Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway

Toxicol Lett. 2020 Jan;318:86-91. doi: 10.1016/j.toxlet.2019.10.016. Epub 2019 Oct 24.

Abstract

Proton pump inhibitors (PPIs) have been used worldwide to treat gastrointestinal disorders. A recent study showed that long-term use of PPIs caused iron deficiency; however, it is unclear whether PPIs affect iron metabolism directly. We investigated the effect of PPIs on the peptide hepcidin, an important iron regulatory hormone. First, we used the FDA Adverse Event Reporting System database and analyzed the influence of PPIs. We found that PPIs, as well as H2 blockers, increased the odds ratio of iron-deficient anemia. Next, HepG2 cells were used to examine the action of PPIs and H2 blockers on hepcidin. PPIs augmented hepcidin expression, while H2 blockers did not. In fact, the PPI omeprazole increased hepcidin secretion, and omeprazole-induced hepcidin upregulation was inhibited by gene silencing or the pharmacological inhibition of the aryl hydrocarbon receptor. In mouse experiments, omeprazole also increased hepatic hepcidin mRNA expression and blood hepcidin levels. In mice treated with omeprazole, protein levels of duodenal and splenic ferroportin decreased. Taken together, PPIs directly affect iron metabolism by suppressing iron absorption through the inhibition of duodenal ferroportin via hepcidin upregulation. These findings provide a new insight into the molecular mechanism of PPI-induced iron deficiency.

Keywords: Hepcidin; Iron deficiency; Proton pump inhibitor.

Publication types

  • Comparative Study

MeSH terms

  • Anemia, Iron-Deficiency / blood
  • Anemia, Iron-Deficiency / chemically induced*
  • Anemia, Iron-Deficiency / physiopathology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cation Transport Proteins / metabolism
  • Duodenum / drug effects*
  • Duodenum / metabolism
  • Duodenum / physiopathology
  • Hep G2 Cells
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Hepcidins / metabolism*
  • Histamine H2 Antagonists / toxicity
  • Humans
  • Intestinal Absorption / drug effects*
  • Iron / blood*
  • Iron / deficiency
  • Male
  • Mice, Inbred C57BL
  • Proton Pump Inhibitors / toxicity*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*

Substances

  • AHR protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Cation Transport Proteins
  • HAMP protein, human
  • Hamp protein, mouse
  • Hepcidins
  • Histamine H2 Antagonists
  • Proton Pump Inhibitors
  • Receptors, Aryl Hydrocarbon
  • metal transporting protein 1
  • Iron