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HIF hydroxylase inhibitors decrease cellular oxygen consumption depending on their selectivity.

Pascale Sulser1, Christina Pickel1, Julia Günter1,2

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Summary
This summary is machine-generated.

Pharmacologic hydroxylase inhibitors (HIs) treat anemia and inflammation. This study developed a novel assay to characterize HIs, revealing off-target effects that redistribute oxygen in cells.

Keywords:
2-oxoglutarate oxygenase inhibitorRoxadustatanemiahypoxiaprolyl hydroxylase inhibitor

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Cell Biology

Background:

  • Pharmacologic hydroxylase inhibitors (HIs) show promise for anemia, inflammation, and ischemia-reperfusion injury.
  • Understanding HI selectivity and off-target effects is crucial for clinical translation.
  • Current assays lack the ability to differentiate inhibition of key HIF hydroxylases.

Purpose of the Study:

  • To develop a novel assay for discriminating between HIF-α prolyl-4-hydroxylase domain (PHD) and factor inhibiting HIF (FIH) inhibition.
  • To characterize 15 clinical and preclinical HIs based on their selectivity.
  • To investigate the impact of HIs on HIF-dependent pathways and cellular oxygen levels.

Main Methods:

  • Development of a novel assay to distinguish between PHD and FIH inhibition.
  • Characterization of 15 HIs into pan-HIF-α hydroxylase, PHD-selective, and FIH-selective categories.
  • Assessment of HIF-dependent gene regulation, erythropoietin production, and cellular energy metabolism.

Main Results:

  • A novel assay successfully discriminated between PHD and FIH inhibition.
  • HIs were categorized into pan-HIF-α hydroxylase, PHD-selective, and FIH-selective groups.
  • Pan-HIs increased pericellular pO2 more than selective inhibitors, suggesting HIF hydroxylase-independent off-target effects.
  • Energy homeostasis was generally maintained, but oxygen redistribution occurred.

Conclusions:

  • HIs can redistribute oxygen within the cellular microenvironment.
  • Off-target effects of pan-HIs contribute to increased pericellular pO2.
  • These findings highlight the importance of considering oxygen redistribution in hypoxia-associated disease treatments.