Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1970 Nov;49(11):2051–2067. doi: 10.1172/JCI106424

Nucleoside deaminase: an enzymatic marker for stress erythropoiesis in the mouse

Ivan K Rothman 1,2,3, Esmail D Zanjani 1,2,3, Albert S Gordon 1,2,3, Robert Silber 1,2,3
PMCID: PMC535782  PMID: 5475986

Abstract

The level of nucleoside deaminase was determined in extracts of mouse tissues obtained during a period of accelerated erythropoiesis induced by hypoxia, hemorrhage, or the injection of phenylhydrazine. Under these conditions a striking (10- to 100-fold) elevation of the enzyme activity occurred in the spleen. Similar results were obtained with the injection of purified erythropoietin. In control animals, only a trace of nucleoside deaminase activity was detected in the blood. During the reticulocyte response which followed erythropoietic stimulation, there was a sharp increase in the blood level of nucleoside deaminase, which rose up to 120 times that of control animals. By differential centrifugation, the enzyme was localized to the reticulocyte-rich fraction. Erythrocyte nucleoside deaminase remained elevated even after the reticulocyte count had fallen to normal in the phenylhydrazine-treated mice or to zero after the cessation of hypoxia. There was a very gradual decline in the enzyme activity in the blood which fell to the barely detectable control levels about 45 days after the initial reticulocyte response, a time period which corresponds to the survival of the mouse red blood cell. The persistence of high levels of nucleoside deaminase for the full life span of a generation of erythrocytes formed during stress, viewed in contrast to the virtual absence of the enzyme from normal erythrocytes of all ages, represents an enzymatic difference between the normal red blood cell and the cell produced under conditions of accelerated erythropoiesis.

Full text

PDF
2051

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ALLISON A. C., BURN G. P. Enzyme activity as a function of age in the human erythrocyte. Br J Haematol. 1955 Jul;1(3):291–303. doi: 10.1111/j.1365-2141.1955.tb05511.x. [DOI] [PubMed] [Google Scholar]
  2. AMBS E. [On large and hemoglobin-rich reticulocytes in crises in anemias]. Schweiz Med Wochenschr. 1960 Apr 9;90:413–419. [PubMed] [Google Scholar]
  3. AUERBACH V. H., WAISMAN H. A. Tryptophan peroxidase-oxidase, histidase, and transaminase activity in the liver of the developing rat. J Biol Chem. 1959 Feb;234(2):304–306. [PubMed] [Google Scholar]
  4. BERLIN N. I., LOTZ C. Life span of the red blood cell of the rat following acute hemorrhage. Proc Soc Exp Biol Med. 1951 Dec;78(3):788–790. doi: 10.3181/00379727-78-19220. [DOI] [PubMed] [Google Scholar]
