354 Original Article
Nitrosative Stress and Apoptosis by Intravenous Ferumoxytol, Iron Isomaltoside 1000, Iron Dextran, Iron Sucrose, and Ferric Carboxymaltose in a Nonclinical Model Authors
J. E. Toblli1, G. Cao1, J. F. Giani2, F. P. Dominici2, M. Angerosa1
Affiliations
1
Key words ▶ caspase 3 ● ▶ nitrotyrosine ● ▶ rat ●
received 28.02.2014 accepted 18.06.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1384534 Published online: July 22, 2014 Drug Res 2015; 65: 354–360 © Georg Thieme Verlag KG Stuttgart · New York ISSN 2194-9379 Correspondence Prof. J. E. Toblli Laboratory of Experimental Medicine Hospital Alemán School of Medicine University of Buenos Aires Av. Pueyrredon, 1640 1118 Buenos Aires Argentina Tel.: + 54/11/4827 7000 Ext.: 2785 Fax: + 54/11/4805 6087 [email protected]
Abstract
▼
Iron is involved in the formation as well as in the scavenging of reactive oxygen and nitrogen species. Thus, iron can induce as well as inhibit both oxidative and nitrosative stress. It also has a key role in reactive oxygen and nitrogen speciesmediated apoptosis. We assessed the differences in tyrosine nitration and caspase 3 expression in the liver, heart, and kidneys of rats treated weekly with intravenous ferumoxytol, iron isomaltoside 1000, iron dextran, iron sucrose and ferric carboxymaltose (40 mg iron/kg body weight) for 5 weeks. Nitrotyrosine was quantified in tissue homogenates by Western blotting and the distribution of nitrotyrosine and caspase 3 was assessed in tissue sections by immunohistochemistry. Ferric carboxymaltose and iron
Introduction
▼
Nitric oxide (NO•) is generated in tissues from L-arginine by 3 nitric oxide synthase (NOS) isoforms in a reaction requiring iron, O2, and reducing equivalents [1]. The inducible NOS isoform (iNOS) produces large amounts of NO• in many cell types. The molecular regulation of iNOS occurs at transcriptional and post-transcriptional levels involving complex cytokine mixtures [2]. NO• has high affinity for transition metals [3] and, in particular, reacts with various iron-containing proteins influencing their activity [4]. The oxidized form of NO• (NO + ) can be produced under physiological conditions, which enable it to affect a variety of molecular targets and regulate cellular responses post-translationally, e. g., by S-nitrosating sulfhydryl groups in proteins [5]. Many of the cytotoxic actions attributed to NO• are mediated by peroxynitrite (ONOO − ), an important biological oxidant and nitrating agent which is formed in the reaction between NO• and super-
Toblli JE et al. Nitrotyrosine and Caspase 3 by i.v. Iron … Drug Res 2015; 65: 354–360
sucrose administration did not result in detectable levels of nitrotyrosine or significant levels of caspase 3 vs. control in any of the tissue studied. Nitrotyrosine and caspase 3 levels were significantly (p
Nitrosative Stress and Apoptosis by Intravenous Ferumoxytol, Iron Isomaltoside 1000, Iron Dextran, Iron Sucrose, and Ferric Carboxymaltose in a Nonclinical Model Authors
J. E. Toblli1, G. Cao1, J. F. Giani2, F. P. Dominici2, M. Angerosa1
Affiliations
1
Key words ▶ caspase 3 ● ▶ nitrotyrosine ● ▶ rat ●
received 28.02.2014 accepted 18.06.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1384534 Published online: July 22, 2014 Drug Res 2015; 65: 354–360 © Georg Thieme Verlag KG Stuttgart · New York ISSN 2194-9379 Correspondence Prof. J. E. Toblli Laboratory of Experimental Medicine Hospital Alemán School of Medicine University of Buenos Aires Av. Pueyrredon, 1640 1118 Buenos Aires Argentina Tel.: + 54/11/4827 7000 Ext.: 2785 Fax: + 54/11/4805 6087 [email protected]
Abstract
▼
Iron is involved in the formation as well as in the scavenging of reactive oxygen and nitrogen species. Thus, iron can induce as well as inhibit both oxidative and nitrosative stress. It also has a key role in reactive oxygen and nitrogen speciesmediated apoptosis. We assessed the differences in tyrosine nitration and caspase 3 expression in the liver, heart, and kidneys of rats treated weekly with intravenous ferumoxytol, iron isomaltoside 1000, iron dextran, iron sucrose and ferric carboxymaltose (40 mg iron/kg body weight) for 5 weeks. Nitrotyrosine was quantified in tissue homogenates by Western blotting and the distribution of nitrotyrosine and caspase 3 was assessed in tissue sections by immunohistochemistry. Ferric carboxymaltose and iron
Introduction
▼
Nitric oxide (NO•) is generated in tissues from L-arginine by 3 nitric oxide synthase (NOS) isoforms in a reaction requiring iron, O2, and reducing equivalents [1]. The inducible NOS isoform (iNOS) produces large amounts of NO• in many cell types. The molecular regulation of iNOS occurs at transcriptional and post-transcriptional levels involving complex cytokine mixtures [2]. NO• has high affinity for transition metals [3] and, in particular, reacts with various iron-containing proteins influencing their activity [4]. The oxidized form of NO• (NO + ) can be produced under physiological conditions, which enable it to affect a variety of molecular targets and regulate cellular responses post-translationally, e. g., by S-nitrosating sulfhydryl groups in proteins [5]. Many of the cytotoxic actions attributed to NO• are mediated by peroxynitrite (ONOO − ), an important biological oxidant and nitrating agent which is formed in the reaction between NO• and super-
Toblli JE et al. Nitrotyrosine and Caspase 3 by i.v. Iron … Drug Res 2015; 65: 354–360
sucrose administration did not result in detectable levels of nitrotyrosine or significant levels of caspase 3 vs. control in any of the tissue studied. Nitrotyrosine and caspase 3 levels were significantly (p
