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. 1967 Sep;46(9):1518–1529. doi: 10.1172/JCI105643

The Effects of Azathioprine (Imuran) on Purine Synthesis in Clinical Disorders of Purine Metabolism*

William N Kelley 1, Frederick M Rosenbloom 1, J Edwin Seegmiller 1,
PMCID: PMC292897  PMID: 16695929

Abstract

Azathioprine, a purine analogue, significantly suppressed the purine synthesis de novo of two gouty patients manifesting overproduction of uric acid, as well as three of four gouty patients who showed normal uric acid production. This suppression is taken as evidence that phosphoribosyl-pyrophosphate amidotransferase, the rate-controlling step in purine synthesis de novo, has a normal sensitivity to feedback inhibitors in the patients who responded to the drug.

Two children afflicted with the familial disorder of hyperuricemia, choreo-athetosis, and self-mutilation described by Lesch and Nyhan showed no reduction in the activity of the biosynthetic pathway in response to azathioprine. This inability to respond to azathioprine can be directly related to the absence in these patients of the enzyme hypoxanthine-guanine phosphoribosyltransferase which is required for conversion of the drug or its metabolites to the biochemically active ribonucleotide form.

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Selected References

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

  1. ATKINSON M. R., MORTON R. K., MURRAY A. W. INHIBITION OF INOSINE 5'-PHOSPHATE DEHYDROGENASE FROM EHRLICH ASCITES-TUMOUR CELLS BY 6-THIONINOSINE 5'-PHOSPHATE. Biochem J. 1963 Oct;89:167–172. doi: 10.1042/bj0890167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. ATKINSON M. R., MURRAY A. W. INHIBITION OF PRUINE PHOSPHORIBOSYLTRANSFERASES OF EHRLICH ASCITES-TUMOUR CELLS BY 6-MERCAPTOPURINE. Biochem J. 1965 Jan;94:64–70. doi: 10.1042/bj0940064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. BENEDICT J. D., FORSHAM P. H., STETTEN D., Jr The metabolism of uric acid in the normal and gouty human studied with the aid of isotopic uric acid. J Biol Chem. 1949 Nov;181(1):183–193. [PubMed] [Google Scholar]
  4. BENEDICT J. D., ROCHE M., YU T. F., BIEN E. J., GUTMAN A. B., STETTEN D., Jr Incorporation of glycine nitrogen into uric acid in normal and gouty man. Metabolism. 1952 Jan;1(1):3–12. [PubMed] [Google Scholar]
  5. BENNETT L. L., Jr, SIMPSON L., GOLDEN J., BARKER T. L. THE PRIMARY SITE OF INHIBITION BY 6-MERCAPTOPURINE ON THE PURINE BIOSYNTHETIC PATHWAY IN SOME TUMORS IN VIVO. Cancer Res. 1963 Oct;23:1574–1580. [PubMed] [Google Scholar]
  6. BRIDGER W. A., COHEN L. H. THE MECHANISM OF INHIBITION OF ADENYLOSUCCINATE LYASE BY 6-MERCAPTOPURINE NUCLEOTIDE (THIOINOSINATE). Biochim Biophys Acta. 1963 Jul 9;73:514–516. doi: 10.1016/0006-3002(63)90455-4. [DOI] [PubMed] [Google Scholar]
  7. Brockman R. W. Resistance to purine antagonists in experimental leukemia systems. Cancer Res. 1965 Oct;25(9):1596–1605. [PubMed] [Google Scholar]
  8. CASKEY C. T., ASHTON D. M., WYNGAARDEN J. B. THE ENZYMOLOGY OF FEEDBACK INHIBITION OF GLUTAMINE PHOSPHORIBOSYLPYROPHOSPHATE AMIDOTRANSFERASE BY PURINE RIBONUCLEOTIDES. J Biol Chem. 1964 Aug;239:2570–2579. [PubMed] [Google Scholar]
  9. Elion G. B., Hitchings G. H. Metabolic basis for the actions of analogs of purines and pyrimidines. Adv Chemother. 1965;2:91–177. doi: 10.1016/b978-1-4831-9930-6.50008-3. [DOI] [PubMed] [Google Scholar]
  10. GRAYZEL A. I., SEEGMILLER J. E., LOVE E. Suppression of uric acid synthesis in the gouty human by the use of 6-diazo-5-oxo-L-norleucine. J Clin Invest. 1960 Mar;39:447–454. doi: 10.1172/JCI104057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. GUTMAN A. B., YU T. F., BLACK H., YALOW R. S., BERSON S. A. Incorporation of glycine-1-C14, glycine-2-C14 and glycine-N15 into uric acid in normal and gouty subjects. Am J Med. 1958 Dec;25(6):917–932. doi: 10.1016/0002-9343(58)90063-9. [DOI] [PubMed] [Google Scholar]
  12. HAMILTON L., ELION G. B. The fate of 6-mercaptopurine in man. Ann N Y Acad Sci. 1954 Dec 6;60(2):304–314. doi: 10.1111/j.1749-6632.1954.tb40021.x. [DOI] [PubMed] [Google Scholar]
  13. HAMPTON A. REACTIONS OF RIBONUCLEOTIDE DERIVATIVES OF PURINE ANALOGUES AT THE CATALYTIC SITE OF INOSINE 5'-PHOSPHATE DEHYDROGENASE. J Biol Chem. 1963 Sep;238:3068–3074. [PubMed] [Google Scholar]