  5. BERNSTEIN R. E. Alterations in metabolic energetics and cation transport during aging of red cells. J Clin Invest. 1959 Sep;38:1572–1586. doi: 10.1172/JCI103936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. BERTINO J. R., SILBER R., FREEMAN M., ALENTY A., ALBRECHT M., GABRIO B. W., HUENNEKENS F. M. STUDIES ON NORMAL AND LEUKEMIC LEUKOCYTES. IV. TETRAHYDROFOLATE-DEPENDENT ENZYME SYSTEMS AND DIHYDROFOLIC REDUCTASE. J Clin Invest. 1963 Dec;42:1899–1907. doi: 10.1172/JCI104875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. BORSOOK H. DNA, RNA AND PROTEIN SYNTHESIS AFTER ACUTE, SEVERE BLOOD LOSS: A PICTURE OF ERYTHROPOIESIS AT THE COMBINED MORPHOLOGICAL AND MOLECULAR LEVELS. Ann N Y Acad Sci. 1964 Oct 7;119:523–539. doi: 10.1111/j.1749-6632.1965.tb54053.x. [DOI] [PubMed] [Google Scholar]
  8. BORSOOK H., LINGREL J. B., SCARO J. L., MILLETTE R. L. Synthesis of haemoglobin in relation to the maturation of erythroid cells. Nature. 1962 Oct 27;196:347–350. doi: 10.1038/196347a0. [DOI] [PubMed] [Google Scholar]
  9. BRECHER G., STOHLMAN F., Jr Reticulocyte size and erythropoietic stimulation. Proc Soc Exp Biol Med. 1961 Aug-Sep;107:887–891. doi: 10.3181/00379727-107-26785. [DOI] [PubMed] [Google Scholar]
  10. BREWER G. J., POWELL R. D. HEXOKINASE ACTIVITY AS A FUNCTION OF AGE OF THE HUMAN ERYTHROCYTE. Nature. 1963 Aug 17;199:704–705. doi: 10.1038/199704a0. [DOI] [PubMed] [Google Scholar]
  11. Brittin G. M., Haley J. E., Brecher G. Increase in red cell size following splenectomy in rats with chronic hemolytic anemia. Proc Soc Exp Biol Med. 1966 Mar;121(3):709–713. doi: 10.3181/00379727-121-30867. [DOI] [PubMed] [Google Scholar]
  12. Brok F., Ramot B., Zwang E., Danon D. Enzyme activities in human red blood cells of different age groups. Isr J Med Sci. 1966 May-Jun;2(3):291–296. [PubMed] [Google Scholar]
  13. Burka E. R. Characteristics of RNA degradation in the erythroid cell. J Clin Invest. 1969 Jul;48(7):1266–1272. doi: 10.1172/JCI106092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Burka E. R. RNase activity in erythroid cell lysates. J Clin Invest. 1969 Sep;48(9):1724–1732. doi: 10.1172/JCI106138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. CARDINI C. E., PALADINI A. C., CAPUTTO R., LELOIR L. F. Liver uridine phosphorylase. Acta Physiol Lat Am. 1950;1(1):57–63. [PubMed] [Google Scholar]
  16. CLINE M. J., BERLIN N. I. Red blood cell life span using DFP as a cohort label. Blood. 1962 Jun;19:715–723. [PubMed] [Google Scholar]
  17. CREASEY W. A. Studies on the metabolism of 5-iodo-2'-deoxycytidine in vitro. Purification of nucleoside deaminase from mouse kidney. J Biol Chem. 1963 May;238:1772–1776. [PubMed] [Google Scholar]
  18. Camiener G. W., Smith C. G. Studies of the enzymatic deamination of cytosine arabinoside. I. Enzyme distribution and species specificity. Biochem Pharmacol. 1965 Oct;14(10):1405–1416. doi: 10.1016/0006-2952(65)90175-9. [DOI] [PubMed] [Google Scholar]
  19. Cantor L. N., Zanjani E. D., Wong K. K., Gordon A. S. The renal erythropoietic factor (REF). IX. Its subcellular distribution. Proc Soc Exp Biol Med. 1969 Mar;130(3):950–952. doi: 10.3181/00379727-130-33695. [DOI] [PubMed] [Google Scholar]
  20. Card R. T., McGrath M. J., Paulson E. J., Valberg L. S. Life-span and autohemolysis of macrocytic erythrocytes produced in response to hemorrhage. Am J Physiol. 1969 Apr;216(4):974–978. doi: 10.1152/ajplegacy.1969.216.4.974. [DOI] [PubMed] [Google Scholar]
