivatives*
  • Hydroxyurea / pharmacology
  • Lipoxygenase Inhibitors / pharmacology*
  • Mice
  • Potassium Channels, Calcium-Activated / agonists*
  • Potassium Channels, Calcium-Activated / physiology


  • Delayed Rectifier Potassium Channels
  • Lipoxygenase Inhibitors
  • Potassium Channels, Calcium-Activated
  • Arachidonate 5-Lipoxygenase
  • zileuton
  • Hydroxyurea