Antioxidant mechanisms glutathione peroxidase

There is considerable body of (indirect) evidence which makes oxidative stress one of the best accepted hypothesis for explaining the cause of Parkinson s disease. For example, the Fe(II)/Fe(III) ratio in the substantia nigra is shifted from 2 1 in the normal brain to 1 2 in Parkinsonian brain.131,132 In the Parkinsonian brain several enzymes which constitute the antioxidative defence mechanisms (glutathione peroxidase, catalase) have a decreased activity, while the activity of superoxide dismutase is increased, relative to the normal brain.133 Furthermore, specific products of radical damage, such as lipid hydroperoxides, were detected at a 10-fold increased level in the Parkinsonian brain.134... 

In the previous section, we have described some of the mechanisms that may lead to the fijrmation of lipid hydroperoxides or peroxyl radicals in lipids. If the peroxyl radical is formed, then this will lead to propagation if no chain-breaking antioxidants are present (Scheme 2.1). However, in many biological situations chain-breaking antioxidants are present, for example, in LDL, and these will terminate the peroxyl radical and are consumed in the process. This will concomitandy increase the size of the peroxide pool in the membrane or lipoprotein. Such peroxides may be metabolized by the glutathione peroxidases in a cellular environment but are probably more stable in the plasma comjxutment. In the next section, the promotion of lipid peroxidation if the lipid peroxides encounter a transition metal will be considered. 

Garlic s proven mechanisms of action include (a) inhibition of platelet function, (b) increased levels of two antioxidant enzymes, catalase and glutathione peroxidase, and (c) inhibition of thiol enzymes such as coenzyme A and HMG coenzyme A reductase. Garlic s anti-hyperlipidemic effects are believed to be in part due to the HMG coenzyme A reductase inhibition since prescription medications for hyperlipidemia have that mechanism of action (statins). It is unknown whether garlic would have the same drug interactions, side effects, and need for precautions as the statins. 

On the other hand, several ROS are highly cytotoxic. Consequently, eukaryotic cells have developed an elaborate arsenal of antioxidant mechanisms to neutrahze their deleterious effects (enzymes such as superoxide dismutases, catalases, glutathione peroxidases, thioredoxin inhibitors of free-radical chain reaction such as tocopherol, carotenoids, ascorbic acid chelating proteins such as lactoferrin and transferrin). It can be postulated that ROS may induce an oxidative stress leading to cell death when the level of intracellular ROS exceeds an undefined threshold. Indeed, numerous observations have shown that ROS are mediators of cell death, particularly apoptosis (Maziere et al., 2000 Girotti, 1998 Kinscherf et al., 1998 Suzuki et al., 1997 Buttke and Sanstrom, 1994 Albina et al., 1993). 

ROS are maintained at tolerable levels through the combined efforts of antioxidant mechanisms, which include both enzymes and nonenzymatic molecules. Important antioxidant enzymes include superoxide dismutases (SODs), catalases (CATs), peroxidases, and those maintaining reduced glutathione (GSH) levels. Nonenzymatic antioxidants include GSH, a tripeptide containing a cysteinamino acid, and vitamins, such as vitamin A, E, and C. 

Selenium is an essential trace element and an integral component of heme oxidase. It appears to augment the antioxidant action of vitamin E to protect membrane lipids from oxidation. The exact mechanism of this interaction is not known however, selenium compounds are found in the selenium analogs of the sulfur-containing amino acids, such as cysteine and methionine. Se-cysteine is found in the active sites of the enzyme glutathione peroxidase, which acts to use glutathione to reduce organic hydroperoxides. 

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