  21. Card R. T., Valberg L. S. Characteristics of shortened survival of stress erythrocytes in the rabbit. Am J Physiol. 1967 Sep;213(3):566–572. doi: 10.1152/ajplegacy.1967.213.3.566. [DOI] [PubMed] [Google Scholar]
  22. Coopersmith A., Ingram M. Red cell volumes and erythropoiesis. II. Age: density: volume relationships of macrocytes. Am J Physiol. 1969 Mar;216(3):473–482. doi: 10.1152/ajplegacy.1969.216.3.473. [DOI] [PubMed] [Google Scholar]
  23. DE VERDIER C. H., POTTER V. R. Alternative pathways of thymine and uracil metabolism in the liver and hepatoma. J Natl Cancer Inst. 1960 Jan;24:13–29. doi: 10.1093/jnci/24.1.13. [DOI] [PubMed] [Google Scholar]
  24. FILMANOWICZ E., GURNEY C. W. Studies on erythropoiesis. XVI. Response to a single dose of erythropoietin in polycythemic mouse. J Lab Clin Med. 1961 Jan;57:65–72. [PubMed] [Google Scholar]
  25. FRIEDKIN M., ROBERTS D. The enzymatic synthesis of nucleosides. II. Thymidine and related pyrimidine nucleosides. J Biol Chem. 1954 Mar;207(1):257–266. [PubMed] [Google Scholar]
  26. FRYERS G. R., BERLIN N. I. Mean red cell life of rats exposed to reduced barometric pressure. Am J Physiol. 1952 Nov;171(2):465–470. doi: 10.1152/ajplegacy.1952.171.2.465. [DOI] [PubMed] [Google Scholar]
  27. Friend C., Patuleia M. C., De Harven E. Erythrocytic maturation in vitro of murine (Friend) virus-induced leukemic cells. Natl Cancer Inst Monogr. 1966 Sep;22:505–522. [PubMed] [Google Scholar]
  28. GIBSON K. D., NEUBERGER A., SCOTT J. J. The purification and properties of delta-aminolaevulic acid dehydrase. Biochem J. 1955 Dec;61(4):618–629. doi: 10.1042/bj0610618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. GOODMAN J. W., SMITH L. H. Erythrocyte life span in normal mice and in radiation bone marrow chimeras. Am J Physiol. 1961 Apr;200:764–770. doi: 10.1152/ajplegacy.1961.200.4.764. [DOI] [PubMed] [Google Scholar]
  30. GORDON A. S. Hemopoietine. Physiol Rev. 1959 Jan;39(1):1–40. doi: 10.1152/physrev.1959.39.1.1. [DOI] [PubMed] [Google Scholar]
  31. GRASSO J. A., WOODARD J. W., SWIFT H. Cytochemical studies of nucleic acids and proteins in erythrocytic development. Proc Natl Acad Sci U S A. 1963 Jul;50:134–140. doi: 10.1073/pnas.50.1.134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ganzoni A., Hillman R. S., Finch C. A. Maturation of the macroreticulocyte. Br J Haematol. 1969 Jan-Feb;16(1):119–135. doi: 10.1111/j.1365-2141.1969.tb00384.x. [DOI] [PubMed] [Google Scholar]
  33. Greengard O. Enzymic differentiation in mammalian liver injection of fetal rats with hormones causes the premature formation of liver enzymes. Science. 1969 Feb 28;163(3870):891–895. doi: 10.1126/science.163.3870.891. [DOI] [PubMed] [Google Scholar]
  34. Hanna I. R., Tarbutt R. G., Lamerton L. F. Shortening of the cell-cycle time of erythroid precursors in response to anaemia. Br J Haematol. 1969 Apr;16(4):381–387. doi: 10.1111/j.1365-2141.1969.tb00415.x. [DOI] [PubMed] [Google Scholar]
