Glutathione Case Study

Evaluate the role of Glutathione in combating oxidative stress

The balance between the production of reactive oxygen species (ROS), also known as free radicals, and antioxidant defences is defined as oxidative stress1. When cellular antioxidant defences are insufficient to keep ROS below a toxic threshold, oxidative stress causes damage to cells. Oxidative stress can be caused by an increase in free radicals and other ROS, or by decrease in antioxidants such as glutathione (GSH). GSH is a naturally occurring intracellular antioxidant found in every cell of the body. Its major role is to neutralise free radicals to prevent cellular damage by oxidative stress Free radicals are oxygen containing molecules that have one or more unpaired electron(s),

They are also formed as necessary intermediates of metal catalysed oxidation reactions. Figure 1 shows examples of common ROS and shows the number of orbiting electron. Atomic oxygen has two unpaired electrons in separate oribits in its outer electron shell making it susceptible to radical formation, and ROS form when oxygen is reduced by the addition of electrons4. ROS are produced naturally from many metabolic processes, but alcohol consumption can also induce oxidative stress3, due to changes in NAD+/NADH ratio due to alcohol metabolism. Oxidative stress can also be caused by excess exposure to UV light, leading to apoptotic or necrotic cell death, which can lead to skin ageing and be responsible for skin cancer and other cutaneous inflammatory disorders5. The typical response of cells with increased exposure to ROS is to leave the cell cycle and enter G0, and continued exposure to high levels of ROS triggers apoptosis

Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) leads to symptoms of the disease. How this loss occurs is not known, but generation of ROS are considered important mediators. Oxidation of dopamine by enzymes leads to the formation of H2O2, which is usually inactivated in a reaction involving glutathione, but can react with Fe2+ and form highly reactive hydroxyl radicals. In PD, GSH levels have been reported to be decreased in the substantia nigra pars compacta and the severity of the disease correlates with GSH loss. How this oxidative stress occurs is not well understood, as GSH synthase levels have been shown to be normal in the substantia nigra. Studies have shown that there is a depletion in GSH levels in the SNpc in PD patients and the severity of the disease correlates with the amount of GSH loss, and there was no corresponding increase in GSSG11. This supports the argument that glutathione decreases the effects of oxidative stress, as when levels of glutathione are decreased, parts of the brain in PD patients are damaged by oxidative