title: Reduction of a marker of oxidative stress with enhancement of iron utilization by erythropoiesis activation following epoetin beta pegol administration in iron-loaded db/db mice.
abstract: Iron, an essential element for various biological processes, can induce oxidative stress. We hypothesized that iron utilization for erythropoiesis, stimulated by epoetin beta pegol (C.E.R.A.), a long-acting erythropoiesis-stimulating agent, contributes to the reduction of iron-induced oxidative stress. We first investigated the sensitivity of several biomarkers to detect oxidative stress in mice by altering the amount of total body iron; we then investigated whether C.E.R.A. ameliorated oxidative stress through enhanced iron utilization. We treated db/db mice with intravenous iron-dextran and evaluated several biomarkers of iron-induced oxidative stress. In mice loaded with 5 mg/head iron, hepatic iron content was elevated and the oxidative stress marker d-ROMs (serum derivatives of reactive oxygen metabolites) was increased, whereas urinary 8-hydroxy-2'-deoxyguanosine and serum malondialdehyde were not, indicating that d-ROMs is a sensitive marker of iron-induced oxidative stress. To investigate whether C.E.R.A. ameliorated oxidative stress, db/db mice were intravenously administered iron-dextran or dextran only, followed by C.E.R.A. Hemoglobin level increased, while hepatic iron content decreased after C.E.R.A.
  
  
  METHODS
  Serum d-ROMs decreased after C.E.R.A. treatment in the iron-dextran-treated group. Our results suggest that C.E.R.A. promotes iron utilization for erythropoiesis through mobilization of hepatic iron storage, leading to a decrease in serum oxidative stress markers in iron-loaded db/db mice.
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan. noguchimrk@chugai-pharm.co.jp.
authors.forename: Mariko
authors.initials: M
authors.lastname: Noguchi-Sasaki
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Matsuo-Tezuka
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yasuno
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Mitsue
authors.initials: M
authors.lastname: Kurasawa
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Yorozu
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shimonaka
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004920:Erythropoiesis / Q000187:drug effects* / Q000502:physiology*; D004921:Erythropoietin / Q000008:administration & dosage* / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; C572502:Erfe protein, mouse; D009124:Muscle Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C508420:continuous erythropoietin receptor activator; D004921:Erythropoietin; D011092:Polyethylene Glycols; D007501:Iron
keywords: ESA; Erythropoiesis; Iron metabolism; Oxidative stress