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. 1972 Jul;51(7):1823–1832. doi: 10.1172/JCI106984

Mechanism of allopurinol-mediated increase in enzyme activity in man

Thomas D Beardmore 1, Jay S Cashman 1, William N Kelley 1
PMCID: PMC292330  PMID: 5032526

Abstract

Allopurinol therapy in man interferes with pyrimidine biosynthesis de novo by inhibition of one or both of the two enzymes, orotate phosphoribosyltransferase (OPRT) and orotidylic decarboxylase (ODC), responsible for the conversion of orotic acid to uridine-5′-monophosphate. Inhibition of this pathway in vivo is followed in 1-3 wk by an increase in the activity of both of these enzymes in erythrocytes and of ODC in circulating leukocytes. This drug-mediated increase in enzyme activity in erythrocytes could not be attributed to enzyme stabilization or induction in vivo but appeared to be due to enzyme “activation.” “Activation” of the OPRT enzyme was directly demonstrated in erythrocytes studied in vitro after incubation with oxipurinol, and to a lesser extent, with allopurinol. No evidence for “activation” of the ODC enzyme was demonstrated in vitro. This response to allopurinol therapy provides an excellent model for examining the mechanism of increased enzyme activity in response to drug administration.

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Selected References

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

  1. Appel S. H. Purification and kinetic properties of brain orotidine 5'-phosphate decarboxylase. J Biol Chem. 1968 Jul 25;243(14):3924–3929. [PubMed] [Google Scholar]
  2. Baehner R. L., Nathan D. G. Quantitative nitroblue tetrazolium test in chronic granulomatous disease. N Engl J Med. 1968 May 2;278(18):971–976. doi: 10.1056/NEJM196805022781801. [DOI] [PubMed] [Google Scholar]
  3. Baggiolini M., Bickel M. H. A new type of incubation apparatus for the determination of metabolically produced 14CO-2. Anal Biochem. 1966 Feb;14(2):290–295. doi: 10.1016/0003-2697(66)90139-4. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Chodirker W. B., Bock G. N., Vaughan J. H. Isolation of human PMN leukocytes and granules: observations on early blood diluion and on heparin. J Lab Clin Med. 1968 Jan;71(1):9–19. [PubMed] [Google Scholar]
  6. Comstock J. P., Udenfriend S. Effect of lactate on collagen proline hydroxylase activity in cultured L-929 fibroblasts. Proc Natl Acad Sci U S A. 1970 Jun;66(2):552–557. doi: 10.1073/pnas.66.2.552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. DANON D., MARIKOVSKY V. DETERMINATION OF DENSITY DISTRIBUTION OF RED CELL POPULATION. J Lab Clin Med. 1964 Oct;64:668–674. [PubMed] [Google Scholar]
  8. Elion G. B., Yü T. F., Gutman A. B., Hitchings G. H. Renal clearance of oxipurinol, the chief metabolite of allopurinol. Am J Med. 1968 Jul;45(1):69–77. doi: 10.1016/0002-9343(68)90008-9. [DOI] [PubMed] [Google Scholar]
  9. FEIGELSON P., DAVIDSON J. D., ROBINS R. K. Pyrazolopyrimidines as inhibitors and substrates of xanthine oxidase. J Biol Chem. 1957 Jun;226(2):993–1000. [PubMed] [Google Scholar]
  10. Fox R. M., O'Sullivan W. J., Firkin B. G. Orotic aciduria. Differing enzyme patterns. Am J Med. 1969 Aug;47(2):332–336. doi: 10.1016/0002-9343(69)90160-0. [DOI] [PubMed] [Google Scholar]
  11. Fox R. M., Royse-Smith D., O'Sullivan W. J. Orotidinuria induced by allopurinol. Science. 1970 May 15;168(3933):861–862. doi: 10.1126/science.168.3933.861. [DOI] [PubMed] [Google Scholar]
  12. Fox R. M., Wood M. H., O'Sullivan W. J. Studies on the coordinate activity and liability of orotidylate phosphoribosyltransferase and decarboxylase in human erythrocytes, and the effects of allopurinol administration. J Clin Invest. 1971 May;50(5):1050–1060. doi: 10.1172/JCI106576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Goldstein A., Goldstein D. B. XIX. Enzyme expansion theory of drug tolerance and physical dependence. Res Publ Assoc Res Nerv Ment Dis. 1968;46:265–267. [PubMed] [Google Scholar]
