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

• Published in: Free radical biology & medicine Vol. 65; pp. 1174 - 1194
• Main Authors: Koskenkorva-Frank, Taija S, Weiss, Günter, Koppenol, Willem H, Burckhardt, Susanna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2013
• Subjects: anemia; Anemia, Iron-Deficiency; antioxidants; Antioxidants - metabolism; Hemoglobins - chemistry; Humans; hydrogen peroxide; Hydrogen Peroxide - chemistry; Hydrogen Peroxide - metabolism; intravenous injection; iron; Iron - metabolism; Iron - therapeutic use; metabolism; nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide - chemistry; nitrogen; nutrient deficiencies; oral administration; Oxidative Stress; Reactive Nitrogen Species - metabolism; salts; superoxide anion; Superoxides - chemistry; Superoxides - metabolism; therapeutics; toxicity; transferrin; transient receptor potential cation channel, mucolipin subfamily, member 1; TfR; divalent metal transporter 1; eNOS; iron sucrose similar; EPO; iron-regulatory element; ferumoxytol; ID(A); iron polymaltose complex; Hb; AID; six-transmembrane epithelial antigen of the prostate 3; heme oxygenase 1; IL; functional iron deficiency; prolyl hydroxylase; iron isomaltoside 1000; IS; IIM; Nitrosative stress; iv; FCM; ARE; superoxide dismutase; IRE; glutathione peroxidase; Oxidative stress; Reactive oxygen species; IRP; Reactive nitrogen species; absolute iron deficiency; PHD; Steap3; Nrf2; Nramp1; ACD; HIF; ISS; SOD; neuronal nitric oxide synthase; ferroportin; hypoxia-inducible factor; iron deficiency (anemia); iron sucrose; iron-regulatory protein; FMX; asc; ferric gluconate; LIP; FBXL5; sodium Fe(III) ethylenediaminetetraacetic acid; malondialdehyde, MPS, mononuclear phagocyte system, NF-κB, nuclear factor-κB; DMT1; transferrin receptor; labile iron pool; MDA; F-box and leucine-rich repeat protein 5; Fe-EDTA; UTR; RNS; endothelial nitric oxide synthase; iNOS; von Hippel–Lindau; natural resistance-associated macrophage protein 1; TRPML1; PSC; Free radicals; NTBI; untranslated region; transferrrin saturation; GPx; gastrointestinal; ROS; nNOS; Intravenous iron; FG; LMWID; ascorbic acid; polyglucose sorbitol carboxymethyl ether; tumor necrosis factor α; FPN; glutathione; HO-1; low-molecular-weight iron dextran; hemoglobin; inducible nitric oxide synthase; intravenous; TSAT; NF-E2-related factor 2; Oral iron; VHL; interleukin; GSH; erythropoietin; FID; GI; antioxidant-responsive elements; ferric carboxymaltose; TNF-α; IPCS; anemia of chronic disease; iron polymaltose complex similar; non-transferrin-bound iron; IPC
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2013.09.001

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.