  14. HAMPTON A. Studies of the action of adenylosuccinase with 6-thio analogues of adenylosuccinic acid. J Biol Chem. 1962 Feb;237:529–535. [PubMed] [Google Scholar]
  15. HENDERSON J. F. Feedback inhibition of purine biosynthesis in ascites tumor cells. J Biol Chem. 1962 Aug;237:2631–2635. [PubMed] [Google Scholar]
  16. HOEFNAGEL D., ANDREW E. D., MIREAULT N. G., BERNDT W. O. HEREDITARY CHOREOATHETOSIS, SELF-MUTILATION AND HYPERURICEMIA IN YOUNG MALES. N Engl J Med. 1965 Jul 15;273:130–135. doi: 10.1056/NEJM196507152730303. [DOI] [PubMed] [Google Scholar]
  17. Henderson J. F. Effects of anticancer drugs on biochemical control mechanisms. Prog Exp Tumor Res. 1965;6:84–125. doi: 10.1159/000391371. [DOI] [PubMed] [Google Scholar]
  18. LESCH M., NYHAN W. L. A FAMILIAL DISORDER OF URIC ACID METABOLISM AND CENTRAL NERVOUS SYSTEM FUNCTION. Am J Med. 1964 Apr;36:561–570. doi: 10.1016/0002-9343(64)90104-4. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. MCCOLLISTER R. J., GILBERT W. R., Jr, ASHTON D. M., WYNGAARDEN J. B. PSEUDOFEEDBACK INHIBITION OF PURINE SYNTHESIS BY 6-MERCAPTOPURINE RIBONUCLEOTIDE AND OTHER PURINE ANALOGUES. J Biol Chem. 1964 May;239:1560–1563. [PubMed] [Google Scholar]
  21. MULLER A. F., BAUER W. Uric acid production in normal and gouty subjects, determined by N15 labeled glycine. Proc Soc Exp Biol Med. 1953 Jan;82(1):47–50. doi: 10.3181/00379727-82-20019. [DOI] [PubMed] [Google Scholar]
  22. NIERLICH D. P., MAGASANIK B. REGULATION OF PURINE RIBONUCLEOTIDE SYNTHESIS BY END PRODUCT INHIBITION. THE EFFECT OF ADENINE AND GUANINE RIBONUCLEOTIDES ON THE 5'-PHOSPHORIBOSYL-PYROPHOSPHATE AMIDOTRANSFERASE OF AEROBACTER AEROGENES. J Biol Chem. 1965 Jan;240:358–365. [PubMed] [Google Scholar]
  23. SALSER J. S., BALIS M. E. THE MECHANISM OF ACTION OF 6-MERCAPTOPURINE. I. BIOCHEMICAL EFFECTS. Cancer Res. 1965 May;25:539–543. [PubMed] [Google Scholar]
  24. SALSER J. S., HUTCHISON D. J., BALIS M. E. Studies on the mechanism of action of 6-mercaptopurine in cell-free preparations. J Biol Chem. 1960 Feb;235:429–432. [PubMed] [Google Scholar]
  25. SEEGMILLER J. E., GRAYZEL A. I., LASTER L., LIDDLE L. Uric acid production in gout. J Clin Invest. 1961 Jul;40:1304–1314. doi: 10.1172/JCI104360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. SKIPPER H. E. On the mechanism of action of 6-mercaptopurine. Ann N Y Acad Sci. 1954 Dec 6;60(2):315–321. doi: 10.1111/j.1749-6632.1954.tb40022.x. [DOI] [PubMed] [Google Scholar]
  27. Seegmiller J. E., Rosenbloom F. M., Kelley W. N. Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science. 1967 Mar 31;155(3770):1682–1684. doi: 10.1126/science.155.3770.1682. [DOI] [PubMed] [Google Scholar]
  28. Sorensen L. B., Benke P. J. Biochemical evidence for a distinct type of primary gout. Nature. 1967 Mar 18;213(5081):1122–1123. doi: 10.1038/2131122b0. [DOI] [PubMed] [Google Scholar]
  29. Sorensen L. B. Suppression of the shunt pathway in primary gout by azathioprine. Proc Natl Acad Sci U S A. 1966 Mar;55(3):571–575. doi: 10.1073/pnas.55.3.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. TAUSSKY H. H. A microcolorimetric determination of creatine in urine by the Jaffe reaction. J Biol Chem. 1954 Jun;208(2):853–861. [PubMed] [Google Scholar]
  31. Tomisek A. J., Hoskins A. P., Reid M. R. Chromatographic studies of purine metabolism. VI. Inhibition of inosine phosphorylase by 6-mercaptopurine. Cancer Res. 1965 Dec;25(11):1925–1932. [PubMed] [Google Scholar]
  32. ULTMANN J. E., FEIGELSON P. The effects of 8-azaguanine and 6-mercaptopurine on purine catabolism in the rat. Cancer Res. 1958 Dec;18(11):1319–1323. [PubMed] [Google Scholar]
  33. WYNGAARDEN J. B. Overproduction of uric acid as the cause of hyperuricemia in primary gout. J Clin Invest. 1957 Oct;36(10):1508–1515. doi: 10.1172/JCI103547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. WYNGAARDEN J. B., SILBERMAN H. R., SADLER J. H. Feedback mechanisms influencing purine ribotide synthesis. Ann N Y Acad Sci. 1958 Oct 13;75(1):45–60. doi: 10.1111/j.1749-6632.1958.tb36850.x. [DOI] [PubMed] [Google Scholar]

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