Iron potentiates acetaminophen-induced oxidative stress and mitochondrial dysfunction in cultured mouse hepatocytes.
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, whereas 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 (PMHs) that are differentiated and have gap junctional intracellular integrity, properties associated with hepatocytes in vivo and important for conducting toxicant studies. Treatment of PMHs 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 PMHs was lower than in the absence of TMHF. In addition, treatment with the iron chelator deferoxamine (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 PMHs.
Moon
Mi Sun
MS
Department of Microbiology and Immunology, Penn State Cancer Institute, Penn State Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Richie
John P
JP
Isom
Harriet C
HC
D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D005296:Ferrous Compounds / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D000075163:Metallocenes; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D005296:Ferrous Compounds; D000075163:Metallocenes; D017382:Reactive Oxygen Species; D000082:Acetaminophen; C050224:3,5,5-trimethylhexanoylferrocene