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PO3-5-24

Proton Pump Inhibitor Involves Abnormality of Iron Metabolism through Hepcidin Regulation

[Speaker] Hirofumi Hamano:1,2
[Co-author] Yasumasa Ikeda:3, Yuya Horinouchi:3, Yoshito Zamami:1,2, Masaki Imanishi:1, Yuki Izawa-Ishizawa:3, Licht Miyamoto:4, Koichiro Tsuchiya:4, Keisuke Ishizawa:1,2, Toshiaki Tamaki:3
1:Department of Pharmacy, Tokushima University Hospital, Japan, 2:Department of Clinical Pharmacy, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan, 3:Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Japan, 4:Department of Medical Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

Background: Proton pump inhibitor (PPI) is used in worldwide as drugs for prevention and treatment of gastrointestinal disorders. Recent study has revealed that anemia with iron deficiency is caused in patients with PPI in the long term. Hepcidin, a secreted hormone derived from hepatocytes, is a key regulator of systemic iron metabolism for regulating iron efflux by the internalization and degradation of ferroportin (FPN). However, the effect of PPI on hepcidin and iron metabolism has remained unclear. In the present study, we investigated the involvement of PPI on iron metabolism via hepcidin.

Methods: First, we used a large human claims database, FDA Adverse Event Reporting System (FAERS), and analyzed the influence of PPIs and other drugs for gastrointestinal disorders. Next, HepG2 cells were used to examine the mechanism of omeprazole (OME), a compound of PPI, on hepcidin regulation in in vitro experiments. In in vivo experiment, OME was orally administered in mice to examine hepatic hepcidin and duodenal FPN.

Results: The result of FAERS analysis showed that PPIs including OME and H2 blocker increased the odds ratio of iron deficient anemia. In in vitro experiments, OME augmented hepcidin expression in HepG2 cells, on the other hand, H2 blocker did not. OME-induced hepcidin upregulation was inhibited by gene silencing or pharmacological inhibition of Aryl Hydrocarbon Receptor. In in vivo experiments, mice with OME treatment showed the elevated hepatic hepcidin mRNA expression compared with vehicle-treated mice. In addition, the protein level of duodenal FPN expression was decreased in mice with OME administration.

Conclusion: These findings indicate that PPI suppresses iron absorption through the inhibition of duodenal FPN via hepcidin upregulation, causing iron deficiency.

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