Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway
Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway
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DOI：
10.1016/j.toxlet.2019.10.016
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发表时间：
2020-01-01
影响因子：
3.5
通讯作者：
Ikeda, Yasumasa
中科院分区：
文献类型：
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作者：
Hamano, Hirofumi;Niimura, Takahiro;Ikeda, Yasumasa
质子泵抑制剂（PPIs）已在世界范围内用于治疗胃肠道疾病。最近的一项研究表明，长期使用质子泵抑制剂会导致缺铁；然而，PPIs是否直接影响铁代谢尚不清楚。我们研究了PPIs对肽hepcidin的影响，hepcidin是一种重要的铁调节激素。首先，我们使用FDA不良事件报告系统数据库，分析ppi的影响。我们发现PPIs以及H2阻滞剂增加了缺铁性贫血的优势比。接下来，用HepG2细胞检测PPIs和H2阻滞剂对hepcidin的作用。PPIs增强了hepcidin的表达，而H2阻滞剂则没有。事实上，PPI奥美拉唑增加了hepcidin的分泌，奥美拉唑诱导的hepcidin上调可通过基因沉默或对芳烃受体的药理抑制来抑制。在小鼠实验中，奥美拉唑还增加了肝脏hepcidin mRNA表达和血液hepcidin水平。用奥美拉唑治疗小鼠，十二指肠和脾脏铁转运蛋白水平降低。综上所述，PPIs通过上调hepcidin抑制十二指肠铁转运蛋白来抑制铁的吸收，从而直接影响铁的代谢。这些发现为ppi诱导铁缺乏的分子机制提供了新的见解。
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.