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Liver disease is responsible for more than 42,000 deaths yearly. Elevated hepatic iron levels have been shown to play a role in chronic liver diseases including hereditary hemochromatosis, thalassemia and chronic hepatitis C, while acetaminophen (APAP) is the leading cause of acute liver failure. The goal of this study was to determine whether increased hepatic iron affects APAP induced cytotoxicity, reactive oxygen species (ROS) production and/or mitochondrial dysfunction in primary mouse hepatocytes (PMH) that are differentiated and have gap junction intracellular integrity, properties associated with hepatocytes in vivo and important for conducting toxicant studies. Treatment of PMH with the iron donor 3,5,5-trimethyl-hexanoyl ferrocene (TMHF) caused an elevation in ferritin, reduction in transferrin receptor 1, and accumulation of hemosiderin, but TMHF treatment alone did not induce ROS or cause mitochondrial dysfunction. The threshold APAP dose that induced PMH cell death after TMHF treatment of PMH was lower than in the absence of TMHF. In addition, treatment with the iron chelator desferoxamine (DFO) protected from APAP and resulted in a higher threshold dose being needed to induce cell death. We also showed that after TMHF treatment, APAP induced ROS and mitochondrial dysfunction at earlier time points than treatment with APAP alone; treatment with DFO increased the length of time required for APAP to induce ROS and mitochondrial dysfunction; and treatment with DFO, subsequent to TMHF, partially protected against TMHF potentiated APAP injury. We conclude that iron potentiates the effects of APAP on cytotoxicity, ROS production, and mitochondrial dysfunction in PMH.
Department of Microbiology and Immunology.
This article was published in the following journal.
Name: Toxicological sciences : an official journal of the Society of Toxicology
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