The chemical mechanism of oxidative stress due to the non-transferrin-bound iron (NTBI)

Plasma iron is normally bound to the iron transport protein transferrin, but there are some iron ions not associated with transferrin. The latter ions are generally termed as non-transferrin-bound iron (NTBI) or labile plasma iron. The NTBI has been thought to play an important role in iron-induced cell damage with resultant peroxidation of cell membrane lipids and other biomolecules, and such oxidative damage is implicated as an important contributor in the pathogenesis of cancer, cardiovascular disease, aging and other degenerative disorders, but little is understood about the chemical composition of NTBI and the origin of toxicity due to NTBI. In this review, we demonstrated the several chemical models for NTBI, and elucidated the chemical mechanism of iron toxicity due to NTBI in human body on the basis of my concept on the mechanism of oxygen activation in biological oxygenases. This has lead to the conclusion that 1) NTBI are divided into two groups, water-in-soluble and water-soluble ones, 2) some of the water-soluble NTBI react with oxygen or hydrogen peroxide, changing these molecules to those exhibiting the reactivity similar to singlet oxygen (1△g), and this is the main reason for NTBI to induce the oxidative stress, and 3) the responsibility of hydroxyl radical or free singlet oxygen is negligible as a “reactive oxygen species” in the human body. Based on the discussions described in this article we have proposed a new technique to prevent the oxidative damage due to NTBI. In order to achieve the purpose, we have synthesized the new superpolyphenols which contain more than 100 molecules of catechol derivative in one polymeric compound; these are sometimes water-insoluble, and in another cases, water-soluble. We have observed that some of these compounds can eliminate NTBI effectively from the plasma, and also some of these derivatives can remove hydrogen peroxide from the solution. Thus, we can hope that our new super-polyphenols should depress greatly the oxidative stress due to NTBI, which may be consistent with the facts that the Japanese tea catechins which contain polyphenols exhibit high preventing effects against lifestyle-related diseases, and that some polyphenols have been known to protect the pathogenesis of Alzheimer’s disease. We also discussed the antioxidative function by zinc(II) ion, which depresses the oxidative damage by NTBI by promoting the formation of iron deposition.