Voriconazole, an antifungal triazol that causes visual side effects, is an inhibitor of TRPM1 and TRPM3 channels

Invest Ophthalmol Vis Sci. 2015 Feb 3;56(2):1367-73. doi: 10.1167/iovs.14-15270.

Abstract

Purpose: Administration of voriconazole, an antifungal triazole, causes transient visual disturbances in patients and attenuates the b-wave of the ERG. We sought to identify the retinal target of voriconazole underlying the effect on the ERG b-wave.

Methods: Electroretinograms were recorded from mice before and after intraperitoneal injection of voriconazole. The effect of voriconazole on ON-bipolar cells was tested by patch-clamp recordings of ON-bipolar cells in mouse retinal slices. Effects of voriconazole on mGluR6 and TRPM3 were assessed by patch-clamp recordings of Chinese hamster ovary (CHO) and HEK293 cells transfected with either TRPM3 or mGluR6 plus Kir3.1/Kir3.4.

Results: Voriconazole attenuated the ERG b-wave in mice, and inhibited ON-bipolar cell responses evoked by application of CPPG, an mGluR6 antagonist, onto the ON-bipolar cell dendrites, indicating that voriconazole blocks a step in the mGluR6-TRPM1 signal transduction pathway. Voriconazole almost completely blocked capsaicin-activated currents in ON-bipolar cells, which have been attributed to direct activation of the TRPM1 cation channel. Furthermore, application of voriconazole to CHO cells expressing TRPM3, a closely related channel to TRPM1, showed that voriconazole reversibly blocked pregnenolone sulfate-stimulated TRPM3 currents in transfected cells. In contrast, voriconazole only slightly inhibited mGluR6-mediated activation of G-protein activated inward rectifier potassium (GIRK) currents in cotransfected cells, suggesting that mGluR6 is not the primary target of voriconazole in ON-bipolar cells.

Conclusions: The visual disturbances associated with voriconazole are likely due to block of TRPM1 channels in retinal ON-bipolar cells. Other neurological effects of voriconazole may be due to block of TRPM3 channels expressed in the brain.

Keywords: TRPM1; b-wave; bipolar cell; mGluR6; voriconazole.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antifungal Agents / toxicity
  • Cells, Cultured
  • Cricetinae
  • Dark Adaptation / drug effects
  • Dark Adaptation / physiology
  • Disease Models, Animal
  • Electroretinography
  • Female
  • Mice
  • Retinal Diseases / chemically induced
  • Retinal Diseases / metabolism*
  • Retinal Diseases / physiopathology
  • TRPM Cation Channels / antagonists & inhibitors*
  • TRPM Cation Channels / metabolism
  • Visual Acuity / drug effects*
  • Voriconazole / toxicity*

Substances

  • Antifungal Agents
  • TRPM Cation Channels
  • TRPM3 protein, mouse
  • Trpm1 protein, mouse
  • Voriconazole