ANIMAL MODEL OF HUMAN DISEASE
Inlhcritcd Erx-throcx-t c;Glutathione DeficienlcAnimal Mfodel: Glutathione Deficiececx- and Partial Y -GIutamx-lcx-seine S-nthetase Deficienicv in Sheep
Contributed by: Joseph E. Smith. DVM. PhD. Department of Pathology. College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
Biologic Features
No overt clinical manifestations have been described for this disorder in sheep. Affected animals may- be more prone to anemia from ingesting kale (Brassica oleracea) than normal animals.' Despite lower glutathione (GSH) levels. affected animals are not sensitive to such "oxidant" drugs as primaquine or nitrofurantoin and have normal erythrocyte life-spans.2 Apparently- two types of glutathione deficiency exist. In some breeds (Corriedale and NMerino). the ervthrocytes have a decrease in the activity of GSH synthetic enzyme, 'y-glutamrylcysteine synthetase (GC sx-nthetase ), 2 and glutathione peroxidase 3 (see Table 1). In another breed (Finnish Landrace), the level of GC synthetase is not decreased, but erN-throcN-tes contain significantly more ornithine and lysine associated w-ith less Na- and K_ than normal and the life-span of red cells is shorter.5 Both types probably are genetically controlled.67 Affected animals can be detected by- determining erVthrocyte GSH levels by the DTN-B method.8 Animals with less than .3.25 gmoles GSH,/'g hemoglobin should be considered deficient. Urine pyroglutamic acid has not been determined. Comparison WM Human Diseases
The clinical manifestations of human glutathione deficiency are those of a congenital nonspherocytic hemolytic anemia. The deficiency is associated w-ith shortened ervthrocyte life-span and increased sensitivity to Publication sponsored hb the RevistrN of Comparatise Pathology of the Xrmed Forces Institute of Service Grant RR 00:301 from the Division of Research Resources. L S Department of Health. Education and Welfare. under the auspices of U nisersities Associated for Research and Education in Patholog\. Inc 233
Patholows and supported bx- Public Health
234
American Journal of Pathology
SMITH
oxidant" drugs.9 A decrease in either GC svnthetase 1' or GSH svnthetase activity 10 is concomitant with decreased erythrocvte GSH. A neurologic disorder also accompanies GC synthetase deficiencv.11 Some patients wvith GSH svnthetase deficiency suffer pyroglutamic aciduria and chronic metabolic acidosis. 12 Table 1-Glutathione Deficiency in Human and Ovine Erythrocytes
Ovine Human
GC synthetase GSH synthetase GSH peroxidase Na- and KBasic amino acid RBC life-span Primaquine sensitivity
GSH
=
Decreased Normal Normal Decreased -
Normal Decreased Normal Decreased Yes
Corriedale Decreased Normal Decreased Normal Normal Normal No
Finn
Normal Normal Normal Decreased Increased Decreased No
glutathione, GC = glutamylcysteine, RBC = red blood cells.
Usefulness of This Model
Despite the absence of any apparent disease or an increased sensitivity to drugs in sheep, they should be useful for determining the importance of glutathione in erythrocy-te metabolism. Studv of glutathione deficiency in sheep erythrocytes should provide: a) a better understanding of how the glutathione-synthesizing enzymes are regulated, b) how they interact -ith other cellular constituents, c) the physiologic function of ery;throcyte GSH, and d) more knowledge of genetic controls of glutathionemetabolizing systems. A better understanding of ervthrocvte glutathione deficiency in sheep could lead to therapy for patients with glutathione deficiency and perhaps for those with other hemolytic disorders involving lo- or unstable glutathione. Availability
Sheep w-ith glutathione-deficient erythrocytes are not commercially available. Animals may be found in flocks (particularly in Corriedale, NIerino, and Finnish Landrace breeds) by determining blood glutathione levels. Alternately, the procurement of a limited supply of the Corriedale-
NMerino type can be arranged through the author.
