title: Effect of diquat-induced oxidative stress on iron metabolism in male Fischer-344 rats.
abstract: Diquat toxicity causes iron-mediated oxidative stress; however, it remains unclear how diquat affects iron metabolism. Here, we examined the effect of diquat-induced oxidative stress on iron metabolism in male Fischer-344 rats, with particular focus on gene expression. Hepatic nonheme iron content was unchanged until 20 h after diquat treatment. Hepatic free iron levels increased markedly in the early stages following treatment and remained elevated for at least 6 h, resulting in severe hepatotoxicity, until returning to control levels at 20 h. The level of hepatic ferritin, especially the H-subunit, increased 20 h after diquat treatment due to elevated hepatic ferritin-H mRNA expression. These results indicate that early elevated levels of free iron in the liver of diquat-treated rats cause hepatotoxicity, and that this free iron is subsequently sequestered by ferritin synthesized under conditions of oxidative stress, thus limiting the pro-oxidant challenge of iron. The plasma iron concentration decreased at 6 and 20 h after diquat treatment, whereas the level of plasma interleukin-6 increased markedly at 3 h and remained high until 20 h. In the liver of diquat-treated rats, expression of hepcidin mRNA was markedly upregulated at 3 and 6 h, whereas ferroportin mRNA expression was downregulated slightly at 20 h. Transferrin receptor 1 mRNA expression was significantly upregulated at 3, 6, and 20 h. These results indicate that inhibition of iron release from iron-storage tissues, through stimulation of the interleukin-6-hepcidin-ferroportin axis, and enhanced iron uptake into hepatocytes, mediated by transferrin receptor 1, cause hypoferremia.
authors.affiliation: Laboratory of Veterinary Biochemistry, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Higuchi
authors.forename: Yasunaga
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Orino
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism; D004178:Diquat / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006540:Herbicides / Q000494:pharmacology*; D015850:Interleukin-6 / Q000097:blood; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D006540:Herbicides; D015850:Interleukin-6; D001052:Apoferritins; D004178:Diquat; D007501:Iron; D000410:Alanine Transaminase