Targeting CYP2J to reduce paclitaxel-induced peripheral neuropathic pain

Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12544-12549. doi: 10.1073/pnas.1613246113. Epub 2016 Oct 17.

Abstract

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxel-treated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.

Keywords: TRPV1; chemotherapy-induced neuropathy; neuropathic pain; oxidized lipids; telmisartan.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Antineoplastic Agents, Phytogenic / toxicity
  • Benzimidazoles / pharmacology*
  • Benzoates / pharmacology*
  • Cytochrome P-450 CYP2J2
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Female
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • HEK293 Cells
  • Humans
  • Linoleic Acids / blood
  • Linoleic Acids / metabolism
  • Male
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy / methods
  • Neuralgia / chemically induced
  • Neuralgia / prevention & control*
  • Paclitaxel / pharmacology*
  • Paclitaxel / toxicity
  • Pain Threshold / drug effects
  • Telmisartan

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Antineoplastic Agents, Phytogenic
  • Benzimidazoles
  • Benzoates
  • CYP2J2 protein, human
  • Cyp2j6 protein, mouse
  • Linoleic Acids
  • 9,10-epoxy-12-octadecenoic acid
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP2J2
  • Paclitaxel
  • Telmisartan