Effects of Metal Ions on Free Radical Modulation

The transition metal ions, particularly iron and copper in the free form, may participate in the activation of oxygen-reactive species. Iron and copper are the most active of the transition metals, partially because of their abundance in biological systems. The creation of hydroxyl radicals depends upon the participation of a metal catalyst such as iron and copper. A transition metal such as iron or copper is required in the lipid peroxidation of cellular membranes (Hochstein and Ernster, 1963). The other side of the iron-copper coin is that they also play an important role in protecting cellular membranes from free-radical activity.

Iron: One of the important plasma constituents is an iron-binding glycoprotein known as transferrin, which serves as the major vehicle for the transfer of iron in the body. Transferrin is bound to membrane receptors localized in many tissues. Each transferrin molecule has a binding capacity of 2 atoms of iron. Acidic hydrogen ion concentrations in the body favor the release of iron from transferrin, and the free iron becomes available for binding by other chelating substances such as ferritin.

Ferritin: The bulk of intracellular iron is sequestered either in association with ferritin in the cytosol of the cell or within the lysosomal intracellular organelles. Ferritin has been found in liver, spleen, and bone marrow. Being a polypeptide chain, ferritin serves as storage for the Fe++ form. Each ferritin molecule has a storage capacity of 4500 iron atoms.

The bioavailability and regulation of iron under physiological conditions depend on the status of circulating transferrin. Thus transferrin may have a two-fold action. On one hand, transferrin may protect cells against lipid peroxidation by preventing free unbound iron from participating in lipid peroxidation reactions. For example, when only partially saturated with iron, transferrin can act as a strong antioxidant in human plasma by binding iron and preventing lipid peroxidation. However, when fully saturated with iron, transferrin my release free iron to the plasma and thus serve as a prooxidant. The exact role played by iron-binding proteins as secondary antioxidant defense systems has not been fully delineated (Yu, 1994).

Copper: Copper's role as an antioxidant is in the form of ceruloplasmin (Ceruloplasm). This is another major protein that mediates free radical metabolism in the extracellular compartments of tissues. Ceruloplasmin is a copper-binding glycoprotein. Under physiological conditions, it binds six or seven copper ions per molecule.

Ceruloplasmin has several functions in free radical metabolism. First ceruloplasmin may serve as a ferroxidase enzyme by catalyzing the oxidation of Fe++ to the Fe+++ state. This enzymatic activity is required for loading Fe++ onto transferrin and apoferritin. Second, ceruloplasmin's role as an antioxidant may relate to its free-radical-scavenging properties. Third, ceruloplasmin is capable of scavenging superoxide. Although this scavenging is weaker than SOD, it may be a significant antioxidant in the extracellular compartments.

Finally, ceruloplasmin's antioxidant may also relate to its cooper-binding ability. Copper metal is a well-know prooxidant catalyst, and its sequestration by ceruloplasmin would lead to a decrease in oxidation (Yu, 1994).

Selenium: The antioxidant ability of selenium resides in the active site of the seleno-enzyme glutathione peroxidase (GSH-PX). The role of glutathione has already been discussed in this chapter. Selenium has unique chemical properties and appears on the Periodic Table of the Elements in a position between the metals and the nonmetals.

The protective action of selenium seems to operate at several levels. Selenium inhibits the microsomal enzymes responsible for the generation of some forms of carcinogens. It may also act at the cellular level to prevent the enzymatic conversion of precarcinogens to carcinogens. Evidence suggests that selenium enhances the detoxification process of carcinogenic substances and protects against carcinogen-induced chromosomal damage. Most carcinogens are thought to be activated through a free-radical-mediated interaction with DNA. Hence, selenium may interfere with the DNA-free radical interaction process. This hypothesis is further supported by the distribution of selenium within the cell: the highest concentration is in the nuclei, followed by the cytosol, mitochondria, and the microsomes.

The precise mechanism of the protective action of selenium against cancer has not been fully defined. It is believed that selenium's protective action against cancer is probably linked to its role in maintaining the cell's optimum level of selenium-dependent GSH-PX. Most cancer patients have a lower blood level of GSH-PX activity compared to healthy subject (Yu, 1994). Excessive intake in selenium may result in carcinogenesis, but this is a matter of controversy, one which has not been determined with any degree of finality (Venugopal and Luckey, 1979).

Manganese: Manganese is one of the elements required for the enzymatic activity for the metalloenzyme superoxide dismutase (SOD). The antioxidant activity of SOD has already been discussed. MnSOD catalyzes the same reactions as do the CuZnSOD's. MnSOD is found in significant quantities in the liver mitochondria (Halliwell and Gutteridge, 1989).

Zinc: Zinc is one of the essential minerals incorporated by the body into protective antioxidant metalloenzymes. Zinc is essential for the enzymatic activity for one of two types of superoxide dismutases. Manganese is the other mineral essential to the development of SOD. There are two SOD forms; one found in the extramitochondrial cytosol and the other in the mitochondria. The mitochondrial matrix SOD contains manganese as previously discussed. The cytosol mitochondrial SOD contains copper and zinc (Halliwell and Gutteridge (1989).

Source:Free Radicals Test