Vol. 82, No. 1 January 1976
GLUTATHIONE DEFICIENCY
235
References 1. Tucker E, Kilgour L The effect of anernia on sheep with inherited differences in red cell reduced glutathione (GSH) concentrations. Res Vet Sci 14:306-311, 1973 2. Smith JE, Lee MS, Mia AS: DecreasedY-glutamylcysteine synthetase: The probable cause of glutathione deficiency in sheep erythrocvtes. J Lab Clin Med 82:713-718, 1973 3. Agar NS, Smith JE: Erythrocyte enzymes and glycolytic intermediates of high- and low-glutathione sheep. Anim Blood Groups Biochem Genet 4:133-140, 1973 4. Ellorv JC, Tucker EM, Deverson EV: The identification of ornithine and lvsine at high concentrations in the red cells of sheep with an inherited deficiency of glutathione. Biochem Biophys Acta 279:481-483, 1972 5. Tucker E: A shortened life span of sheep red cells with a glutathione deficiency. Res XVet Sci 16:19-22, 1974 6. Tucker EM, Kilgour L An inherited glutathione deficiency and a concomitant reduction in potassium concentration in sheep red cells. Experientia 26:203-204, 1970 Tucker E, Kilgour L: A glutathione deficiency in the red cells of certain Merino sheep. J Agri Sci Camb 79:515-516, 1972 8. Beutler E, Duron 0, Kelly BM: Improved method for the determination of blood glutathione. J Lab Clin Med 61:882-888, 1963 9. Pins H, Loos J, Zurcher C: Glutathione deficiency. Hereditary Disorders of Ervthrocvte Metabolism, Edited by E Beutler. New York, Grune & Stratton, 1968, pp 165-184 10. Konrad PN, Richards F II, \Valentine WN, Paglia DE: -) -Glutamyl-cysteine synthetase deficiency. A cause of hereditary hemolytic anemia. N Engl J Med 286:57-561, 1972 11. Minnich V, Smith MB, Brauner MJ, Majerus PW: Glutathione biosynthesis in human erythrocytes. I. Identification of the enzvmes of glutathione synthesis in hemolvsates. J Clin Invest 50:507-513, 1971 12. Wellner V, Sekura R, Meister A, Larsson A: Glutathione synthetase deficiencv, an inborn error of metabolism involving the Y -glutamyl cycle in patients with 5oxoprolinuria (pyroglutamic aciduria). Proc Natl Acad Sci USA 71:2505-2509, 1974
236
American Journal of Pathology
SMITH
[End of Article]
Inlhcritcd Erx-throcx-t c;Glutathione DeficienlcAnimal Mfodel: Glutathione Deficiececx- and Partial Y -GIutamx-lcx-seine S-nthetase Deficienicv in Sheep
Contributed by: Joseph E. Smith. DVM. PhD. Department of Pathology. College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
Biologic Features
No overt clinical manifestations have been described for this disorder in sheep. Affected animals may- be more prone to anemia from ingesting kale (Brassica oleracea) than normal animals.' Despite lower glutathione (GSH) levels. affected animals are not sensitive to such "oxidant" drugs as primaquine or nitrofurantoin and have normal erythrocyte life-spans.2 Apparently- two types of glutathione deficiency exist. In some breeds (Corriedale and NMerino). the ervthrocytes have a decrease in the activity of GSH synthetic enzyme, 'y-glutamrylcysteine synthetase (GC sx-nthetase ), 2 and glutathione peroxidase 3 (see Table 1). In another breed (Finnish Landrace), the level of GC synthetase is not decreased, but erN-throcN-tes contain significantly more ornithine and lysine associated w-ith less Na- and K_ than normal and the life-span of red cells is shorter.5 Both types probably are genetically controlled.67 Affected animals can be detected by- determining erVthrocyte GSH levels by the DTN-B method.8 Animals with less than .3.25 gmoles GSH,/'g hemoglobin should be considered deficient. Urine pyroglutamic acid has not been determined. Comparison WM Human Diseases
The clinical manifestations of human glutathione deficiency are those of a congenital nonspherocytic hemolytic anemia. The deficiency is associated w-ith shortened ervthrocyte life-span and increased sensitivity to Publication sponsored hb the RevistrN of Comparatise Pathology of the Xrmed Forces Institute of Service Grant RR 00:301 from the Division of Research Resources. L S Department of Health. Education and Welfare. under the auspices of U nisersities Associated for Research and Education in Patholog\. Inc 233
Patholows and supported bx- Public Health
234
American Journal of Pathology
SMITH
oxidant" drugs.9 A decrease in either GC svnthetase 1' or GSH svnthetase activity 10 is concomitant with decreased erythrocvte GSH. A neurologic disorder also accompanies GC synthetase deficiencv.11 Some patients wvith GSH svnthetase deficiency suffer pyroglutamic aciduria and chronic metabolic acidosis. 12 Table 1-Glutathione Deficiency in Human and Ovine Erythrocytes
Ovine Human
GC synthetase GSH synthetase GSH peroxidase Na- and KBasic amino acid RBC life-span Primaquine sensitivity
GSH
=
Decreased Normal Normal Decreased -
Normal Decreased Normal Decreased Yes
Corriedale Decreased Normal Decreased Normal Normal Normal No
Finn
Normal Normal Normal Decreased Increased Decreased No
glutathione, GC = glutamylcysteine, RBC = red blood cells.
