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

Abstract

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.

Keywords: ACD; AID; ARE; DMT1; EPO; F-box and leucine-rich repeat protein 5; FBXL5; FCM; FG; FID; FMX; FPN; Fe-EDTA; Free radicals; GI; GPx; GSH; HIF; HO-1; Hb; ID(A); IIM; IL; IPC; IPCS; IRE; IRP; IS; ISS; Intravenous iron; LIP; LMWID; MDA; NF-E2-related factor 2; NTBI; Nitrosative stress; Nramp1; Nrf2; Oral iron; Oxidative stress; PHD; PSC; RNS; ROS; Reactive nitrogen species; Reactive oxygen species; SOD; Steap3; TNF-α; TRPML1; TSAT; TfR; UTR; VHL; absolute iron deficiency; anemia of chronic disease; antioxidant-responsive elements; asc; ascorbic acid; divalent metal transporter 1; eNOS; endothelial nitric oxide synthase; erythropoietin; ferric carboxymaltose; ferric gluconate; ferroportin; ferumoxytol; functional iron deficiency; gastrointestinal; glutathione; glutathione peroxidase; heme oxygenase 1; hemoglobin; hypoxia-inducible factor; iNOS; inducible nitric oxide synthase; interleukin; intravenous; iron deficiency (anemia); iron isomaltoside 1000; iron polymaltose complex; iron polymaltose complex similar; iron sucrose; iron sucrose similar; iron-regulatory element; iron-regulatory protein; iv; labile iron pool; low-molecular-weight iron dextran; malondialdehyde, MPS, mononuclear phagocyte system, NF-κB, nuclear factor-κB; nNOS; natural resistance-associated macrophage protein 1; neuronal nitric oxide synthase; non-transferrin-bound iron; polyglucose sorbitol carboxymethyl ether; prolyl hydroxylase; reactive nitrogen species; reactive oxygen species; six-transmembrane epithelial antigen of the prostate 3; sodium Fe(III) ethylenediaminetetraacetic acid; superoxide dismutase; transferrin receptor; transferrrin saturation; transient receptor potential cation channel, mucolipin subfamily, member 1; tumor necrosis factor α; untranslated region; von Hippel–Lindau.