  35. Hillman R. S. Characteristics of marrow production and reticulocyte maturation in normal man in response to anemia. J Clin Invest. 1969 Mar;48(3):443–453. doi: 10.1172/JCI106001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hillman R. S., Giblett E. R. Red cell membrane alteration associated with "marrow stress". J Clin Invest. 1965 Oct;44(10):1730–1736. doi: 10.1172/JCI105280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. ITO K., SCHMAUS J. W., REISSMANN K. R. PROTEIN METABOLISM AND ERYTHROPOIESIS. 3. THE ERYTHROID MARROW IN PROTEIN-STARVED RATS AND ITS RESPONSE TO ERYTHROPOIETIN. Acta Haematol. 1964 Nov;32:257–264. doi: 10.1159/000209570. [DOI] [PubMed] [Google Scholar]
  38. KILLMANN S. A. ON THE SIZE OF NORMAL HUMAN RETICULOCYTES. Acta Med Scand. 1964 Nov;176:529–533. doi: 10.1111/j.0954-6820.1964.tb00654.x. [DOI] [PubMed] [Google Scholar]
  39. LEVY L. M., WALTER H., SASS M. D. Enzymes and radioactivity in erythorcytes of different ages. Nature. 1959 Aug 22;184(Suppl 9):643–644. doi: 10.1038/184643a0. [DOI] [PubMed] [Google Scholar]
  40. LOBUE J., DORNFEST B. S., GORDON A. S., HURST J., QUASTLER H. Marrow distribution in rat femurs determined by cell enumeration and Fe59 labeling. Proc Soc Exp Biol Med. 1963 Apr;112:1058–1062. doi: 10.3181/00379727-112-28250. [DOI] [PubMed] [Google Scholar]
  41. LOTZ M., SMITH L. H., Jr The effect of reticulocytosis in the rabbit on the activities of enzymes in pyrimidine biosynthesis. Blood. 1962 May;19:593–600. [PubMed] [Google Scholar]
  42. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  43. MARKS P. A., JOHNSON A. B., HIRSCHBERG E., BANKS J. Studies on the mechanism of aging of human red blood cells. Ann N Y Acad Sci. 1958 Oct 13;75(1):95–105. doi: 10.1111/j.1749-6632.1958.tb36853.x. [DOI] [PubMed] [Google Scholar]
  44. MARKS P. A. Red cell glucose-6-phosphate and 6-phosphogluconic dehydrogenases and nucleoside phosphorylase. Science. 1958 Jun 6;127(3310):1338–1339. doi: 10.1126/science.127.3310.1338. [DOI] [PubMed] [Google Scholar]
  45. METCALF D., FURTH J., BUFFETT R. F. Pathogenesis of mouse leukemia caused by Friend virus. Cancer Res. 1959 Jan;19(1):52–58. [PubMed] [Google Scholar]
  46. MILLETTE R. L., GLOWACKI E. R. IN VIVO MATURATION OF IMMATURE RETICULOCYTES TRANSFUSED INTO A NORMAL RABBIT. Nature. 1964 Dec 19;204:1207–1209. doi: 10.1038/2041207b0. [DOI] [PubMed] [Google Scholar]
  47. MIRAND E. A., PRENTICE T., HOFFMAN J. G., GRACE J. T., Jr Effect of Friend virus in Swiss and DBA/1 mice on Fe59 uptake. Proc Soc Exp Biol Med. 1961 Feb;106:423–426. doi: 10.3181/00379727-106-26358. [DOI] [PubMed] [Google Scholar]
  48. Mirand E. A. Erythropoietic response of animals infected with various strains of Friend virus. Natl Cancer Inst Monogr. 1966 Sep;22:483–503. [PubMed] [Google Scholar]
  49. NEUBERGER A., NIVEN J. S. F. Haemoglobin formation in rabbits. J Physiol. 1951 Feb;112(3-4):292–310. doi: 10.1113/jphysiol.1951.sp004530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Orlic D., Gordon A. S., Rhodin J. A. An ultrastructural study of erythropoietin-induced red cell formation in mouse spleen. J Ultrastruct Res. 1965 Dec;13(5):516–542. doi: 10.1016/s0022-5320(65)90012-2. [DOI] [PubMed] [Google Scholar]
