MOA Iron is incorporated into various proteins to serve biological functions as a structural component or cofactor. Once ferric or ferrous cation from intestinal enterocytes or reticuloendothelial macrophages is bound to circulating transferrin, iron-transferrin complex binds to the cell-surface transferrin receptor (TfR) 1, resulting in endocytosis and uptake of the metal cargo. Internalized iron is transported to mitochondria for the synthesis of heme or iron-sulfur clusters, which are integral parts of several metalloproteins [A32514]. Excess iron is stored and detoxified in cytosolic ferritin [A32514]. Internalized Fe2+ exported across the basolateral membrane into the bloodstream via Fe+2 transporter ferroportin, which is coupled by reoxidation to Fe3+ via membrane-bound ferroxidase hephaestin or ceruloplasmin activity [A32514]. Fe+3 is again scavenged by transferrin which maintains the ferric iron in a redox-inert state and delivers it into tissues [A32514].; ; Fe3+ participates in the autoxidation reaction, where it can be chelated by DNA. It mainly binds to the backbone phosphate group, whereas at higher metal ion content, the cation binds to both guanine N-7 atom and the backbone phosphate group [A32520].

ABSORPTION Iron absorption and systemic iron homeostasis are regulated by hepcidin, which is a peptide hormone that also regulates the activity of the iron-efflux protein, ferroportin-1 [A32514]. Iron is mostly absorbed in the duodenum and upper jejunum [L2258]. Fe3+ displays low solubility at the neutral pH of the intestine and is mainly be converted to ferrous iron (Fe2+) by ferric reductases [T28], as ferric salts are only half as well absorbed as ferrous salts [L2258]. Once converted in the intestinal lumen, Fe+2 is transported across the apical membrane of enterocytes [A32514]. The absorption rate of non-haem iron is 2-20% [A32514]. Stored iron may be liberated via ferroportin-mediated efflux, which is coupled by reoxidation of Fe2+ to Fe3+ by ceruloplasmin in the serum or hephaestin in the enterocyte membrane [A32524]. Fe3+ subsequently binds to transferrin, which keeps ferric cation in a redox-inert state and delivers it into tissues [A32514].; ; It is proposed that there may be separate cellular uptake pathways for ferrous iron and ferric iron. While ferrous iron is primarily carried by divalent metal transporter-1 (DMAT-1), cellular uptake of ferric iron is predominantly mediated by beta-3 integrin and mobilferrin, which is also referred to as calreticulin in some sources as a homologue [A32507]. However, the most dominant pathway in humans is unclear [A32507].