Usefulness of This Model
Despite the absence of any apparent disease or an increased sensitivity to drugs in sheep, they should be useful for determining the importance of glutathione in erythrocy-te metabolism. Studv of glutathione deficiency in sheep erythrocytes should provide: a) a better understanding of how the glutathione-synthesizing enzymes are regulated, b) how they interact -ith other cellular constituents, c) the physiologic function of ery;throcyte GSH, and d) more knowledge of genetic controls of glutathionemetabolizing systems. A better understanding of ervthrocvte glutathione deficiency in sheep could lead to therapy for patients with glutathione deficiency and perhaps for those with other hemolytic disorders involving lo- or unstable glutathione. Availability
Sheep w-ith glutathione-deficient erythrocytes are not commercially available. Animals may be found in flocks (particularly in Corriedale, NIerino, and Finnish Landrace breeds) by determining blood glutathione levels. Alternately, the procurement of a limited supply of the Corriedale-
NMerino type can be arranged through the author.
Vol. 82, No. 1 January 1976
GLUTATHIONE DEFICIENCY
235
References 1. Tucker E, Kilgour L The effect of anernia on sheep with inherited differences in red cell reduced glutathione (GSH) concentrations. Res Vet Sci 14:306-311, 1973 2. Smith JE, Lee MS, Mia AS: DecreasedY-glutamylcysteine synthetase: The probable cause of glutathione deficiency in sheep erythrocvtes. J Lab Clin Med 82:713-718, 1973 3. Agar NS, Smith JE: Erythrocyte enzymes and glycolytic intermediates of high- and low-glutathione sheep. Anim Blood Groups Biochem Genet 4:133-140, 1973 4. Ellorv JC, Tucker EM, Deverson EV: The identification of ornithine and lvsine at high concentrations in the red cells of sheep with an inherited deficiency of glutathione. Biochem Biophys Acta 279:481-483, 1972 5. Tucker E: A shortened life span of sheep red cells with a glutathione deficiency. Res XVet Sci 16:19-22, 1974 6. Tucker EM, Kilgour L An inherited glutathione deficiency and a concomitant reduction in potassium concentration in sheep red cells. Experientia 26:203-204, 1970 Tucker E, Kilgour L: A glutathione deficiency in the red cells of certain Merino sheep. J Agri Sci Camb 79:515-516, 1972 8. Beutler E, Duron 0, Kelly BM: Improved method for the determination of blood glutathione. J Lab Clin Med 61:882-888, 1963 9. Pins H, Loos J, Zurcher C: Glutathione deficiency. Hereditary Disorders of Ervthrocvte Metabolism, Edited by E Beutler. New York, Grune & Stratton, 1968, pp 165-184 10. Konrad PN, Richards F II, \Valentine WN, Paglia DE: -) -Glutamyl-cysteine synthetase deficiency. A cause of hereditary hemolytic anemia. N Engl J Med 286:57-561, 1972 11. Minnich V, Smith MB, Brauner MJ, Majerus PW: Glutathione biosynthesis in human erythrocytes. I. Identification of the enzvmes of glutathione synthesis in hemolvsates. J Clin Invest 50:507-513, 1971 12. Wellner V, Sekura R, Meister A, Larsson A: Glutathione synthetase deficiencv, an inborn error of metabolism involving the Y -glutamyl cycle in patients with 5oxoprolinuria (pyroglutamic aciduria). Proc Natl Acad Sci USA 71:2505-2509, 1974
236
American Journal of Pathology
SMITH
[End of Article]