  51. Orlic D., Gordon A. S., Rhodin J. A. Ultrastructural and autoradiographic studies of erythropoietin-induced red cell production. Ann N Y Acad Sci. 1968 Mar 29;149(1):198–216. doi: 10.1111/j.1749-6632.1968.tb15153.x. [DOI] [PubMed] [Google Scholar]
  52. PRENTICE T. C., MIRAND E. A. Effect of hypoxia on plasma erythropoietin in the rabbit. Proc Soc Exp Biol Med. 1961 Mar;106:501–502. doi: 10.3181/00379727-106-26383. [DOI] [PubMed] [Google Scholar]
  53. Pfrogner N. Adenosine deaminase from calf spleen. I. Purificiation. Arch Biochem Biophys. 1967 Mar;119(1):141–146. doi: 10.1016/0003-9861(67)90439-0. [DOI] [PubMed] [Google Scholar]
  54. Piomelli S., Corash L. M., Davenport D. D., Miraglia J., Amorosi E. L. In vivo lability of glucose-6-phosphate dehydrogenase in GdA- and GdMediterranean deficiency. J Clin Invest. 1968 Apr;47(4):940–948. doi: 10.1172/JCI105786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. RUBINSTEIN D., OTTOLENGHI P., DENSTEDT O. F. The metabolism of the erythrocyte. XIII. Enzyme activity in the reticulocyte. Can J Biochem Physiol. 1956 Mar;34(2):222–235. [PubMed] [Google Scholar]
  56. SASS M. D., LEVY L. M., WALTER H. CHARACTERISTICS OF ERYTHROCYTES OF DIFFERENT AGES. II. ENZYME ACTIVITY AND OSMOTIC FRAGILITY. Can J Biochem Physiol. 1963 Nov;41:2287–2296. [PubMed] [Google Scholar]
  57. SENO S., MIYAHARA M., ASAKURA H., OCHI O., MATSUOKA K., TOYAMA T. MACROCYTOSIS RESULTING FROM EARLY DENUCLEATION OF ERYTHROID PRECURSORS. Blood. 1964 Nov;24:582–593. [PubMed] [Google Scholar]
  58. SIEGLER R., RICH M. A. COMPARATIVE PATHOGENESIS OF MURINE VIRAL LYMPHOMA. Cancer Res. 1964 Sep;24:1406–1417. [PubMed] [Google Scholar]
  59. SILBER R., COX R. P., HADDAD J. R., FRIEND C. ENZYME STUDIES IN VIRUS-INDUCED NEOPLASMS. I. THE EFFECT OF A MURINE LEUKEMIA ON ENZYMES OF ONE-CARBON METABOLISM AND ON PHOSPHOMONOESTERASES. Cancer Res. 1964 Dec;24:1892–1897. [PubMed] [Google Scholar]
  60. SMITH L. H., TOHA J. Survival of mouse-grown rat erythrocytes. Proc Soc Exp Biol Med. 1958 May;98(1):125–128. doi: 10.3181/00379727-98-23961. [DOI] [PubMed] [Google Scholar]
  61. STOHLMAN F., Jr Erythropoiesis. N Engl J Med. 1962 Aug 16;267:342–348. doi: 10.1056/NEJM196208162670707. [DOI] [PubMed] [Google Scholar]
  62. STOHLMAN F., Jr Humoral regulation of erythropoiesis. VI. Mechanism of action of erythropoietine in the irradiated animal. Proc Soc Exp Biol Med. 1961 Aug-Sep;107:751–754. doi: 10.3181/00379727-107-26744. [DOI] [PubMed] [Google Scholar]
  63. STOHLMAN F., Jr Humoral regulation of erythropoiesis. VII. Shortened survival of erythrocytes produced by erythropoietine or severe anemia. Proc Soc Exp Biol Med. 1961 Aug-Sep;107:884–887. doi: 10.3181/00379727-107-26784. [DOI] [PubMed] [Google Scholar]
  64. STOHLMAN F., Jr, LUCARELLI G., HOWARD D., MORSE B., LEVENTHAL B. REGULATION OF ERYTHROPOIESIS. XVI. CYTOKINETIC PATTERNS IN DISORDERS OF ERYTHROPOIESIS. Medicine (Baltimore) 1964 Nov;43:651–660. doi: 10.1097/00005792-196411000-00007. [DOI] [PubMed] [Google Scholar]
  65. Sassa S., Takaku F., Nakao K. Regulation of erythropoiesis in the Friend leukemia mouse. Blood. 1968 Jun;31(6):758–765. [PubMed] [Google Scholar]
