Heme-oxygenase-mediated iron accumulation in the liver.
Heme oxygenase (HO) isozymes, HO-1 and HO-2, catalyze the conversion of heme to iron, carbon monoxide, and biliverdin. The present study was aimed at elucidating the role of the HO system in iron accumulation and oxidative stress in the liver. We have also studied the regulation of an iron exporter, ferroportin-1 (FPN-1), as an adaptive response mechanism to increased iron levels. Sprague-Dawley rats were treated with HO inducer hemin or HO inhibitor tin-protoporphyrin IX (SnPPIX) for 1 month. A portion of liver tissues was subjected to RT-PCR for HO-1, HO-2, and FPN-1 gene expression as well as an HO activity assay. Paraffin-embedded tissues were stained for iron with Prussian blue. Hepatic iron concentration was measured by High Resolution-Inductively Coupled Plasma-Mass Spectrometry. 8-hydroxy-2'-deoxyguanosine (8-OHdG) stain, a sensitive and specific marker of oxidative DNA damage, was performed to assess oxidative stress. Hemin treatment led to augmented HO expression and activity in association with increased iron accumulation and oxidative stress. FPN-1 expression was also found to be upregulated. SnPPIX treatment reduced HO activity, intracellular iron levels, and oxidative stress as compared to controls. Our data provides evidence of increased HO activity as an important pro-oxidant mechanism leading to iron accumulation in the liver.
Khan
Zia A
ZA
Department of Pathology, University of Western Ontario, London, Canada.
Barbin
Yousef P
YP
Cukiernik
Mark
M
Adams
Paul C
PC
Chakrabarti
Subrata
S
D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D003300:Copper / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D007150:Immunohistochemistry; D007424:Intracellular Fluid / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D018384:Oxidative Stress; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000098742:Ferroportin
D027682:Cation Transport Proteins; D007527:Isoenzymes; D008665:Metalloporphyrins; D011524:Protoporphyrins; D012333:RNA, Messenger; D000098742:Ferroportin; D006427:Hemin; D003300:Copper; C032628:tin protoporphyrin IX; D007501:Iron; D006419:Heme Oxygenase (Decyclizing)