  14. HATFIELD D., WYNGAARDEN J. B. 3-RIBOSYLPURINES. I. SYNTHESIS OF (3-RIBOSYLURIC ACID) 5'-PHOSPHATE AND (3-RIBOSYLXANTHINE) 5'-PHOSPHATE BY A PYRIMIDINE RIBONUCLEOTIDE PYROPHOSPHORYLASE OF BEEF ERYTHROCYTES. J Biol Chem. 1964 Aug;239:2580–2586. [PubMed] [Google Scholar]
  15. KASBEKAR D. K., NAGABHUSHANAM A., GREENBERG D. M. PURIFICATION AND PROPERTIES OF OROTIC ACID-DECARBOXYLATING ENZYMES FROM CALF THYMUS. J Biol Chem. 1964 Dec;239:4245–4249. [PubMed] [Google Scholar]
  16. KASBEKAR D. K., NAGABHUSHANAM A., GREENBERG D. M. PURIFICATION AND PROPERTIES OF OROTIC ACID-DECARBOXYLATING ENZYMES FROM CALF THYMUS. J Biol Chem. 1964 Dec;239:4245–4249. [PubMed] [Google Scholar]
  17. Kelley W. N., Beardmore T. D. Allopurinol: alteration in pyrimidine metabolism in man. Science. 1970 Jul 24;169(3943):388–390. doi: 10.1126/science.169.3943.388. [DOI] [PubMed] [Google Scholar]
  18. Kelley W. N., Rosenbloom F. M., Henderson J. F., Seegmiller J. E. A specific enzyme defect in gout associated with overproduction of uric acid. Proc Natl Acad Sci U S A. 1967 Jun;57(6):1735–1739. doi: 10.1073/pnas.57.6.1735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Klinenberg J. R., Goldfinger S., Bradley K. H., Seegmiller J. E. An enzymatic spectrophotometric method for the determination of xanthine and hypoxanthine. Clin Chem. 1967 Oct;13(10):834–846. [PubMed] [Google Scholar]
  20. Krooth R. S. Molecular models for pharmacological tolerance and addiction. Ann N Y Acad Sci. 1971 Jul 6;179:548–560. doi: 10.1111/j.1749-6632.1971.tb46932.x. [DOI] [PubMed] [Google Scholar]
  21. LIDDLE L., SEEGMILLER J. E., LASTER L. The enzymatic spectrophotometric method for determination of uric acid. J Lab Clin Med. 1959 Dec;54:903–913. [PubMed] [Google Scholar]
  22. 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]
  23. Pinsky L., Krooth R. S. Studies on the control of pyrimidine biosynthesis in human diploid cell strains, I. Effect of 6-azauridine on cellular phenotype. Proc Natl Acad Sci U S A. 1967 Apr;57(4):925–932. doi: 10.1073/pnas.57.4.925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Pinsky L., Krooth R. S. Studies on the control of pyrimidine biosynthesis in human diploid cell strains. II. Effects of 5-azaorotic acid, barbituric acid, and pyrimidine precursors on cellular phenotype. Proc Natl Acad Sci U S A. 1967 May;57(5):1267–1274. doi: 10.1073/pnas.57.5.1267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. RABKIN M. T., FREDERICK E. W., LOTZ M., SMITH L. H., Jr Pyrimidine metabolism in man. V. The measurement in vivo of the biochemical effect of antineoplastic agents in animal and human subjects. J Clin Invest. 1962 Apr;41:871–883. doi: 10.1172/JCI104544. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rogers L. E., Warford L. R., Patterson R. B., Porter F. S. Hereditary orotic aciduria. I. A new case with family studies. Pediatrics. 1968 Sep;42(3):415–422. [PubMed] [Google Scholar]
  27. Rundles R. W., Metz E. N., Silberman H. R. Allopurinol in the treatment of gout. Ann Intern Med. 1966 Feb;64(2):229–258. doi: 10.7326/0003-4819-64-2-229. [DOI] [PubMed] [Google Scholar]
  28. Scott C. D. Analysis of urine for its ultraviolet-absorbing constituents by high-pressure anion-exchange chromatography. Clin Chem. 1968 Jun;14(6):521–528. [PubMed] [Google Scholar]
  29. Smith L. H., Sullivan M., Huguley C. M. PYRIMIDINE METABOLISM IN MAN. IV. THE ENZYMATIC DEFECT OF OROTIC ACIDURIA. J Clin Invest. 1961 Apr;40(4):656–664. doi: 10.1172/JCI104298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Tubergen D. G., Krooth R. S., Heyn R. M. Hereditary orotic aciduria with normal growth and development. Am J Dis Child. 1969 Dec;118(6):864–870. doi: 10.1001/archpedi.1969.02100040866009. [DOI] [PubMed] [Google Scholar]

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