Journal Article

Acute Acetaminophen Intoxication Leads to Hepatic Iron Loading by Decreased Hepcidin Synthesis

Rachel P. L. van Swelm, Coby M. M. Laarakkers, Linda Blous, Janny G. P. Peters, Esmeralda N. Blaney Davidson, Peter M. van der Kraan, Dorine W. Swinkels, Rosalinde Masereeuw and Frans G. M. Russel

in Toxicological Sciences

Volume 129, issue 1, pages 225-233
Published in print September 2012 | ISSN: 1096-6080
Published online May 2012 | e-ISSN: 1096-0929 | DOI:
Acute Acetaminophen Intoxication Leads to Hepatic Iron Loading by Decreased Hepcidin Synthesis

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Acetaminophen (APAP), a major cause of acute liver injury in the Western world, is mediated by metabolism and oxidative stress. Recent studies have suggested a role for iron in potentiating APAP-induced liver injury although its regulatory mechanism is not completely understood. The current study was designed to unravel the iron-regulating pathways in mice after APAP-induced hepatotoxicity. Mice with severe injury showed a significant increase in liver iron concentration and oxidative stress. Concurrently, the plasma concentration of hepcidin, the key regulator in iron metabolism, and hepatic hepcidin antimicrobial peptide (Hamp) mRNA expression levels were significantly reduced. We showed that hepcidin transcription was inhibited via several hepcidin-regulating factors, including the bone morphogenetic protein/small mother against decapentaplegic (BMP/SMAD) pathway, CCAAT/enhancer-binding protein α (C/EBPα), and possibly also via erythropoietin (EPO). Downregulation of the BMP/SMAD signaling pathway was most likely caused by hypoxia-inducible factor 1α (HIF-1α), which was increased in mice with severe APAP-induced liver injury. HIF-1α stimulates cleaving of hemojuvelin, the cofactor of the BMP receptor, thereby blocking BMP-induced signaling. In addition, gene expression levels of C/ebpα were significantly reduced, and Epo mRNA expression levels were significantly increased after APAP intoxication. These factors are regulated through HIF-1α during oxidative stress and suggest that HIF-1α is a key modulator in reduced hepcidin transcription after APAP-induced hepatotoxicity. In conclusion, acute APAP-induced liver injury leads to activation of HIF-1α, which results in a downregulation in hepcidin expression through a BMP/SMAD signaling pathway and through C/EBPα inhibition. Eventually, this leads to hepatic iron loading associated with APAP cytotoxicity.

Keywords: Drug-induced liver injury; HAMP; oxidative stress; Bmp; Smad

Journal Article.  5878 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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