title: Heme oxygenase-1 induction by the ROS-JNK pathway plays a role in aluminum-induced anemia.
abstract: Aluminum (Al) overload is correlated with hypochromic anemia. It is possible that Al impedes heme biosynthesis and degradation by affecting the activity of biosynthetic enzymes. However, the molecular mechanisms by which Al affects these enzymes are unknown. Here, we show that long-term exposure of Sprague-Dawley rats to Al decreased hemoglobin concentration and the hematocrit level. In addition, the activity of aminolevulinic acid dehydratase (ALA-D) in rat liver was reduced, but heme oxygenase (HO) activity was enhanced, suggesting an impairment of heme homeostasis. The increase in HO activity was due to up-regulation of mRNA and protein of an inducible HO isozyme, HO-1. Furthermore, we found that reactive oxygen species (ROS)-mediated activation of c-Jun N-terminal kinase (JNK) was critical for HO-1 induction by Al, because ROS scavengers and JNK inhibitors abrogated enhancement of HO-1 by Al in rat hepatocytes. Thus, Al enhances HO-1 expression through the ROS-JNK pathway, which may enhance HO activity and accelerate degradation of heme, leading to hypochromic anemia.
authors: Ph.D. Program in Nutrition and Food Science, Fu-Jen Catholic University, Hsinchuang, New Taipei City, Taiwan.
authors: Chia-Yeh
authors: CY
authors: Lin
authors: Wei-Chun
authors: WC
authors: Hsiao
authors: Chang-Jen
authors: CJ
authors: Huang
authors: Cheng-Fu
authors: CF
authors: Kao
authors: Guoo-Shyng W
authors: GS
authors: Hsu
mesh_terms: D000535:Aluminum / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D000740:Anemia / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006400:Hematocrit; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D007274:Injections, Intraperitoneal; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006454:Hemoglobins; D017382:Reactive Oxygen Species; D000535:Aluminum; D051547:Heme Oxygenase-1; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8
keywords: Aluminum; Heme oxygenase; Hypochromic anemia; Reactive oxygen species; c-Jun N-terminal kinase