The protective role of glutathione Essays

The protective role of glutathione Essays The protective role of glutathione Essay The protective role of glutathione Essay Glutathione is the most abundant intracellular non- protein thiol and has been implemented in many cellular functions including detoxification of xenobiotics, cell cycle regulation, regulation of gene expression, protection of macromolecules and as an anti-oxidant.  Glutathione synthesis is a two step process catalysed respectively by ?-glutamylcysteine synthase and glutathione synthase.  Step 1) L-glutamate + L-cysteine + ATP( L-Y-glutamyl- L-cysteine + ADP + Pi . Step 2) L-Y-glutamyl L-cysteine + glycine + ATP ( GSH + ADP +Pi  Glutathione appears to be synthesised primarily in the cytosol, yet serves its function in other compartments including the nucleus, mitochondrial matrix, endoplasmic reticulum and in the extracellular environment. There appear to be two intracellular glutathione pools, one accounts for between 70 and 85 percent, is located in the cytosol and exhibits a rapid turnover with a half -life of between 30 minutes and 2 hours. A less significant pool resides within the mitochondria having a longer half-life of around 30 hours. Glutathione breakdown is catalysed by a specific enzyme, glutamyltransferase located on the luminal plasma membrane of epithelial cells.  Protective functions of glutathione.  The role of glutathione in xenobiotic metabolism.  The metabolism or biotransformation of foreign compounds can be divided into two phases. Phase one, the modification of a compound, achieved by the addition of a functional group such as a hydroxyl group and phase two, the conjugation of the functional group to convert the compound into a more polar and hence more readily excreted form.  Glutathione conjugation is probably the most important phase two reaction, being a major detoxification pathway for many compounds with a chemically reactive centre. Such substrates include aromatic rings, double bonds, halogenated aromatics, aliphatics and acyclics. Conjugation of various epoxides with glutathione.  The dimeric enzymes catalysing these transformations are glutathione-S-transferases and exist in four major classes;  An example of glutathione conjugation is in the metabolism of large doses of paracetamol, (acetaminophen), a widely used analgesic and anti-pyretic drug. Paracetamol is relatively safe when taken at therapeutic doses, however it is becoming increasingly common for overdoses of the drug to be taken for suicidal intent. Paracetamol poisoning causes primary centrilobar hepatic necrosis and possible renal damage and failure. The metabolism of therapeutic doses of the drug is generally via glucoromidation, but for doses in excess of aound 10 tablets, glutathione conjugation becomes significant. One product of paracetamol oxidation via cytochrome P450 is N-acetyl-p-benzoquinoneimine (NAPQI). This electrophile is detoxified in the liver via conjugation with glutathione, alternatively, it is reduced back to its parent compound also by the action of glutathione. In the case of an overdose, reduced glutathione can become saturated and as a consequence, when the levels drop to around 20 percent of normal, NAPQI has a tendency to react with other molecules within the cell possessing sulphydril groups. This leads to the oxidation of these cellular proteins, particularly enzymes, for example the plasma Ca2+ATPase. The inhibition of this calcium pump leads to the increased storage of calcium by the endoplasmic reticulum and by the mitochondria, however, these two stores have a finite capacity and if saturated, the intracellular concentration of calcium can become extremely high, resulting in cellular damage. It has been observed in rats fasted overnight and then administered with a paracetamol overdose, that as glutathione levels drop to around 20 percent, lipid peroxidation can occur. In conclusion, glutathione appears to be very important in paracetamol toxicity, in fact reduced glutathione is administered clinically in cases of paracetamol overdose and if given in time can limit the potential damage caused in such cases.  Detoxification of H2O2 and other organic peroxides.  Oxygen, although critical for aerobic life, is potentially toxic. Dioxygen (O2) itself is a free radical, but is relatively stable owing to the position of its free electrons- occupying parallel spin positions. However, the reduction or partial reduction of oxygen can generate damaging free radicals, their unpaired electrons conveying high chemical reactivity on the molecule, such as the superoxide anion. All aerobic cells generate these free radicals as a consequence of oxidative metabolism. Glutathione can protect against oxidative damage in the cell in two ways, both directly and indirectly.  Free radicals, owing to their high chemical reactivity, attack a wide range of macromolecules. Often, this results in chain reactions whereby the product of one reaction serves to propagate further reactions. One means of terminating this process is by one free radical attacking another. However, free radicals are relatively rare in biological systems, therefore, various protection mechanisms have evolved. One such mechanism is that of free radical traps and glutathione itself serves as a free radical trap. Being small and water-soluble it works in the aqueous phase of the cell, reacting with free radicals to yield glutathione radicals and a reduced form of the free radical. In contrast to many free radicals, the glutathione radical is stable, un-reactive and does not go on to propagate further reactions.  Glutathione can partake in the protection against free radicals indirectly via the action of glutathione peroxidase. Glutathione peroxidase is an enzyme abundant in areas of high oxidative stress. It was discovered in 1957 by Mills and is unusual in possessing a selenium co-factor, which works as illustrated.