Glutathione metabolism, enzyme deficiency

Deficiencies of enzymes involved in glycolysis, the hexose monophosphate pathway, the closely related glutathione metabolism and synthesis, and nucleotide metabolism have emerged as causes of hereditary nonspherocytic hemolytic anemias (Table 1) (F10, Fll, M27). Some enzyme deficiencies, such as diphospho-glycerate mutase deficiency, lactate dehydrogenase deficiency, and NADH cy-... 

In 1956 selenium was identified (123) as an essential micronutrient in nutrition. In conjunction with vitamin E, selenium is effective in the prevention of muscular dystrophy in animals. Sodium selenite is administered to prevent exudative diathesis in chicks, a condition in which fluid leaks out of the tissues white muscle disease in sheep and infertility in ewes (see Feed additives). Selenium lessens the incidence of pneumonia in lambs and of premature, weak, and stillborn calves controls hepatosis dietetica in pigs and decreases muscular inflammation in horses. White muscle disease, widespread in sheep and catde of the selenium-deficient areas of New Zealand and the United States, is insignificant in high selenium soil areas. The supplementation of animal feeds with selenium was approved by the U.S. FDA in 1974 (see Feed additives). Much of selenium s metabolic activity results from its involvement in the selenoprotein enzyme, glutathione peroxidase. 

Diet. The constituents and amount of food (deficiency/starvation) may influence disposition and hence toxicity of chemicals. Food constituents may be enzyme inducers or inhibitors. Lack of food or specific constituents (e.g., protein or vitamins) may decrease metabolic capability, for example, a protein-deficient diet decreases cytochrome P-450 activity. Lack of sulfur amino acids decreases glutathione level. The effect on toxicity will depend on the role of metabolism. 

A number of these enzymes are expressed in other tissues as well but cause a notable deficiency predominantly in red blood cells because of the life span of the erythrocyte after the loss of protein synthesis. Once an enzyme is degraded or otherwise becomes nonfunctional, it cannot be replaced by new or other compensating proteins because of the lack of nucleus, mitochondria, ribosomes, and other cell organelles in mature red cells. Disorders have been described in the EMP, HMP, Rapoport-Luebering cycle, the glutathione pathway (Figure 21-9), purine-pyrimidine metabolism and methemoglobin reduction. 

Selenomethionine metabolism to selenide and the incorporation into selenium-specific proteins may occur by two pathways metabolism to methane selenol and selenide or via selenocysteine. Evidence that the incorporation of selenium from selenomethionine into protein is by the transsulfuration pathway (methionine to cysteine) comes from studies of selenomethionine metabolism in lymphoblast cell lines deficient in cystathionine lyase and cystathionine synthetase, enzymes of the transsulfuration pathway (Beilstein and Whanger 1992). Deficiency in these enzymes greatly reduces the incorporation of selenomethionine into glutathione peroxidase. 

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