Evidence that diclofenac and celecoxib are thyroid hormone receptor beta antagonists

Using in silico and in vitro methods we have shown that both celecoxib and diclofenac but not naproxen exhibit off-target thyroid hormone receptor β antagonist behaviour, which may be linked to their detrimental side effects

Mire Zloh; Noelia Perez-Diaz; Leslie Tang; Pryank Patel; Louise S. Mackenzie


Scholarcy highlights

  • Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase, the enzymes that are responsible for prostaglandin production
  • Using Virtualtox screening programme, structures for diclofenac and celecoxib were assessed for the potential binding to a series of target protein known to be correlated with the side effects, and a normalized toxicity potenital was calculated
  • Our data is the first to demonstrate that T3 induces vasodilation of rat mesenteric arteries, which can be significantly reduced by the thyroid hormone receptor β antagonist MLS
  • Reports vary in opinion on T3 mediated dilation, which has been shown to be endothelium independent, partially endothelium independent or endothelial cells mediated via the interaction with eNOS
  • While TRβ was not found in human umbilical vein endothelial cells or bovine aorta endothelial cells, TRα was found to be highly expressed in HUVECs and BAECs and cross-couples to the phosphoinositol 3-kinase pathway
  • Studies in rat arteries indicate that T3 mediates dilation in endothelium denuded mesenteric arteries, femoral arteries and skeletal muscle resistance arteries, and is not significantly reduced by inhibition with antagonists of the nitric oxide pathway, potassium channels, L-Type calcium channels, calcium sensing receptor, G proteins or protein kinases, and so the actual underlying TRβ T3 dilation remains elusive
  • Diclofenac and celecoxib shared binding profiles with other known thyroid hormone receptor β binding molecules, and exhited TRβ antagonistic behaviours in the reporter assay as well as inhibiting T3 mediated vasodilation

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