Figure 7

Transport pathway, cellular and molecular mechanisms of toxicity associated with cellular exposure to carbon nanotubes and leached metal. Intracellular iron uptake can occur by transferrin receptor (TfR) on cellular membranes (the reductase present in acidified endosomes converts Fe³⁺ to Fe²⁺ before transport into the cytosolic space by divalent metal transporter-1 (DMT-1)) or carbon nanotube endocytosis/phagocytosis followed by acid-enhanced Fe²⁺ release in endosome and lysosome. By increasing the intracellular iron, the level of labile iron pool (LIP) is upregulated. The resultant Fe²⁺ within the LIP (1) activates the regulatory iron regulatory protein/iron regulatory element (IRP/IRE) system; (2) is sequestered by chaperones or storage proteins, such as ferritin and metallothioneins (MTs); (3) reoxidizes into Fe³⁺ and effluxes out of the cell via CP (ceruloplasmin) and IREG1 (iron-regulated gene 1); or (4) participates in iron-catalyzed reactions to generate reactive species. SOD, superoxide dismutase.