Glutathione appears to function as a free- radical scavenger in the gastro-intestinal tract, protecting organisms from oxidants derived from the diet or produced as a consequence of bacterial metabolism. One study , investigated the effects of luminal exposure to various oxidants on intestinal thiol status in rats and provided evidence for the role of glutathione in the maintenance of sulphdryl groups of proteins in their reduced form in the gut. The results also suggested that oxidant exposure stimulates the uptake of glutathione (GSH) from the circulation to maintain mucosal levels.
The hyper-production of oxygen-centred free radicals is frequently observed during certain critical conditions and may have a detrimental effect on the clinical state of patients receiving intensive therapy. In one study , 40 such patients were treated with parenteral administration of reduced glutathione (70mg/Kg). Free radical production was measured by means of ethane levels in expired air and erythrocyte membrane examination.
Results were compared with those from a control group and lead to a conclusion that glutathione administration, in this case, lead to a decrease in free radical production. Glutathione was proposed as a supplement for patients receiving intensive therapy. Glutathione protection in the erythrocyte. Glutathione serves a protective role in the red blood cell in maintaining haemoglobin in its reduced (Fe2+) state. The role of erythrocytes in transport of oxygen around the circulatory system leads to the formation of considerable amounts of the superoxide anion. It is estimated that around 107 such ions are formed per day in the cell.
SUPEROXIDE ION FORMATION
Cl- Hb + O2 MetHb + O2- (Fe2+) (Fe3+) The removal of the superoxide ion is via the superoxide dismutase- catalysed reaction as described earlier. The reduction of glutathione by glutathione reductase requires NADPH as a co-factor. As red cells posses no mitochondria, this NADPH is generated via the first step in the pentose phosphate pathway. In 1926 a new anti-malarial drug, Palmiquine was introduced.
Severe side effects were observed in a few patients including black urine, jaundice and low haemoglobin levels. Around 30 years later, this was shown to be due to a deficiency in glucose-6-phosphate dehydrogenase, the enzyme which generated NADPH. The clinical symptoms were a consequence of a failure to reduce glutathione, therefore red blood cells were more susceptible to haemolysis and damage by toxic peroxides. This deficiency was found to be an X-linked disorder, its incidence probably highest in Sephardic Jews from Kurdistan at up to 53 percent.
Glucose-6-phosphate dehydrogenase deficiency is now described as a drug-induced haemolytic anaemia. Some drugs distort the surface of the erythrocyte and in the absence of glutathione, no protection is available. The anaemia observed is due to the removal and destruction of damaged red blood cells by the spleen. Glutathione and disease. Lowered levels of glutathione have been reported in the blood of subjects suffering from various diseases such as arthritis, diabetes and heart disease. These diminished levels could occur as a result of decreased synthesis, for example due to poor nutrition, cysteine deficiency or from impaired activity of the two biosynthetic enzymes. Alternatively, they could result from a failure to regenerate GSH from GSSG.
The association of glutathione levels with disease states has been highlighted in the case of HIV infection. GSH levels in plasma and peripheral mononuclear cells are generally lowered in HIV patients. Sulphydril groups, which glutathione serves to maintain in their reduced form, play a significant role in lymphocyte function and it has been proposed that decreased glutathione levels may contribute to disease progression.
This has received some attention as a possible therapeutic interest. Oxidative stress, brought about by the oxidant-producing activity of tumour necrosis factor and other cytokines, could deplete GSH levels by generating GSSG. There has been some speculation that suppression of GSH synthesis of regeneration by certain viruses is a strategy employed to increase chances of survival in the host.
1. Benand, O. and Balasubramanian, K. A. Biochemical Pharmacology. 45 (10): 2011-5, (1993).
2. Ortolani, O. et al. Bolletino- Societa Italiana Biologia Sperimentale. 68 (4): 239-44, (1992).