TY - JOUR T1 - The complex interplay of iron metabolism, reactive oxygen species, and reactive nitrogen species: insights into the potential of various iron therapies to induce oxidative and nitrosative stress. AU - Koskenkorva-Frank,Taija S, AU - Weiss,Günter, AU - Koppenol,Willem H, AU - Burckhardt,Susanna, Y1 - 2013/09/12/ PY - 2013/07/17/received PY - 2013/09/05/revised PY - 2013/09/05/accepted PY - 2013/9/17/entrez PY - 2013/9/17/pubmed PY - 2014/9/3/medline KW - ACD KW - AID KW - ARE KW - DMT1 KW - EPO KW - F-box and leucine-rich repeat protein 5 KW - FBXL5 KW - FCM KW - FG KW - FID KW - FMX KW - FPN KW - Fe-EDTA KW - Free radicals KW - GI KW - GPx KW - GSH KW - HIF KW - HO-1 KW - Hb KW - ID(A) KW - IIM KW - IL KW - IPC KW - IPCS KW - IRE KW - IRP KW - IS KW - ISS KW - Intravenous iron KW - LIP KW - LMWID KW - MDA KW - NF-E2-related factor 2 KW - NTBI KW - Nitrosative stress KW - Nramp1 KW - Nrf2 KW - Oral iron KW - Oxidative stress KW - PHD KW - PSC KW - RNS KW - ROS KW - Reactive nitrogen species KW - Reactive oxygen species KW - SOD KW - Steap3 KW - TNF-α KW - TRPML1 KW - TSAT KW - TfR KW - UTR KW - VHL KW - absolute iron deficiency KW - anemia of chronic disease KW - antioxidant-responsive elements KW - asc KW - ascorbic acid KW - divalent metal transporter 1 KW - eNOS KW - endothelial nitric oxide synthase KW - erythropoietin KW - ferric carboxymaltose KW - ferric gluconate KW - ferroportin KW - ferumoxytol KW - functional iron deficiency KW - gastrointestinal KW - glutathione KW - glutathione peroxidase KW - heme oxygenase 1 KW - hemoglobin KW - hypoxia-inducible factor KW - iNOS KW - inducible nitric oxide synthase KW - interleukin KW - intravenous KW - iron deficiency (anemia) KW - iron isomaltoside 1000 KW - iron polymaltose complex KW - iron polymaltose complex similar KW - iron sucrose KW - iron sucrose similar KW - iron-regulatory element KW - iron-regulatory protein KW - iv KW - labile iron pool KW - low-molecular-weight iron dextran KW - malondialdehyde, MPS, mononuclear phagocyte system, NF-κB, nuclear factor-κB KW - nNOS KW - natural resistance-associated macrophage protein 1 KW - neuronal nitric oxide synthase KW - non-transferrin-bound iron KW - polyglucose sorbitol carboxymethyl ether KW - prolyl hydroxylase KW - reactive nitrogen species KW - reactive oxygen species KW - six-transmembrane epithelial antigen of the prostate 3 KW - sodium Fe(III) ethylenediaminetetraacetic acid KW - superoxide dismutase KW - transferrin receptor KW - transferrrin saturation KW - transient receptor potential cation channel, mucolipin subfamily, member 1 KW - tumor necrosis factor α KW - untranslated region KW - von Hippel–Lindau SP - 1174 EP - 1194 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 65 N2 - Production of minute concentrations of superoxide (O2(*-)) and nitrogen monoxide (nitric oxide, NO*) plays important roles in several aspects of cellular signaling and metabolic regulation. However, in an inflammatory environment, the concentrations of these radicals can drastically increase and the antioxidant defenses may become overwhelmed. Thus, biological damage may occur owing to redox imbalance-a condition called oxidative and/or nitrosative stress. A complex interplay exists between iron metabolism, O2(*-), hydrogen peroxide (H2O2), and NO*. Iron is involved in both the formation and the scavenging of these species. Iron deficiency (anemia) (ID(A)) is associated with oxidative stress, but its role in the induction of nitrosative stress is largely unclear. Moreover, oral as well as intravenous (iv) iron preparations used for the treatment of ID(A) may also induce oxidative and/or nitrosative stress. Oral administration of ferrous salts may lead to high transferrin saturation levels and, thus, formation of non-transferrin-bound iron, a potentially toxic form of iron with a propensity to induce oxidative stress. One of the factors that determine the likelihood of oxidative and nitrosative stress induced upon administration of an iv iron complex is the amount of labile (or weakly-bound) iron present in the complex. Stable dextran-based iron complexes used for iv therapy, although they contain only negligible amounts of labile iron, can induce oxidative and/or nitrosative stress through so far unknown mechanisms. In this review, after summarizing the main features of iron metabolism and its complex interplay with O2(*-), H2O2, NO*, and other more reactive compounds derived from these species, the potential of various iron therapies to induce oxidative and nitrosative stress is discussed and possible underlying mechanisms are proposed. Understanding the mechanisms, by which various iron formulations may induce oxidative and nitrosative stress, will help us develop better tolerated and more efficient therapies for various dysfunctions of iron metabolism. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/24036104/The_complex_interplay_of_iron_metabolism_reactive_oxygen_species_and_reactive_nitrogen_species:_insights_into_the_potential_of_various_iron_therapies_to_induce_oxidative_and_nitrosative_stress_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(13)00596-0 DB - PRIME DP - Unbound Medicine ER -