  66. Schröter W., Beckmann H., Grundherr G., Neth R. Biochemische und cytochemische Charakterisierung von Reticulocyten und Pseudoreticulocyten. Klin Wochenschr. 1967 Mar 15;45(6):312–313. doi: 10.1007/BF01747103. [DOI] [PubMed] [Google Scholar]
  67. Scribner V. A., Siegel C. D., Gordon A. S., LoBue J. Hematopoiesis in the newborn mouse. Biol Neonat. 1968;12(1):93–101. doi: 10.1159/000240094. [DOI] [PubMed] [Google Scholar]
  68. Shadduck R., Howard D., Stohlman F., Jr A difference in erythropoietin production between anemic and hypoxic mice. Proc Soc Exp Biol Med. 1968 May;128(1):132–136. doi: 10.3181/00379727-128-32961. [DOI] [PubMed] [Google Scholar]
  69. Silber R. Regulatory mechanisms in the human leukocyte. I. The feedback control of deoxycytidylate deaminase. Blood. 1967 Jun;29(6):896–905. [PubMed] [Google Scholar]
  70. Stryckmans P. A., Cronkite E. P., Giacomelli G., Schiffer L. M., Schnappauf H. The maturation and fate of reticulocytes after in vitro labeling with tritiated amino acids. Blood. 1968 Jan;31(1):33–43. [PubMed] [Google Scholar]
  71. Tarbutt R. G. Cell population kinetics of the erythroid system in the rat. The response to protracted anaemia and to continuous gamma-irradiation. Br J Haematol. 1969 Jan-Feb;16(1):9–24. doi: 10.1111/j.1365-2141.1969.tb00374.x. [DOI] [PubMed] [Google Scholar]
  72. ULTMANN J. E., GORDON C. S. LIFE SPAN AND SITES OF SEQUESTRATION OF NORMAL ERYTHROCYTES IN NORMAL AND SPLENECTOMIZED MICE AND RATS. Acta Haematol. 1965 Feb;33:118–126. doi: 10.1159/000209520. [DOI] [PubMed] [Google Scholar]
  73. VAN PUTTEN L. M. The life span of red cells in the rat and the mouse as determined by labeling with DFP32 in vivo. Blood. 1958 Aug;13(8):789–794. [PubMed] [Google Scholar]
  74. Van Gastel C., Bishop C. Changes in activities of some enzymes during in vivo aging of mouse erythrocytes. Proc Soc Exp Biol Med. 1968 Apr;127(4):1067–1071. doi: 10.3181/00379727-127-32872. [DOI] [PubMed] [Google Scholar]
  75. Walter H., Selby F. W. Counter-current distribution of red blood cells of slightly different ages. Biochim Biophys Acta. 1966 Jan 4;112(1):146–153. doi: 10.1016/s0926-6585(96)90016-3. [DOI] [PubMed] [Google Scholar]
  76. Wilmanns W., Sauer H., Gelinsky P. Beziehungen zwischen enzymatischer Formiataktivierung und Erythrozytenlebensdauer. Blut. 1969 Nov;19(8):457–469. doi: 10.1007/BF01631055. [DOI] [PubMed] [Google Scholar]
  77. Wisdom G. B., Orsi B. A. The purification and properties of cytidine aminohydrolase from sheep liver. Eur J Biochem. 1969 Jan;7(2):223–230. doi: 10.1111/j.1432-1033.1969.tb19595.x. [DOI] [PubMed] [Google Scholar]
  78. ZIMMERMAN M., SEIDENBERG J. DEOXYRIBOSYL TRANSFER. I. THYMIDINE PHOSPHORYLASE AND NUCLEOSIDE DEOXYRIBOSYLTRANSFERASE IN NORMAL AND MALIGNANT TISSUES. J Biol Chem. 1964 Aug;239:2618–2621. [PubMed] [Google Scholar]
  79. Zícha B., Buric L. Deoxycytidine and radiation response: exceedingly high deoxycytidine aminohydrolase activity in human liver. Science. 1969 Jan 10;163(3863):191–192. doi: 10.1126/science.163.3863.191. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES